DRUGDEX DRUG EVALUATIONS

AMPICILLIN/SULBACTAM

0.0 OVERVIEW A. Ampicillin/sulbactam is an antibiotic combination composed of ampicillin, a beta-lactam antibiotic, and sulbactam, a beta-lactamase inhibitor. The addition of sulbactam extends the antimicrobial spectrum of ampicillin; sulbactam itself has minimal antibacterial activity. B. DOSING INFORMATION: The usual adult dose of ampicillin/sulbactam is 1 to 2 g ampicillin/500 mg to 1 g sulbactam administered intravenously every 6 hours. C. PHARMACOKINETICS: Peak serum levels of ampicillin (120 mcg/mL) and sulbactam (60 mcg/mL) are achieved after intravenous doses of 2 g ampicillin/1 g sulbactam. Ampicillin and sulbactam are only moderately protein bound; 17 to 28% and 38%, respectively. Ampicillin and sulbactam penetrate well into body tissues and fluids; penetration into cerebrospinal fluid is minimal unless meninges are inflamed. The half-lives of ampicillin and sulbactam are similar; 1 to 1.8 hours and 1 to 1.3 hours, respectively. D. CAUTIONS: Adverse reactions to ampicillin/sulbactam appear to be similar to those seen with ampicillin alone, the most common of which are diarrhea and maculopapular rash. E. CLINICAL APPLICATIONS: Ampicillin/sulbactam is useful in the treatment of patients with suspected or documented infections due to betalactamase-producing organisms; however, data is not available to determine whether this agent will replace any of the currently available antibiotics for the initial treatment of any infection. 1.0 DOSING INFORMATION 1.1 DOSAGE FORMS A. Information on specific products and dosage forms can be obtained by referring to the Product Index. 1.3 ADULT DOSAGE 1.3.1 NORMAL DOSE A. PARENTERAL 1. The manufacturer recommends a dose of 1.5 grams (1 gram of ampicillin and 0.5 gram of sulbactam) or 3 grams (2 grams of ampicillin and 1 gram of sulbactam) every 6 hours. The total daily dose of sulbactam should not exceed 4 grams daily. Ampicillin/sulbactam can be given intravenously or intramuscularly (Prod Info Unasyn(R), 1995). 2. Because therapeutic success rates were found to be similar regardless of whether 1.5-gram (g) or 3-gram doses were used, at least one hospital has adopted new ampicillin/sulbactam guidelines based on patient age, weight, and creatinine clearance (Akinwande et al, 1998). A regimen of 1.5 g

ampicillin/sulbactam every 6 hours is used for patients with normal renal function weighing less than 80 kilograms (kg) and under the age of 65. For those in that weight range over the age of 65, 1.5 gram is given every 8 hours. A regimen of 3 grams every 6 or 8 hours is recommended for patients with normal renal function weighing more than 80 kg, the time between dosing intervals determined by patient age, as for the 1.5-gram dose. Intervals for either dose are adjusted to 12 hours for patients with creatinine clearance rates of 15 to 29 mL/min/1.73m(2) and to 24 hours for patients with clearance rates of 5 to 14 mL/min/1.73m(2). 3. If injection site pain occurs with intramuscular administration of ampicillin/sulbactam, the dose may be dissolved in 0.5% lidocaine (CampoliRichards & Brogden, 1987). B. INTRAVENOUS RATE OF ADMINISTRATION 1. The manufacturer recommends administering ampicillin/sulbactam over 10 to 15 minutes when administering by direct intravenous injection, and administering it over 15 to 30 minutes when diluted with 50 or 100 milliliters of a compatible intravenous solution (Prod Info Unasyn(R), 1995). 2. Intravenous ampicillin/sulbactam may be administered by bolus injection over 3 minutes or by intravenous infusion over 15 to 30 minutes (CampoliRichards & Brogden, 1987). C. GONOCOCCAL INFECTIONS 1. Sulbactam or ampicillin/sulbactam administered alone do not appear effective in the treatment of uncomplicated gonorrhea (Caine et al, 1984; Kim et al, 1986; Odugbemi, 1987). However, single doses of 1 gram probenecid orally plus 1 gram ampicillin/0.5 gram sulbactam or 2 grams ampicillin/1 gram sulbactam have been effective in the treatment of infections due to penicillinase-producing N gonorrhea (Kim et al, 1986; Ngeow et al, 1991). D. RESPIRATORY TRACT INFECTIONS 1. Sulbactam pivoxyl 750 milligrams plus bacampicillin 800 milligrams orally twice daily for 10 days has been effective in acute exacerbations of chronic bronchitis due to H influenzae, S pneumonia, and B catarrhalis (Davies et al, 1982). E. SOFT TISSUE INFECTIONS 1. Clinical trials have utilized dosages of 2 grams ampicillin/1 gram sulbactam intravenously every 6 hours in the treatment of soft tissue and BONE AND JOINT INFECTIONS (Stromberg et al, 1986). Alternatively, sulbactam 1 gram three times daily plus ampicillin 2 grams three times daily for 8 to 16 days has also been effective in the initial treatment of serious soft tissue and bone and joint infections (Loffler et al, 1986). F. SURGICAL PROPHYLAXIS 1. The recommended dose of ampicillin/sulbactam for prophylaxis of surgical infections is 1.5 grams to 3 grams before induction of anesthesia. This dose may be repeated every 6 hours for up to 24 hours. Dosage is

based on total ampicillin content plus total sulbactam content of the combination (Campoli-Richards & Brogden, 1987). 2. Ampicillin/sulbactam has been used effectively as prophylaxis in patients undergoing COLORECTAL SURGERY. Dosages of 500 milligrams ampicillin/500 milligrams sulbactam were given intravenously, starting during induction of anesthesia and followed by 6 subsequent doses at 8hour intervals (Kager et al, 1982). 3. In another trial evaluating the efficacy of ampicillin/sulbactam as chemoprophylaxis in colorectal surgery, 4 doses of 1 gram ampicillin/1 gram sulbactam were administered beginning at induction of anesthesia, with subsequent doses administered at 6-hour intervals (de la Hunt et al, 1986). 4. Ampicillin 1 gram/sulbactam 0.5 gram administered intramuscularly 30 to 90 minutes before GENITOURINARY SURGERY and then intravenously every 8 hours thereafter for a further 3 doses has been effective in preventing infection in patients undergoing TRANSURETHRAL SURGERY (Dorflinger & Madsen, 1985). G. URINARY TRACT INFECTIONS 1. A single intravenous dose of 1 gram sulbactam sodium plus 2 grams ampicillin administered over 15 minutes has been used to treated bacterial CYSTITIS in women (Bailey & Peddie, 1985). These authors found that single-dose therapy using ampicillin/sulbactam was not sufficiently effective in the treatment of uncomplicated urinary tract infections. 1.3.2 DOSAGE IN RENAL FAILURE A. Urinary excretion of ampicillin and sulbactam is decreased in patients with renal dysfunction. However, the ratio of ampicillin to sulbactam is similar in patients with good renal function or in patients with poor renal function. In patients with severely impaired renal function, dosage of ampicillin/sulbactam should be decreased (Campoli-Richards & Brogden, 1987; Prod Info Unasyn(R), 1995). B. The manufacturer recommends the following ampicillin/sulbactam dose modifications for patients with renal impairment (gt = greater than) (Prod Info Unasyn(R), 1995):
Creatinine Recommended Clearance Unasyn(R) (mL/min/ Dosage 1.73 m(2)) --------------------------gt or = 30 1.5-3 g Q6-8H 15-29 1.5-3 g Q12H 5-14 1.5-3 g Q24H

1.3.3 DOSAGE IN HEPATIC INSUFFICIENCY A. Ampicillin/sulbactam has been administered safely in doses of 3 grams to 9 grams/day intramuscularly or intravenously to patients with chronic liver disease. Adverse effects observed were minor (oral candidiasis and local

injection-site pain) and infrequent; blood chemistry tests were unchanged following therapy (Gallante et al, 1987). 1.4 PEDIATRIC DOSAGE 1.4.1 NORMAL DOSE A. PARENTERAL 1. The recommended dose of ampicillin/sulbactam in INFANTS AND NEONATES is 150 milligrams/kilogram/day intravenously or intramuscularly divided every 6 to 8 hours. (This dose is based on the total ampicillin content plus the total sulbactam content of the combination.) In severely ill patients (eg, meningitis), additional ampicillin may be given. In PRETERM INFANTS and during the first week of life, the dosing interval is usually every 12 hours (same total daily dose) (Campoli-Richards & Brogden, 1987). B. BONE AND JOINT INFECTIONS 1. Successful treatment of OSTEOMYELITIS and/or SEPTIC ARTHRITIS was reported in 9 children (Arnoff et al, 1986). Dosages administered were sulbactam 12.5 milligrams/kilogram/dose plus ampicillin 50 milligrams/kilogram/dose given parenterally at 6-hour intervals. Parenteral therapy was continued for a minimum of 5 days or until defervescence and clinical improvement were observed. Subsequent therapy with oral sultamicillin was administered at a maximum dosage of 25 milligrams/kilogram/dose given every 6 hours for a minimum total duration of 21 days for septic arthritis and 30 days for osteomyelitis. C. CERVICAL ADENITIS 1. Sulbactam 50 milligrams/kilogram/day plus 100 or 150 milligrams ampicillin per kilogram/day administered by intravenous infusion (over 2 to 3 minutes) every 6 hours for 4 to 11 days has been effective in the treatment of urinary tract infections, cervical adenitis, and lobar pneumonia in children (aged 2 months to 11 years) (Syriopoulou et al, 1986). D. EPIGLOTTITIS 1. Parenteral sulbactam sodium (30 milligrams/kilogram/day) plus ampicillin (200 milligrams/kilogram/day) appear to be effective in the treatment of acute epiglottits (Wald et al, 1986). E. MENINGITIS 1. Meningitis was treated successfully in patients 1 month to 14 years with dosages of sulbactam 50 milligrams/kilogram/day plus ampicillin 400 milligrams/kilogram/day (Rodriguez et al, 1986). Ampicillin/sulbactam was administered in equally divided doses over 30 to 60 minutes every 4 or 6 hours. F. PNEUMONIA 1. Sulbactam 50 milligrams/kilogram/day plus 100 or 150 milligrams ampicillin per kilogram/day administered by intravenous infusion (over 2 to 3 minutes) every 6 hours for 4 to 11 days has been effective in the treatment

of urinary tract infections, cervical adenitis, and lobar pneumonia in children (aged 2 months to 11 years) (Syriopoulou et al, 1986). G. URINARY TRACT INFECTIONS 1. Sulbactam 50 milligrams/kilogram/day plus 100 or 150 milligrams ampicillin per kilogram/day administered by intravenous infusion (over 2 to 3 minutes) every 6 hours for 4 to 11 days has been effective in the treatment of urinary tract infections, cervical adenitis, and lobar pneumonia in children (aged 2 months to 11 years) (Syriopoulou et al, 1986). 1.4.2 DOSAGE IN RENAL FAILURE A. Urinary excretion of sulbactam is decreased in patients with renal dysfunction. In patients with severely impaired renal function, dosage of ampicillin/sulbactam should be decreased (Campoli-Richards & Brogden, 1987). 2.0 PHARMACOKINETICS 2.2 DRUG CONCENTRATION LEVELS 2.2.1 THERAPEUTIC A. The pharmacokinetics of ampicillin are not affected by co-administration of sulbactam. Fifteen-minute infusions of a combination of 2 g ampicillin and 1 g sulbactam to healthy volunteers have been reported to result in peak serum concentrations of 120 mcg ampicillin/mL and 60 mcg sulbactam/mL. After infusion of 1 g ampicillin and 0.5 g sulbactam, peak concentrations of 50 mcg ampicillin/mL and 30 mcg sulbactam/mL were observed (Foulds et al, 1985; Foulds, 1986). B. Three assay methods for quantifying sulbactam were compared in the presence of ampicillin: synergistic bioassay, gas chromatography detection by mass spectrometry, and high-performance liquid chromatography (Foulds et al, 1986). All three methods were similar in accuracy and precision. 2.3 ADME 2.3.1 ABSORPTION A. BIOAVAILABILITY 1. INTRAMUSCULAR: 92% ampicillin; 100% sulbactam (Foulds, 1986). 2.3.2 DISTRIBUTION 2.3.2.1 DISTRIBUTION SITES A. TOTAL PROTEIN BINDING: ampicillin 17% to 28%, sulbactam 38% (Kucers & Bennett, 1979; Foulds, 1986; Prod Info Unasyn(R), 1995) B. OTHER DISTRIBUTION SITES: 1. BILE: ampicillin 471 mcg/mL; sulbactam 19.4 mcg/mL (Morris et al, 1986) a. Mean peak biliary concentrations of ampicillin (471 mcg/mL) and sulbactam (19.4 mcg/mL) occur 0.5 to 1 hour after a single intravenous dose of ampicillin 1 g/sulbactam 0.5 g in patients with normal liver function undergoing biliary tract surgery (Morris et al, 1986). 2. BRONCHIAL SECRETIONS: ampicillin 6%; sulbactam 8% (Wildfeuer et al, 1994)

 a. Bronchial fluid, bronchial tissue, and simultaneous serum concentrations of ampicillin/sulbactam were determined in 15 patients undergoing lung biopsy. All patients received a dose of ampicillin 2 grams and sulbactam 1 gram; samples were taken 30 minutes after ampicillin/sulbactam administration. Bronchial tissue samples were 40% and 70% of simultaneous serum samples for ampicillin and sulbactam, respectively. Bronchial fluid concentrations were 6% and 8% of simultaneous serum concentrations for ampicillin and sulbactam, respectively (Wildfeuer et al, 1994). 3. CARTILAGE: ampicillin 8% to 25%; sulbactam 18% to 42% (Meier et al, 1994) a. The concentration of ampicillin/sulbactam in cartilage was studied in 21 children undergoing thorax surgery (Meier et al, 1994). Forty-five minutes after the administration of ampicillin/sulbactam, cartilage concentration of ampicillin ranged from 8% to 25% of corresponding serum concentrations and sulbactam concentrations ranged from 18% to 42% of simultaneous serum concentrations. 4. CEREBROSPINAL FLUID: 30% (Foulds et al, 1987). a. SUMMARY: Sulbactam and ampicillin do not generally penetrate well into cerebrospinal fluid; however, appreciable concentrations may be obtained in patients with inflamed meninges (Prod Info Unasyn(R), 1995; Foulds et al, 1987; Stahl et al, 1986). b. The combination of intravenous sulbactam 50 mg/kg/day and intravenous ampicillin 400 mg/kg/day (in 4 to 6 divided doses) produced cerebrospinal fluid levels of approximately 1/3 those achieved in serum in infants and children with meningitis. Cerebrospinal fluid was obtained by lumbar puncture within 1 hour after doses of sulbactam and ampicillin; Cerebrospinal fluid levels of 5.5 and 16 mcg/mL of sulbactam and ampicillin, respectively, and were achieved approximately 48 hours after initiation of therapy. However, several days later, serum levels had declined to 1.9 and 5.2 mcg/mL, respectively; 6 to 11 days after the first sample, cerebrospinal fluid levels were 0.89 and 3.6 mcg/mL, respectively. These data suggest that sulbactam and ampicillin readily penetrate the cerebrospinal fluid in patients with bacterial meningitis but that concentrations in cerebrospinal fluid decline during the course of treatment (Foulds et al, 1987). 5. PERITONEAL FLUID: ampicillin 92%; sulbactam 96% (Wise et al, 1983). a. Sulbactam and ampicillin readily penetrate into peritoneal fluid. In one series of 25 patients undergoing elective intra-abdominal surgery, preoperative doses of 1 or 2 g ampicillin intravenously plus 1 g sulbactam intravenously yielded mean peritoneal fluid concentrations of ampicillin and sulbactam which were 92% and 96% of serum levels, respectively (Wise et al, 1983).

 b. In women undergoing elective laparoscopy, single intravenous injections of 0.5 g ampicillin and 0.5 g sulbactam produced mean peak peritoneal fluid concentrations of 7.1 and 14.5 mcg/mL, respectively (Houang et al, 1985). 2.3.2.2 DISTRIBUTION KINETICS A. VOLUME OF DISTRIBUTION (Vd): 360 mL/kg (Foulds, 1986) 1. A Vd of 340 mL/kg for sulbactam in pediatric patients (aged 2 to 14 years) is reported (Schaad et al, 1986). The Vd of sulbactam was significantly increased (700 mL/kg) in children with cystic fibrosis. 2.3.4 EXCRETION 2.3.4.1 BREAST MILK A. BREASTFEEDING: SAFE B. After maternal doses of 0.5 to 1 g sulbactam plus 1 to 2 g ampicillin, peak breast milk concentrations of less than 3 mcg/mL were observed for each drug (Foulds et al, 1983a; Foulds et al, 1985a). It is estimated that a nursing infant would receive 1% to 2% of the usual adult dose of ampicillin/sulbactam (Foulds, 1986). 2.3.4.2 KIDNEY A. RENAL EXCRETION: 75% to 85% of ampicillin and sulbactam (Prod Info Unasyn(R), 1995) 1. Sulbactam is eliminated primarily via urinary excretion, and appears to be secreted by the renal tubules (Foulds, 1986; Brown et al, 1982; Rogers et al, 1983; Caine et al, 1984). Approximately 75% of an administered dose of sulbactam is recovered in the urine as unchanged drug (Foulds et al, 1983). 2.3.4.3 OTHER A. OTHER EXCRETION: 1. BILE: 2.8% of ampicillin; 1% of sulbactam (Morris et al, 1986) 2.3.5 HALF-LIFE 2.3.5.1 PARENT COMPOUND A. ELIMINATION HALF-LIFE (T1/2-beta): ampicillin 1 to 1.8 hours; sulbactam 1 to 1.3 hours (Foulds, 1986; Emmerson et al, 1983; Prod Info Unasyn(R), 1995). 1. A number of studies indicate that the half-life for ampicillin in the newborn infant is longer than that for adults and ranges from 2 to 4 hours (Yoshioka et al, 1974; Colburn et al, 1976; Kaplan et al, 1974). In the premature infant, the half-life may be as long as 6 hours (Kaplan et al, 1974). Increased mean elimination half-lives of sulbactam and ampicillin were reported in 16 newborns; 7.9 hours and 9.4 hours, respectively (Sutton et al, 1986). 2. The elimination of ampicillin and sulbactam are similarly prolonged in patients with renal dysfunction. The ratio of ampicillin to sulbactam is similar in patients with normal renal function and those with impaired renal function (Prod Info Unasyn(R), 1995). 3.0 CAUTIONS 3.1 CONTRAINDICATIONS

 A. Hypersensitivity to penicillins 3.2 PRECAUTIONS A. Hypersensitivity to cephalosporins B. Patients with mononucleosis 3.3 ADVERSE REACTIONS 3.3.1 BLOOD A. HEMATOLOGIC EFFECTS 1. Epistaxis and mucosal bleeding have been reported in less than 1% of patients on ampicillin/sulbactam. Hematologic laboratory test abnormalities include decreases in hemoglobin, hematocrit, white blood cells, and platelets; increases in lymphocytes, monocytes, basophils, eosinophils, and platelets have been reported to the manufacturer (Prod Info Unasyn(R), 1995). 3.3.2 CARDIOVASCULAR A. THROMBOPHLEBITIS 1. The manufacturer reports pain after intravenous injection in 3% of patients, and thrombophlebitis in 3% of patients (Prod Info Unasyn(R), 1995). 2. After intravenous injections of sulbactam, several authors have reported mild to moderate pain or discomfort at the area of administration. This pain was noted to last 5 to 30 minutes (Caine et al, 1984; Bailey & Peddie, 1985). 3.3.3 CENTRAL NERVOUS SYSTEM A. CENTRAL NERVOUS SYSTEM EFFECTS 1. Central nervous system reactions occur only rarely in patients receiving ampicillin/sulbactam. Adverse effect reported in less than 1% of patients include headache, malaise, and fatigue (Prod Info Unasyn(R), 1995). 2. Seizures have not yet been reported with ampicillin/sulbactam therapy; however, ampicillin alone has been associated with seizure activity. Two cases of SEIZURES were associated with high ampicillin serum concentrations in a report (Hodgman et al, 1984). Seizures occurred in a 29year-old obese woman following three days of ampicillin therapy (1 g intravenously every 6 hours) in combination with clindamycin and amikacin. The second patient, a 64-year-old woman, developed seizures following five days of ampicillin therapy (500 mg intravenously initially, followed by maintenance doses based upon serum levels). In both patients, serum levels exceeded 140 mcg/mL; however, cerebrospinal fluid levels were not obtained. It is unclear from the data presented if ampicillin was definitely the cause of seizures in these patients. 3.3.4 ENDOCRINE/METABOLIC A. ENDOCRINE EFFECTS 1. Animal studies have demonstrated that sulbactam administration results in sequestration of protein-bound glycogen in hepatocytes. However, in a prospective randomized trial including 26 diabetic patients, no significant

alterations in glucose availability following ampicillin/sulbactam administration were found (Chiodini et al, 1985). 3.3.5 GASTROINTESTINAL A. GASTROINTESTINAL EFFECTS 1. SUMMARY: The most frequently reported adverse reaction to ampicillin/sulbactam therapy is DIARRHEA. This adverse effect occurs in approximately 3% of patients. Other gastrointestinal effects, occurring in less than 1% of patients, are nausea, vomiting, flatulence, and abdominal distention (Prod Info Unasyn(R), 1995). Clinical trials using ampicillin/sulbactam have reported NAUSEA and DIARRHEA (Davies et al, 1982; Dorflinger & Madsen, 1985; Bailey & Peddie, 1985). Use of ampicillin alone has resulted in pseudomembranous colitis (Bartlett, 1981; George, 1980) and hemorrhagic colitis (Gould et al, 1982). 2. Moderate to severe diarrhea was reported in 2 of 20 patients receiving ampicillin/sulbactam for chronic bronchitis (Davies et al, 1982). 3. The average duration of ampicillin-associated diarrhea is reported to be 9 days, with resolution of symptoms in an average of 8 days. Uncomplicated cases will usually resolve upon termination of ampicillin therapy (Gurwith et al, 1977). B. PSEUDOMEMBRANOUS COLITIS 1. Pseudomembranous colitis, also known as ANTIBIOTIC ASSOCIATED COLITIS, has occurred with almost every antibiotic including ampicillin/sulbactam. Treatment of the colitis depends on the severity of the condition. For mild cases the ampicillin/sulbactam should be discontinued; for more severe cases ampicillin/sulbactam should be discontinued and the patient should be given oral antibiotics such as metronidazole or vancomycin and fluid replacement (Prod Info Unasyn(R), 1995). 2. Ampicillin-associated pseudomembranous colitis (PMC) generally occurs within the first 10 days of antibiotic therapy, with symptoms of chills, fever, vomiting, loose watery stools (that may contain blood and/or mucus), bowelmovement frequency of greater than 10 times per day, abdominal extension, and intermittent or persistent abdominal cramping (Read & Cove-Smith, 1977; Hakkal, 1976; Christie & Ament, 1975; Rothschild et al, 1977; Berkowitz et al, 1976; Prince & Neu, 1979). Occasionally symptoms will occur 2 to 3 weeks after antibiotic therapy has been discontinued; these patients usually present with more acute and severe symptoms than those patients developing PMC during the course of antibiotic therapy (Christie & Ament, 1975; Stanley et al, 1974; Prince et al, 1979). The disease can progress further to produce toxic megacolon, peritonitis, or sepsis (Prince et al, 1979; Auritt et al, 1978). The cause of pseudomembranous colitis has been related to an endotoxin elaborated by various strains of clostridia bacteria, which are often resistant to ampicillin. C difficile is the most common pathogen and the toxin, activates adenyl cyclase, producing a

hyper-secretory response in the colon (Prince et al, 1979; Larson et al, 1978; Bartlett et al, 1978; George et al, 1978). 3. In a study of 329 patients, ampicillin and clindamycin were the most frequent causative agents in clostridium difficile-induced diarrhea or colitis (Bartlett, 1981). 4. For More Information: See Drug Consult reference: "ANTIBIOTIC-ASSOCIATED PSEUDOMEMBRANOUS COLITIS" 3.3.6 KIDNEY/GENITOURINARY A. GENITOURINARY EFFECTS 1. The manufacturer reports that urinary retention and dysuria is reported in less than 1% of patients receiving ampicillin/sulbactam. Increases in blood urea nitrogen and serum creatinine have also been reported (Prod Info Unasyn(R), 1995). Interstitial nephritis has been reported with ampicillin therapy (Gilbert et al, 1970). 3.3.10 SKIN A. RASH 1. SUMMARY: Skin rash has been reported in clinical trials of ampicillin/sulbactam (Dorflinger & Madsen, 1985; Bailey & Peddie, 1985; Davies et al, 1982), and is commonly reported with ampicillin alone (BCDSP, 1972; Kagan, 1977). Rash is reported in less than 2% of patients receiving ampicillin/sulbactam (Prod Info Unasyn(R), 1995). 2. Skin rashes due to ampicillin are common (7% to 10%), but are 2 to 3 times more frequent in patients with hyperuricemia or concurrent allopurinol therapy (Anon, 1972) and extremely common (50% to 100%) in patients with mononucleosis (Patel, 1967; Pullen et al, 1967; Levene & Baker, 1968; Sanders, 1969; Speck, 1971; Nazareth et al, 1972; Gregg, 1973; Kerr et al, 1980) and lymphatic leukemia (Cameron, 1971). These frequent rashes are suspected to be non-allergic in nature (Anon, 1972). 3. Ampicillin-induced rash usually occurs within 1 to 28 days (mean 7 to 10 days) after initiating therapy, although on some occasions it can occur even following discontinuation of the drug. Discontinuation of the drug results in resolution within 2 weeks, with or without other supportive types of treatment. Patients who develop the rash during episodes of mononucleosis may not necessarily have recurrence of the rash upon subsequent reexposure to the drug (Nazareth et al, 1972). The rash is generally not considered to be a sign of definitive penicillin hypersensitivity, although some ampicillin rashes may have some allergic components (Bronsert, 1971; Kerns et al, 1973; Anon, 1972; Potter, 1972; Bierman et al, 1972). Interestingly, the occurrence of JARISCH-HERXHEIMER REACTION was reported in 2 patients treated with ampicillin with undiagnosed syphilis; maculopapular rash developed within 24 hours (Harris et al, 1972). B. PAIN ON INJECTION

 1. After intravenous injection of sulbactam, several authors have reported mild-to-moderate pain or discomfort at the area of administration. This pain was noted to last 5 to 30 minutes (Caine et al, 1984; Bailey & Peddie, 1985). 2. If injection site pain occurs with IM administration of ampicillin/sulbactam, the dose may be dissolved in 0.5% to 2% lidocaine (Campoli-Richards & Brogden, 1987; Prod Info Unasyn(R), 1995). C. PEMPHIGUS VULGARIS 1. Ampicillin therapy was associated with a case of pemphigus vulgaris in a 52-year-old female following 3 to 4 days of intravenous administration. Erythema, followed by formation of flaccid bullae, occurred on the hands and lower extremities. Intraepidermal bullae and positive intercellular IgG verified the diagnosis. Ampicillin was discontinued and the lesions improved with topical steroids only (Fellner & Mark, 1980). D. TOXIC EPIDERMAL NECROLYSIS 1. A case of ampicillin-induced toxic epidermal necrolysis was reported in a patient whose skin tests with the causative drug demonstrated a strong delayed hypersensitivity reaction (Tagami et al, 1983). 3.3.12 OTHER A. OVERDOSE See POISINDEX(R) Management "PENICILLIN" B. ANAPHYLAXIS 1. Hypersensitivity reactions involving facial swelling, erythema, rash, chest pain, and tightness in the throat have been reported with ampicillin/sulbactam therapy. Ampicillin/sulbactam is contraindicated in patients with a history of hypersensitivity reaction to any penicillin (Prod Info Unasyn(R), 1995). 2. A case of anaphylaxis after opening a bottle of ampicillin has been reported (Bajoghli, 1975). Upon admission to the hospital, the patient was apprehensive, dyspneic, and had a total body urticarial rash and a blood pressure of 80/60. The patient responded to therapy with intravenous fluids and epinephrine, and was noted to have an allergic history to penicillin. C. CROSS-SENSITIVITY 1. A case of pruritic eruption on the palms and soles of a 45-year-old female receiving 250 mg ampicillin four times daily for 12 days has been reported (Stewart & Webster, 1970). The rash developed 2 days after discontinuing the drug and progressed to involve the proximal extremities and trunk. Treatment with prednisone resulted in clearing of the problem within one week. It was noted that several years previously the patient developed an acute urticarial skin reaction following penicillin G therapy. See Drug Consult reference: "CEPHALOSPORIN-PENICILLIN CROSSSENSITIVITY" D. OTOTOXICITY 1. Two studies indicate that administration of high-dose (125 to 350 mg/kg/day) ampicillin, with or without chloramphenicol, in the treatment of H influenzae meningitis for a duration of 10 to 25 days has been associated

with HEARING LOSS in one or both ears. Hearing loss was characterized as a slight sensori-neural loss, and in one study it was confirmed by audiometry (Svenungsson et al, 1976; Jones & Hanson, 1977). E. SUPERINFECTION 1. Candidiasis was noted in 3 of 44 patients receiving ampicillin/sulbactam for chemoprophylaxis in colorectal surgery (de la Hunt et al, 1986). 3.4 TERATOGENICITY/EFFECTS IN PREGNANCY A. TERATOGENICITY 1. U.S. Food and Drug Administration's Pregnancy Category B (Prod Info Unasyn(R), 1997). See Drug Consult reference: "PREGNANCY RISK CATEGORIES" 2. Ampicillin crosses the placenta rapidly; serum levels of ampicillin can be detected in the fetus within 30 minutes. Amniotic fluid levels are detectable within 90 minutes, and reach 20% of maternal serum level by 8 hours (Philipson, 1977; Noschel et al, 1982). Ampicillin does not appear to exert a toxic effect on fetal development (Friedman et al, 1980) and there have been no reports of congenital defects caused by ampicillin alone (Briggs et al, 1986; Heinonen et al, 1977). 3.5 DRUG INTERACTIONS 3.5.1 DRUG-DRUG COMBINATIONS A. ACETYLCYSTEINE 1. Severity: not specified 2. Onset: not specified 3. Documentation: poor 4. Literature Reports: a. A significant increase in MIC was observed in an in vitro study of the combined use of acetylcysteine and ampicillin, penicillin G, cloxacillin, methicillin, oxacillin, quinacillin, cephaloridine, or tetracycline (Lawson & Saggers, 1965). However, the results of one in vivo study on the use of combination therapy in respiratory tract infections found no inactivation of the antibiotic when aerosolized acetylcysteine was used with ampicillin, cephaloridine, cloxacillin, erythromycin, fusidic acid, gentamicin, lincomycin, methicillin, novobiocin, sulfadiazine, sulfamethazine, or tetracycline (Saggers & Lawson, 1968). Clinical reports of such an interaction are lacking, suggesting that it is unlikely to be of clinical importance. B. ALLOPURINOL 1. Summary: Concurrent use of allopurinol and ampicillin has been associated with an increase in the frequency of rash due to ampicillin (Anon, 1972; Jick & Porter, 1981). The cause of this increase is not known. It is not necessary to avoid this combination, but clinicians should be aware of the increased incidence of rash. 2. Adverse Effect: a higher probability of ampicillin rash 3. Clinical Management: Patients should be cautioned about the increased incidence of rash associated with this combination.

4. Severity: minor 5. Onset: delayed 6. Documentation: fair 7. Probable Mechanism: unknown C. AMINOGLYCOSIDES 1. Summary: Concomitant penicillin and aminoglycoside therapy has been reported to result in inactivation of the aminoglycoside both in vivo and in vitro. Amikacin appears to possess the greatest stability in the presence of penicillins; the half-life of amikacin is minimally affected by the presence of carbenicillin. It appears that, in the treatment of severely ill patients requiring both penicillin and aminoglycoside therapy, amikacin is the aminoglycoside of choice (Farchione, 1981; Jorgensen & Crawford, 1982). 2. Adverse Effect: loss of aminoglycoside efficacy 3. Clinical Management: Monitor patients for aminoglycoside effectiveness. 4. Severity: minor 5. Onset: rapid 6. Documentation: fair 7. Probable Mechanism: chemical inactivation of the aminoglycoside 8. Literature Reports: a. Although penicillins and aminoglycosides are often used in combination for their synergistic effect, a number of reports have shown that a high penicillin to aminoglycoside ratio (greater than 50:1) for a prolonged period of time results in chemical inactivation of both compounds (Blair et al, 1982; Pickering & Gearhart, 1979; Ervin et al, 1976; Weibert et al, 1976; Davies et al, 1975; Riff & Jackson, 1972; Eykyn et al, 1971; McLaughlin & Reeves, 1971a; McLaughlin & Reeves, 1971b; Noone & Pattison, 1971; Riff & Jackson, 1971). This seems to occur in vitro when both drugs are physically mixed together, and in vivo in patients with poor renal function where renal excretion of the drugs is delayed. D. ENTACAPONE 1. Summary: Because entacapone is excreted via the bile, caution should be exercised when other drugs which are known to interfere with biliary excretion, glucuronidation, or intestinal beta-glucuronidase are coadministered, including ampicillin (Prod Info Stalevo(TM), 2003; Prod Info Comtan(R), 1999). 2. Adverse Effect: an increased risk of enhanced entacapone adverse effects (diarrhea, dyskinesias) 3. Clinical Management: If entacapone and ampicillin are coadministered, monitor the patient for signs of excessive entacapone adverse effects. 4. Severity: moderate 5. Onset: delayed 6. Documentation: fair 7. Probable Mechanism: reduced entacapone biliary excretion

E. ATENOLOL 1. Summary: Concurrent use of ampicillin and atenolol has resulted in reduced atenolol serum concentrations in 2 studies, but the clinical significance of this has not been demonstrated (Schafer-Korting et al, 1983; McLean et al, 1984). Higher doses of ampicillin (1 g vs 250 mg) resulted in a greater decrease in atenolol's AUC (McLean et al, 1984). 2. Adverse Effect: decreased atenolol effectiveness 3. Clinical Management: If used concurrently, monitor blood pressure and adjust atenolol dose if necessary. 4. Severity: minor 5. Onset: rapid 6. Documentation: fair 7. Probable Mechanism: decreased atenolol bioavailability 8. Literature Reports: a. Schafer-Korting et al (1983) presented a study of the pharmacokinetics of atenolol in 6 healthy subjects after 100 mg of atenolol as monotherapy for 6 days. The same subjects received atenolol 100 mg with 1 g ampicillin, 500 mg aspirin, and 300 mg allopurinol. Allopurinol and aspirin did not substantially alter the kinetics of atenolol, but ampicillin reduced the bioavailability, mean peak plasma levels, mean steady-state concentration, urinary recovery and the area under the plasma concentration-time curve. Exercise tachycardia was significantly higher with the combination of ampicillin and atenolol, than with atenolol alone. F. CHLORAMPHENICOL 1. Summary: Concomitant ampicillin and chloramphenicol therapy may result in inhibition of the bactericidal effects of ampicillin (Jawetz, 1968). This interaction is not significant clinically in most patients if therapeutic doses of each drug are administered and if ampicillin is administered several hours prior to or after chloramphenicol administration (Hansten & Horn, 1989). 2. Severity: not specified 3. Onset: not specified 4. Documentation: poor G. CHLOROQUINE 1. Summary: A reduction in the bioavailability of ampicillin was observed during concomitant therapy with chloroquine (Ali, 1985). This was postulated to be secondary to a slowing of gastric emptying and enhancement of gut motility from chloroquine. Concurrent oral administration of both drugs should be avoided; however, separation of doses by at least two hours should prevent the interaction if combined use is necessary. 2. Severity: not specified 3. Onset: not specified 4. Documentation: poor

H. CIMETIDINE 1. Severity: none 2. Onset: not specified 3. Documentation: poor 4. Literature Reports: a. Concomitant administration of ampicillin and cimetidine has not been reported to result in decreased absorption of ampicillin from the gastrointestinal tract (Morrison et al, 1980) or altered pharmacokinetics of either agent (Sorkin & Darvey, 1983). I. DIGITOXIN 1. Summary: Concomitant administration of digitoxin and ampicillin has been reported to result in no significant change in the elimination half-life or serum concentrations of digitoxin (Lucena et al, 1987). This study suggests that both drugs can be given simultaneously without dosing alterations of digitoxin. 2. Severity: none 3. Onset: not specified 4. Documentation: poor J. ETHINYL ESTRADIOL 1. Summary: Ampicillin may alter intestinal flora which, in turn, alters the enterohepatic circulation of combination contraceptives. Concomitant use has been associated with unintended pregnancies and menstrual changes (True, 1982; Back et al, 1981; Szoka & Edgren, 1988). 2. Adverse Effect: decreased contraceptive effectiveness 3. Clinical Management: During concurrent use of ampicillin and combination contraceptives, an additional form of birth control should be used. 4. Severity: major 5. Onset: delayed 6. Documentation: fair 7. Probable Mechanism: decreased enterohepatic circulation 8. Literature Reports: a. In a study of 11 regularly menstruating women, ages 21 to 39, concurrent ampicillin administration appeared not to diminish the effectiveness of the oral contraceptive studied (Friedman et al, 1980). Demulen(R) (1 mg ethynodiol diacetate and 50 mcg ethinyl estradiol) was given to each subject for 2 consecutive menstrual cycles, 21 days on and 7 days off. Ampicillin 250 mg or placebo was taken 4 times a day from day 1 through day 16 of each study cycle. Two subjects experienced breakthrough bleeding while taking ampicillin. One subject reported spotting with Demulen(R)-placebo combination, but not with Demulen(R)-ampicillin. There was no difference in quantity of menstrual flow between the two study cycles. One subject reported mid-cycle abdominal pain while on Demulen(R)-ampicillin. All

cycles appeared to be anovulatory with no significant difference in FSH, LH, and steroid hormone levels in patients on Demulen(R)-ampicillin versus patients on Demulen(R)-placebo. K. ETONOGESTREL 1. Summary: Ampicillin may alter intestinal flora which, in turn, alters the enterohepatic circulation of combination contraceptives. Concomitant use has been associated with unintended pregnancies and menstrual changes (True, 1982; Back et al, 1981; Szoka & Edgren, 1988). 2. Adverse Effect: decreased contraceptive effectiveness 3. Clinical Management: During concurrent use of ampicillin and combination contraceptives, an additional form of birth control should be used. 4. Severity: major 5. Onset: delayed 6. Documentation: fair 7. Probable Mechanism: decreased enterohepatic circulation 8. Literature Reports: a. In a study of 11 regularly menstruating women, ages 21 to 39, concurrent ampicillin administration appeared not to diminish the effectiveness of the oral contraceptive studied (Friedman et al, 1980). Demulen(R) (1 mg ethynodiol diacetate and 50 mcg ethinyl estradiol) was given to each subject for 2 consecutive menstrual cycles, 21 days on and 7 days off. Ampicillin 250 mg or placebo was taken 4 times a day from day 1 through day 16 of each study cycle. Two subjects experienced breakthrough bleeding while taking ampicillin. One subject reported spotting with Demulen(R)-placebo combination, but not with Demulen(R)-ampicillin. There was no difference in quantity of menstrual flow between the two study cycles. One subject reported mid-cycle abdominal pain while on Demulen(R)-ampicillin. All cycles appeared to be anovulatory with no significant difference in FSH, LH, and steroid hormone levels in patients on Demulen(R)-ampicillin versus patients on Demulen(R)-placebo. L. KHAT 1. Summary: Khat chewing significantly reduced the rate and extent of ampicillin urinary excretion in 8 healthy subjects except when ampicillin was taken 2 hours after the end of the khat chewing session (Attef et al, 1997). 2. Adverse Effect: reduced effectiveness of ampicillin 3. Clinical Management: Administer ampicillin 2 hours after khat chewing. 4. Severity: moderate 5. Onset: rapid 6. Documentation: fair 7. Probable Mechanism: reduced absorption of ampicillin speculated to result from formation of insoluble, unabsorbable complexes between the tannin content of khat and ampicillin

 8. Literature Reports: a. Khat chewing significantly reduced the percentage excreted unchanged and maximum peak excretion in urine, and increased in the maximum time to reach the peak excretion of ampicillin in 8 healthy male subjects in a crossover study. A single dose of ampicillin 500 milligrams was taken orally in 5 conditions with a washout period of 7 days between each condition: (A) alone under fasting conditions, (B) just before khat chewing, (C) just before khat chewing with regular food and drink, (D) 2 hours before khat chewing, (E) midway through the 4 hour khat chewing session, and (F) 2 hours after the end of the khat chewing session. Khat ('Sauty') was obtained from a local market in Yemen. Urine measures of excretion were used to estimate bioavailability; urine was collected at 0, 1, 2, 3, 4, 5, 6, 7, 8, and 12 hours after the ampicillin dose. Percentage excreted unchanged and maximum peak excretion in urine were significantly reduced, and maximum time to reach the peak excretion was significantly increased in conditions B, C, D, and E (p less than 0.05). Ampicillin excretion was not affected when taken 2 hours after the end of the khat chewing session (condition F) (Attef et al, 1997). M. LANSOPRAZOLE 1. Summary: Lansoprazole produces extensive and long lasting inhibition of gastric acid secretion. For some drugs, including ampicillin, absorption from the GI tract is enhanced by the presence of gastric acid. When ampicillin is coadministered with lansoprazole, reduced acidity may compromise ampicillin absorption, thus decreasing its bioavailability (Prod Info Prevacid(R), 2002). 2. Adverse Effect: loss of ampicillin efficacy 3. Clinical Management: Absorption of ampicillin may be affected due to profound and long lasting inhibition of gastric acid secretion. Monitor patients for continued antimicrobial efficacy. 4. Severity: moderate 5. Onset: rapid 6. Documentation: fair 7. Probable Mechanism: decreased gastrointestinal absorption due to reduced acidity N. LIVE TYPHOID VACCINE 1. Summary: Antibiotics which possess bacterial activity against salmonella typhi organisms may interfere with the immunological response to the live typhoid vaccine. Allow 24 hours or more to elapse between the administration of the last dose of the antibiotic and the live typhoid vaccine (Prod Info Vivotif Berna(R) Vaccine, 1997; CDC, 1994). 2. Adverse Effect: a decreased immunological response to the typhoid vaccine 3. Clinical Management: Allow 24 hours or more to elapse between the last dose of antibiotic and the administration of oral live typhoid vaccine.

4. Severity: moderate 5. Onset: delayed 6. Documentation: poor 7. Probable Mechanism: antimicrobial activity against the salmonella typhi organism O. MEFLOQUINE 1. Summary: Ampicillin significantly affects the pharmacokinetic characteristics of mefloquine. Karbwang et al (1991) administered a single dose of mefloquine 250 mg in combination with a therapeutic regimen of ampicillin (250 mg four times daily for five days) in healthy Thai males. The whole blood concentration of mefloquine was elevated by ampicillin (1648 vs. 1228 ng/mL). The terminal half-life (15.3 vs. 17.7 days), mean residence time (20.1 vs. 23.4 days), and volume of distribution at steady-state (14.1 vs. 19.4 L/kg) were reduced by ampicillin. These changes may be due to both an increase in bioavailability and a reduction in the enterohepatic recycling of mefloquine. 2. Severity: not specified 3. Onset: not specified 4. Documentation: poor P. MESTRANOL 1. Summary: Ampicillin may alter intestinal flora which, in turn, alters the enterohepatic circulation of combination contraceptives. Concomitant use has been associated with unintended pregnancies and menstrual changes (True, 1982; Back et al, 1981; Szoka & Edgren, 1988). 2. Adverse Effect: decreased contraceptive effectiveness 3. Clinical Management: During concurrent use of ampicillin and combination contraceptives, an additional form of birth control should be used. 4. Severity: major 5. Onset: delayed 6. Documentation: fair 7. Probable Mechanism: decreased enterohepatic circulation 8. Literature Reports: a. In a study of 11 regularly menstruating women, ages 21 to 39, concurrent ampicillin administration appeared not to diminish the effectiveness of the oral contraceptive studied (Friedman et al, 1980). Demulen(R) (1 mg ethynodiol diacetate and 50 mcg ethinyl estradiol) was given to each subject for 2 consecutive menstrual cycles, 21 days on and 7 days off. Ampicillin 250 mg or placebo was taken 4 times a day from day 1 through day 16 of each study cycle. Two subjects experienced breakthrough bleeding while taking ampicillin. One subject reported spotting with Demulen(R)-placebo combination, but not with Demulen(R)-ampicillin. There was no difference in quantity of menstrual flow between the two study cycles. One subject

reported mid-cycle abdominal pain while on Demulen(R)-ampicillin. All cycles appeared to be anovulatory with no significant difference in FSH, LH, and steroid hormone levels in patients on Demulen(R)-ampicillin versus patients on Demulen(R)-placebo. Q. NORELGESTROMIN 1. Summary: Ampicillin may alter intestinal flora which, in turn, alters the enterohepatic circulation of combination contraceptives. Concomitant use has been associated with unintended pregnancies and menstrual changes (True, 1982; Back et al, 1981; Szoka & Edgren, 1988). 2. Adverse Effect: decreased contraceptive effectiveness 3. Clinical Management: During concurrent use of ampicillin and combination contraceptives, an additional form of birth control should be used. 4. Severity: major 5. Onset: delayed 6. Documentation: fair 7. Probable Mechanism: decreased enterohepatic circulation 8. Literature Reports: a. In a study of 11 regularly menstruating women, ages 21 to 39, concurrent ampicillin administration appeared not to diminish the effectiveness of the oral contraceptive studied (Friedman et al, 1980). Demulen(R) (1 mg ethynodiol diacetate and 50 mcg ethinyl estradiol) was given to each subject for 2 consecutive menstrual cycles, 21 days on and 7 days off. Ampicillin 250 mg or placebo was taken 4 times a day from day 1 through day 16 of each study cycle. Two subjects experienced breakthrough bleeding while taking ampicillin. One subject reported spotting with Demulen(R)-placebo combination, but not with Demulen(R)-ampicillin. There was no difference in quantity of menstrual flow between the two study cycles. One subject reported mid-cycle abdominal pain while on Demulen(R)-ampicillin. All cycles appeared to be anovulatory with no significant difference in FSH, LH, and steroid hormone levels in patients on Demulen(R)-ampicillin versus patients on Demulen(R)-placebo. R. NORETHINDRONE 1. Summary: Ampicillin may alter intestinal flora which, in turn, alters the enterohepatic circulation of combination contraceptives. Concomitant use has been associated with unintended pregnancies and menstrual changes (True, 1982; Back et al, 1981; Szoka & Edgren, 1988). 2. Adverse Effect: decreased contraceptive effectiveness 3. Clinical Management: During concurrent use of ampicillin and combination contraceptives, an additional form of birth control should be used. 4. Severity: major 5. Onset: delayed

6. Documentation: fair 7. Probable Mechanism: decreased enterohepatic circulation 8. Literature Reports: a. In a study of 11 regularly menstruating women, ages 21 to 39, concurrent ampicillin administration appeared not to diminish the effectiveness of the oral contraceptive studied (Friedman et al, 1980). Demulen(R) (1 mg ethynodiol diacetate and 50 mcg ethinyl estradiol) was given to each subject for 2 consecutive menstrual cycles, 21 days on and 7 days off. Ampicillin 250 mg or placebo was taken 4 times a day from day 1 through day 16 of each study cycle. Two subjects experienced breakthrough bleeding while taking ampicillin. One subject reported spotting with Demulen(R)-placebo combination, but not with Demulen(R)-ampicillin. There was no difference in quantity of menstrual flow between the two study cycles. One subject reported mid-cycle abdominal pain while on Demulen(R)-ampicillin. All cycles appeared to be anovulatory with no significant difference in FSH, LH, and steroid hormone levels in patients on Demulen(R)-ampicillin versus patients on Demulen(R)-placebo. S. NORGESTREL 1. Summary: Ampicillin may alter intestinal flora which, in turn, alters the enterohepatic circulation of combination contraceptives. Concomitant use has been associated with unintended pregnancies and menstrual changes (True, 1982; Back et al, 1981; Szoka & Edgren, 1988). 2. Adverse Effect: decreased contraceptive effectiveness 3. Clinical Management: During concurrent use of ampicillin and combination contraceptives, an additional form of birth control should be used. 4. Severity: major 5. Onset: delayed 6. Documentation: fair 7. Probable Mechanism: decreased enterohepatic circulation 8. Literature Reports: a. In a study of 11 regularly menstruating women, ages 21 to 39, concurrent ampicillin administration appeared not to diminish the effectiveness of the oral contraceptive studied (Friedman et al, 1980). Demulen(R) (1 mg ethynodiol diacetate and 50 mcg ethinyl estradiol) was given to each subject for 2 consecutive menstrual cycles, 21 days on and 7 days off. Ampicillin 250 mg or placebo was taken 4 times a day from day 1 through day 16 of each study cycle. Two subjects experienced breakthrough bleeding while taking ampicillin. One subject reported spotting with Demulen(R)-placebo combination, but not with Demulen(R)-ampicillin. There was no difference in quantity of menstrual flow between the two study cycles. One subject reported mid-cycle abdominal pain while on Demulen(R)-ampicillin. All cycles appeared to be anovulatory with no significant difference in FSH, LH,

and steroid hormone levels in patients on Demulen(R)-ampicillin versus patients on Demulen(R)-placebo. T. OMEPRAZOLE 1. Summary: Omeprazole produces extensive and long-lasting inhibition of gastric acid secretion. For some drugs, including ampicillin, absorption from the GI tract is enhanced by the presence of gastric acid. When ampicillin is coadministered with omeprazole, reduced acidity may compromise ampicillin absorption, thus decreasing its bioavailability (Prod Info Prilosec(R), 1995). 2. Adverse Effect: reduced ampicillin bioavailability 3. Clinical Management: Monitor the patient for ampicillin efficacy if omeprazole is being using concurrently. 4. Severity: moderate 5. Onset: rapid 6. Documentation: fair 7. Probable Mechanism: reduced gastric pH, resulting in decreased absorption of ampicillin U. PANTOPRAZOLE 1. Summary: Pantoprazole produces extensive and long lasting inhibition of gastric acid secretion. For some drugs, including ampicillin, absorption from the GI tract is enhanced by the presence of gastric acid. When ampicillin is coadministered with pantoprazole, reduced acidity may compromise ampicillin absorption, thus decreasing its bioavailability (Prod Info Protonix(R), 2001). 2. Adverse Effect: loss of ampicillin efficacy 3. Clinical Management: Absorption of ampicillin may be affected due to profound and long lasting inhibition of gastric acid secretion. Monitor patients for continued antimicrobial efficacy. 4. Severity: moderate 5. Onset: rapid 6. Documentation: fair 7. Probable Mechanism: decreased gastrointestinal absorption V. PROBENECID 1. Summary: Concomitant probenecid and ampicillin therapy has been reported to result in higher and more prolonged serum levels of ampicillin. This combination is used to eradicate the typhoid carrier state in which the antibiotic tends to concentrate in the biliary tract where the Salmonella typhosa reside. Single dose sessions of the combination have been successfully employed to treat gonorrhea in areas of high resistance. The uricosuric effect of probenecid does not appear to be altered by ampicillin. Inhibition of renal tubular secretion of ampicillin by probenecid retards the excretion of the antibiotic. Probenecid diminishes the apparent volume of distribution of ampicillin, but does not alter the antibiotic's biotransformation

(Levy, 1965; Tuano et al, 1966a; Gibaldi & Schwartz, 1968; Anon, 1968; Simon & Miller, 1966; Keys et al, 1969; Gundersen, et al, 1969; Johnson et al, 1970; Willcox, 1970a; Robinson, 1964; Eickhoff et al, 1965). 2. Severity: not specified 3. Onset: not specified 4. Documentation: poor 5. Literature Reports: a. In 1968 the Medical Letter recommended that divided daily doses of oral ampicillin (6.0 g daily) and probenecid (2.0 g daily) be given for a period of six weeks to treat adult typhoid carriers (Simon & Miller, 1966). Failures in therapy have been attributed to the insensitivity of the bacteria to the antibiotic since the prescribed regimen assured high antibiotic serum and tissue levels. In one report, 10 of 15 carriers suffered mild drug-induced side effects, but none required discontinuation of therapy (Simon & Miller, 1966). Oral and parenteral single doses of ampicillin (1.0 to 3.5 g) with probenecid have been tested in patients with gonorrhea (Keys et al, 1969; Gundersen et al, 1969). The cure rate with ampicillin in two studies was better than suboptimal doses of injectable penicillin G salts (2.4 million units) but in one study equal success was obtained with a single session procedure of penicillin G (6.0 million units) and probenecid (Johnson et al, 1970). b. Ampicillin 1 gram given as a single intravenous dose had no significant influence on the uricosuric effect of oral probenecid 2 grams in six healthy volunteers (Sommers & Schoeman, 1987). Probenecid was administered first, followed three hours later by the ampicillin. W. RABEPRAZOLE 1. Summary: Rabeprazole produces extensive and long lasting inhibition of gastric acid secretion (Prod Info Aciphex(R), 2002). For some drugs, including ampicillin, absorption from the GI tract is enhanced by the presence of gastric acid. Though this interaction has not been studied, when ampicillin is coadministered with rabeprazole, reduced acidity may compromise ampicillin absorption, thus decreasing its bioavailability. 2. Adverse Effect: loss of ampicillin efficacy 3. Clinical Management: Monitor patients for continued antimicrobial efficacy. 4. Severity: moderate 5. Onset: rapid 6. Documentation: fair 7. Probable Mechanism: decreased gastrointestinal absorption due to reduced acidity X. RALOXIFENE 1. Summary: The peak concentration of raloxifene is decreased by 28% and the overall absorption is reduced by 14% when coadministered with ampicillin. These decreases may be caused by reduced enterohepatic

cycling associated with antibiotic reduction of enteric bacteria. However, the systemic exposure and the elimination rate of raloxifene are not affected by ampicillin cotherapy, and concurrent administration of ampicillin and raloxifene is considered safe (Prod Info Evista(R), 2000). 2. Severity: none 3. Onset: not specified 4. Documentation: poor Y. THEOPHYLLINE 1. Summary: It is reported that concurrent administration of ampicillin in the treatment of severe asthma has resulted in no significant difference in mean theophylline half-life (Kadlec et al, 1978). 2. Severity: none 3. Onset: not specified 4. Documentation: poor 3.5.2 DRUG-FOOD COMBINATIONS A. FOOD 1. Summary: When given with food, the amount absorbed and peak levels of ampicillin may be decreased by 25% to 50% (Welling, 1984; Welling et al, 1977). 2. Adverse Effect: decreased ampicillin concentrations 3. Clinical Management: Ampicillin should be administered on an empty stomach, at least one-half hour before meals or two hours after meals. 4. Severity: moderate 5. Onset: rapid 6. Documentation: good 7. Probable Mechanism: delayed absorption 8. Literature Reports: a. When taken immediately following a standard meal, there was a prolonged delay in antibiotic absorption (New, 1974; Neuvonen et al, 1977), with peak serum levels reduced by 25% (Eshelman & Spyker, 1978) to 50% (Welling et al, 1977). Area under the plasma concentration time curve also decreased in the nonfasting situation (Eshelman & Spyker, 1978). The concentrations when food was ingested were below the MIC for many organisms (Sabto et al, 1973). b. Pediatric patients given ampicillin suspension in 25 mg/kg doses followed by 4 ox. of milk showed no significant alterations in ampicillin bioavailability (McCracken et al, 1978). 3.5.3 DRUG-LAB MODIFICATIONS A. SULFITE OXIDASE DEFICIENCY TEST 1. Summary: Urine specimens containing frequently prescribed ampicillin often give a falsely positive reaction in testing for sulfite oxidase deficiency, making interpretation of the positive spot test result difficult (Shin, 1983). 2. Severity: minor

 3. Onset: rapid 4. Documentation: poor B. URINE GLUCOSE TEST 1. Summary: MacCara & Parker (1981) report that the penicillins (ampicillin, carbenicillin, penicillin G, and penicilloic acid) can cause falsely elevated or falsely decreased Clinitest readings. Therefore, patients on penicillins who use Clinitest, a quantitative test for glycosuria, should recheck their results with a qualitative test such as the glucose oxidase tests. 2. Severity: minor 3. Onset: delayed 4. Documentation: poor 3.5.4 INTRAVENOUS ADMIXTURES 3.5.4.1 COMPATIBILITIES - SOLUTIONS A. DEXTROSE IN SODIUM CHLORIDE 1. Dextrose 5% in sodium chloride 0.45% (with ampicillin 2 mg/mL and sulbactam 1 mg/mL had a utility time of only 5 hours at 24 degrees C with 6% ampicillin decomposition and 2% sulbactam decomposition) (Mushinsky et al, 1986) B. DEXTROSE IN WATER 1. Dextrose 5% in water (with ampicillin 2 mg/mL and sulbactam 1 mg/mL had a utility time of 8 hours at 24 degrees C with 10% ampicillin decomposition and 1% sulbactam decomposition; with ampicillin 20 mg/mL and sulbactam 10 mg/mL had a utility time of only 5 hours at 24 degrees C with 10% ampicillin decomposition and no sulbactam decomposition) (Mushinsky et al, 1986) C. INVERT SUGAR 1. Invert sugar 10% (with ampicillin 2 mg/mL and sulbactam 1 mg/mL had a utility time of only 5 hours at 24 degrees C with 8% ampicillin decomposition and 2% sulbactam decomposition) (Mushinsky et al, 1986) D. LACTATED RINGER'S INJECTION 1. Lactated Ringer's injection (with ampicillin 30 mg/mL and sulbactam 15 mg/mL had a utility time of 8 hours at 24 degrees C with 10% ampicillin decomposition and 4% sulbactam decomposition or a utility time of 8 hours under refrigeration with 8% ampicillin decomposition and no sulbactam decomposition) (Mushinsky et al, 1986) E. SODIUM CHLORIDE 1. Sodium chloride 0.9% (with ampicillin 30 mg/mL and sulbactam 15 mg/mL had a utility time of 8 hours at 24 degrees C with 7% ampicillin decomposition and 3% sulbactam decomposition or a utility time of 24 hours under refrigeration with 8% ampicillin decomposition and 5% sulbactam decomposition; with ampicillin 20 mg/mL and sulbactam 10 mg/mL had a utility time of 48 hours under refrigeration with 10% ampicillin decomposition and 6% sulbactam decomposition) (Mushinsky et al, 1986) F. SODIUM LACTATE

 1. Sodium lactate 1.67 M (with ampicillin 30 mg/mL and sulbactam 15 mg/mL had a utility time of 8 hours under refrigeration with 6% ampicillin decomposition and 2% sulbactam decomposition) (Mushinsky et al, 1986) G. STERILE WATER FOR INJECTION 1. Sterile water for injection (with ampicillin 30 mg/mL and sulbactam 15 mg/mL had a utility time of 8 hours at 24 degrees C with 6% ampicillin decomposition and 3% sulbactam decomposition or a utility time of 24 hours under refrigeration with 8% ampicillin decomposition and 3% sulbactam decomposition; with ampicillin 20 mg/mL and sulbactam 10 mg/mL had a utility time of 72 hours under refrigeration with 10% ampicillin decomposition and 3% sulbactam decomposition; with ampicillin 250 mg/mL and sulbactam 125 mg/mL had a utility time of 1 hour at 24 degrees C with 7% ampicillin decomposition and 2% sulbactam decomposition) (Mushinsky et al, 1986) 3.5.4.2 COMPATIBILITIES - DRUGS A. AMIFOSTINE 1. Amifostine 10 mg/mL in dextrose 5% in water with ampicillin sodiumsulbactam sodium 20/10 mg/mL in 0.9% sodium chloride injection, USP, compatible during simulated Y-site administration (Trissel & Martinez, 1995) B. AZTREONAM 1. Aztreonam 40 mg/mL in 5% dextrose in water with ampicillin sodiumsulbactam sodium 20/10 mg/mL in Sodium chloride 0.9%, compatible for up to 4 hours at 23 degrees C (Trissel & Martinez, 1995) C. ENALAPRIL 1. Ampicillin/sulbactam 15 mg/mL with enalaprilat 50 mcg/mL, visually compatible for 24 hours at room temperature in sodium chloride 0.9% under fluorescent light (Halpern et al, 1989a) D. FAMOTIDINE 1. Famotidine (prepared as an intravenous solution according to manufacturer's instructions in dextrose 5% in water with ampicillin/sulbactam 30 mg/mL in sodium chloride 0.9% visually compatible for 14 hours; exact famotidine concentration and test conditions not specified) (Fong & Ward, 1989) E. FENOLDOPAM 1. Ampicillin sodium/sulbactam sodium 20/10 mg/mL in Sodium chloride 0.9% injection with fenoldopam mesylate 80 mcg/mL in Sodium chloride 0.9% injection, visually and physically compatible for up to 4 hours at 23 degrees C in a clear glass tube under constant fluorescent light during simulated Y-site administration (Trissel et al, 2003). F. FILGRASTIM 1. Ampicillin sodium-sulbactam sodium (20/10) mg/mL in dextrose 5% in water with filgrastim 30 mcg/mL in dextrose 5% in water, compatible for up to 4 hours at 22 degrees C (Trissel & Martinez, 1994) G. FLUCONAZOLE

 1. Ampicillin/sulbactam 60 milligrams/milliliter (mg/mL) with fluconazole 2 mg/mL, visually compatible for 24 hours at 25 degrees C under fluorescent light (Lor et al, 1991) H. FLUDARABINE 1. Ampicillin 20 mg/mL and sulbactam 10 mg/mL in sodium chloride 0.9% with fludarabine 1 mg/mL in dextrose 5% in water, visually compatible for a 4-hour study period at room temperature under fluorescent light (Trissel et al, 1991a) I. GALLIUM NITRATE 1. Ampicillin sodium 45 mg/mL and sulbactam sodium 22.4 mg/mL in a glass test tube with gallium nitrate 1 mg/mL in a plastic syringe, both solutions in sodium chloride 0.9%, no visual incompatiblity for up to 24 hours at room temperature under fluorescent light when admixed in a 1:1 ratio simulating Y-site administration; however chemical stability was not tested and the authors note that ampicillin/sulbactam solutions were previously found to be chemically stable for less than 24 hours at room temperature (Lober & Dollard, 1993) J. INSULIN 1. Ampicillin/sulbactam 30 mg/mL in sodium chloride 0.9% with insulin 0.2 U/mL in sodium chloride 0.9%, visually compatible for a 2-hour study period at 25 degrees C under fluorescent light (Smythe & Malouf, 1991) K. LIDOCAINE 1. Ampicillin 250 mg/mL and sulbactam 125 mg/mL with lidocaine 0.5% or 2% had a utility time of 1 hour at 24 degrees C with 6% ampicillin decomposition and 1% sulbactam decomposition (Mushinsky et al, 1986) L. MEPERIDINE 1. Meperidine (10 mg/mL with ampicillin/sulbactam 30 mg/mL, both in sodium chloride 0.9%, visually compatible for a 1-hour study period at 25 degrees C under fluorescent light) (Smythe et al, 1990) M. MORPHINE 1. Morphine (1 mg/mL with ampicillin/sulbactam 30 mg/mL, both in sodium chloride 0.9%, visually compatible for a 1-hour study period at 25 degrees C under fluorescent light) (Smythe et al, 1990) N. PACLITAXEL 1. Ampicillin 20 mg/mL and sulbactam 10 mg/mL in 0.9% sodium chloride injection with paclitaxel 1.2 mg/mL in 5% dextrose injection, no visual or turbidimetric evidence of incompatibility during simulated Y-site injection (Trissel & Martinez, 1993) O. TACROLIMUS 1. Ampicillin/sulbactam 50 mg/mL in 5% dextrose injection with tacrolimus 1 mg/mL in 0.9% sodium chloride injection, visually compatible for 24 hours at room temperature under fluorescent light (Min et al, 1992) P. TOTAL PARENTERAL NUTRITION

 1. Ampicillin 20 mg/mL and sulbactam 10 mg/mL in Sodium chloride 0.9% added to total parenteral nutrition solution compatible in simulated Y-site administration for 4 hours at 23 degrees C; specific composition of total parenteral nutrition solution listed below (Trissel et al, 1997):
Amino acids 10% (Aminosyn(R) II) 3.5% Dextrose 5% Sterile water for injection 516.8 mL Potassium phosphates 3.5 mM Sodium chloride 25 mEq Potassium chloride 35 mEq Magnesium sulfate 8 mEq Multivitamins 10 mL Trace elements 1 mL Calcium gluconate 9.3 mEq

2. Ampicillin 20 mg/mL and sulbactam 10 mg/mL in Sodium chloride 0.9% added to total parenteral nutrition solution compatible in simulated Y-site administration for 4 hours at 23 degrees C; specific composition of total parenteral nutrition solution listed below (Trissel et al, 1997):
Amino acids 10% (FreAmine(R) III) 3.5% Dextrose 5% Sterile water for injection 516.75 mL Sodium chloride 37.5 mEq Potassium chloride 40 mEq Magnesium sulfate 8 mEq Multivitamins 10 mL Trace elements 1 mL Calcium gluconate 5 mEq

3. Ampicillin 20 mg/mL and sulbactam 10 mg/mL in Sodium chloride 0.9% added to total parenteral nutrition solution compatible in simulated Y-site administration for 4 hours at 23 degrees C; specific composition of total parenteral nutrition solution listed below (Trissel et al, 1997):
Amino acids 10% (Aminosyn(R) II) 4.25% Dextrose 25% Sterile water for injection 161 mL Potassium phosphates 15 mM Sodium chloride 25 mEq Potassium chloride 18 mEq Magnesium sulfate 8 mEq Multivitamins 10 mL Trace elements 1 mL Calcium gluconate 9.15 mEq

4. Ampicillin 20 mg/mL and sulbactam 10 mg/mL in Sodium chloride 0.9% added to total parenteral nutrition solution compatible in simulated Y-site administration for 4 hours at 23 degrees C; specific composition of total parenteral nutrition solution listed below (Trissel et al, 1997):
Amino acids 10% (FreAmine(R) III) 4.25% Dextrose 25% Sterile water for injection 158.6 mL Potassium phosphates 5.75 mM Sodium chloride 40 mEq

Potassium chloride Magnesium sulfate Multivitamins Trace elements Calcium gluconate

25 mEq 8 mEq 10 mL 1 mL 7.5 mEq

Q. VANCOMYCIN 1. IMPORTANT NOTE: The compatibility of vancomycin with beta-lactam antibiotics is concentration dependent.
2. Concentration Vancomycin Vancomycin (mg/mL)* 2 mg/mL 20mg/mL --------------------------------------------------Ampicillin 250/125 C TP sodium/ sulbactam 50/25 C C sodium 10/5 C C 1/0.5 C C * milligrams/millliter C = compatible; no particles, precipitate or haze TP = transient precipitate; followed by clear solution IC = incompatible; haze, cloudiness or precipitate Y-Site compatibilites at 23 degrees Celsius over 4 hours; Trissel et al, 1998 Test Drug

3.5.4.3 INCOMPATIBILITIES - SOLUTIONS A. DEXTROSE IN SODIUM CHLORIDE 1. Dextrose 5% in sodium chloride 0.45% (with ampicillin 2 mg/mL and sulbactam 1 mg/mL, 11% ampicillin decomposition and 4% sulbactam decomposition in 8 hours at 24 degrees C; with ampicillin 10 mg/mL and sulbactam 5 mg/mL, 13% ampicillin decomposition in 4 hours and 8% sulbactam decomposition in 4 hours under refrigeration) (Mushinsky et al, 1986) B. INVERT SUGAR 1. Invert sugar 10% (with ampicillin 2 mg/mL and sulbactam 1 mg/mL, 16% ampicillin decomposition and 8% sulbactam decomposition in 8 hours at 24 degrees C; with ampicillin 20 mg/mL and sulbactam 10 mg/mL, 15% ampicillin decomposition and 9% sulbactam decomposition in 3 hours under refrigeration) (Mushinsky et al, 1986) 3.5.4.4 INCOMPATIBILITIES - DRUGS A. IDARUBICIN 1. Ampicillin/sulbactam 30 mg/mL with idarubicin 1 mg/mL, both in sodium chloride 0.9%, immediate moderate color change and haze formation reported with formation of a severe precipitate reported within 20 minutes at 25 degrees C under fluorescent light (Turowski & Durthaler, 1991) B. NICARDIPINE 1. Nicardipine (100 mcg/mL with ampicillin/sulbactam 15 mg/mL, immediate turbidity reported in dextrose 5% in water or sodium chloride 0.9%) (Halpern et al, 1989a) C. ONDANSETRON

 1. Ampicillin/sulbactam (ampicillin 20 mg/mL and sulbactam 10 mg/mL) with ondansetron 1 mg/mL in sodium chloride 0.9%, caused a change in the turbidity resulting in the formation of a flocculent precipitate (Trissel et al, 1991b; Tech Info Zofran(R), 1999). D. SARGRAMOSTIM 1. Ampicillin 20 mg/mL and sulbactam 10 mg/mL with sargramostim 10 mcg/mL, both in sodium chloride 0.9%, no particulate formation reported in 4 hours at 22 degrees C under fluorescent light only when the sargramostim was added to the ampicillin solution; however, a few particles were reported when the ampicillin was added to the sargramostim (Trissel et al, 1992) 4.0 CLINICAL APPLICATIONS 4.1 MONITORING PARAMETERS 4.1.1 THERAPEUTIC A. Clinical signs and symptoms of infection B. Fever C. WBC count D. Culture and sensitivities as indicated 4.1.2 TOXIC A. Diarrhea B. Skin rash C. Hematologic studies (RBC, CBC with differential, platelets) 4.2 PATIENT INSTRUCTIONS
AMPICILLIN/SULBACTAM (am-pi-SIL-in/sul-BAK-tam) (INJECTION): - Treats infections. - Belongs to a class of drugs called penicillin antibiotics. BRAND NAME(S): Unasyn(R) WHEN YOU SHOULD NOT TAKE THIS MEDICINE: - Do not take this medicine if you have ever had an allergic reaction to ampicillin or any penicillin medicine. HOW TO TAKE AND STORE THIS MEDICINE - Your doctor will prescribe your exact dose and tell you how often it should be given. Keep all - medicine out of the reach of children. INTRAMUSCULAR (IM) INJECTION/ INTRAVENOUS (IV) INFUSION: - An IM injection is a shot given in your muscle (upper arm, thigh, buttocks). An IV infusion is medicine that is put directly into your body through one of your veins. - This medicine should be given by a person trained to give IV or IM medicine, such as a nurse. Sometimes you, a family member, or friend can be taught to give your medicine. - If you have your treatments at home, you should be given a special container for the used needles. Keep it where children or pets cannot reach it. - If you are receiving IV medicine, check the bag to

make sure there are no leaks. Also make sure the solution is clear. If you see particles in the solution, do not use it. - Store in a refrigerator. Do not freeze. Take it out of the refrigerator an hour before the time for your next dose and allow it to warm to room temperature in a clean, dry place. IF YOU MISS A DOSE: - This medicine needs to be given on a regular schedule. Take the missed dose as soon as you remember, and take the rest of the doses for the day at regularly spaced time intervals. - If you miss more than one dose, call your doctor for instructions. DRUGS AND FOODS TO AVOID: Ask your doctor or pharmacist before taking any other medicine, including over-the-counter products. - Make sure your doctor knows if you are taking probenecid (Benemid(R)) or allopurinol before you take this medicine. - Birth control pills may not work as well while taking ampicillin. Use another kind of birth control while you are taking this medicine. WARNINGS: - Make sure your doctor knows if you have ever had an allergic reaction to any cephalosporin antibiotic such as Keflex(R) or Ceclor(R) before you take this medicine. - Make sure your doctor knows if you have mononucleosis (mono), stomach or intestinal disease, asthma, liver disease, hay fever, or other allergies before you take this medicine. - If your infection does not improve, or if it gets worse while taking this medicine, talk to your doctor. - If you have severe diarrhea while taking ampicillin/sulbactam, check with your doctor before taking medicine to stop the diarrhea. - If you are pregnant or breastfeeding, talk to your doctor before taking this medicine. SIDE EFFECTS Call your doctor right away if you have any of these side effects: - Rash or hives - Blistering or peeling skin - Swelling of the face, throat, or lips - Wheezing or trouble breathing - Severe diarrhea (watery or bloody) - Swelling, pain, or redness near where your IV is located If you have problems with these less serious side effects, talk with your doctor. - Mild diarrhea or nausea - Sore mouth or tongue

- Vaginal itching or discharge - Pain where your IM shot was given IF YOU HAVE OTHER SIDE EFFECTS THAT YOU THINK ARE CAUSED BY THIS MEDICINE, TELL YOUR DOCTOR.

4.3 PLACE IN THERAPY A. Ampicillin/sulbactam is useful as an alternative to broad-spectrum penicillins or cephalosporins in the treatment of a variety of infections where organisms producing Richmond type II, III, IV, and V beta lactamases are a concern. B. Sulbactam in combination with ampicillin appears to have greatest potential in the treatment of polymicrobial aerobic or anaerobic infections. It is felt that the injectable preparation be considered for hospital formularies for the treatment of these infections. Further well-controlled studies comparing ampicillin/sulbactam with other regimens including ampicillin alone, amoxicillin/clavulanate, sulfonamides, and third-generation cephalosporins are needed to determine the drug's ultimate place in therapy. C. Based upon a critical review of the literature, ampicillin/sulbactam may be useful as a first-line agent for the treatment of mixed aerobic/anaerobic infections, where nosocomial pathogens (pseudomonas) are not confirmed and are unlikely (Benson & Nahata, 1988). The combination may be a more cost-effective approach to treating or preventing abdominal and gynecologic infections as compared to other current therapies. 4.4 MECHANISM OF ACTION/PHARMACOLOGY A. MECHANISM OF ACTION 1. Ampicillin/sulbactam is an antibiotic combination product composed of ampicillin, a beta-lactamase-sensitive antibiotic, and sulbactam, a betalactamase inhibitor. The addition of sulbactam extends the antimicrobial spectrum of ampicillin to include resistant B fragilis, Klebsiella, S aureus, and H influenzae. Sulbactam itself has little antimicrobial activity, with the exception of moderate activity against beta-lactamase-positive and -negative N gonorrheae (Campoli-Richards & Brogden, 1987). B. MECHANISM OF ACTION - AMPICILLIN 1. Ampicillin is a semisynthetic penicillin (beta-lactam antibiotic) and shares the same mechanism of action as the other penicillins. Peptidoglycan, a cellwall component, provides mechanical stability through a highly cross-linked latticework structure. Peptidoglycan is composed of glycan chains which are cross-linked by peptide chains or "bridges"; the composition of these peptide bridges is characteristic of individual microbial species. Cross-linkage of the peptidoglycan structure is accomplished through a transpeptidation reaction which occurs outside the cell membrane. Beta-lactam antibiotics, such as ampicillin, act at this stage to interrupt cell-wall biosynthesis. By binding to penicillin-binding proteins which are associated with the bacterial cell membrane, beta-lactam antibiotics disrupt cell-wall integrity. Penicillinbinding proteins vary between bacterial species, and have a variable affinity

for different beta-lactam antibiotics (Mandell et al, 1995; Gilman et al, 1985; Neu, 1983; Yocum et al, 1980; Spratt, 1975; Spratt, 1980). 2. Resistance to ampicillin occurs as a result of inactivation by betalactamase (penicillinase) hydrolysis. In general, gram-positive organisms secrete large amounts of beta-lactamase extracellularly, while gramnegative organisms secrete small amounts directly into the periplasmic space between the inner and outer cell membranes (Gilman et al, 1985; Sykes & Matthew, 1976). C. MECHANISM OF ACTION - SULBACTAM 1. Sulbactam has been demonstrated to inhibit the hydrolysis of a variety of beta-lactams, including ampicillin (English et al, 1978; Wise, 1979; Wise et al, 1980; Retsema et al, 1981; Yu & Washington, 1981). Sulbactam is a semisynthetic beta-lactam sulfone which inhibits beta-lactamases of the Richmond types II, III, IV, and V (plasmid or chromosomally mediated). Sulbactam is less effective in inhibiting the Richmond type I betalactamases (Fu & Neu, 1979). A comprehensive review of the classification of beta-lactamases is provided (Bauernfeind, 1986). 2. The inhibition of beta-lactamases by sulbactam has been reported to be both reversible and irreversible (Fu & Neu, 1979; English et al, 1978; Labia et al, 1980; Retsema et al, 1981; Sawai & Tskukamoto, 1982; Labia et al, 1986). Sulbactam acts as a suicide inhibitor by forming a reversible enzymesulbactam complex which is inactive. This reversible acyl-intermediate may then revert to a more stable complex which irreversibly inhibits the betalactamase (Labia et al, 1980; Retsema et al, 1981; Labia et al, 1986; Fisher et al, 1981). By rendering beta-lactamases inactive, sulbactam is able to protect the activity of various beta-lactam antibiotics, including ampicillin. In addition, sulbactam may be somewhat synergistic with ampicillin due to sulbactam's limited affinity for penicillin-binding proteins and subsequent antibacterial activity. Sulbactam does not appear to have any betalactamase-inducing properties (Labia et al, 1986; Moosdeem et al, 1986). 3. On a mg-for-mg basis, sulbactam appears to be a less potent betalactamase inhibitor than clavulanic acid (Easton & Knowles, 1984; English et al, 1978; Wise et al, 1980; Wise et al, 1981). However, this difference in potency is offset by sulbactam's greater tissue penetration, greater stability, and lesser likelihood of inducing chromosomal beta-lactamases. 4. A review of the chemistry, pharmacology, kinetics, efficacy, and toxicity of sulbactam is provided (Noguchi & Gill, 1988). D. SPECTRUM OF ACTIVITY 1. AMPICILLIN a. Ampicillin is usually active against the following gram-positive cocci (Kucers & Bennett, 1979; Mandell et al, 1995). Most staphylococcal strains are ampicillin-resistant due to inactivation of ampicillin by staphylococcal penicillinase.

 (1) Anaerobic gram-positive cocci (Peptococcus and Peptostreptococcus spp, anaerobic streptococci) (2) Group B streptococci (ampicillin plus gentamicin is synergistic) (3) Enterococcus faecalis (ampicillin plus gentamicin is synergistic against all strains) (4) Strep pneumoniae (5) Strep pyogenes (6) Strep viridans (alpha-hemolytic) b. The following gram-positive bacilli are usually sensitive to ampicillin (Mandell et al, 1995). (1) C diphtheriae (2) Clostridium spp (including Cl tetani, Cl perfringens, and Cl botulinum) (3) Listeria monocytogenes (ampicillin plus gentamicin is synergistic) (4) Haemophilus influenza c. The following gram-negative aerobes are usually sensitive to ampicillin (Mandell et al, 1995): (1) E coli (more than 50% of strains may be resistant) (2) P mirabilis (other Proteus spp are resistant) (3) Salmonella spp (S typhimurium may be 30% to 40% resistant) (4) Shigella flexneri (up to 80% of S sonnei strains may be resistant) d. The following gram-negative anaerobes are usually sensitive to ampicillin (Mandell et al, 1995). (1) Fusobacterium spp 2. SULBACTAM a. Sulbactam alone has little in vitro antimicrobial activity (Aswapokee & Neu, 1978; English et al, 1978). In vitro activity against N gonorrhea has been demonstrated (Retsema et al, 1980; Caine et al, 1981); however, sulbactam alone has not been effective in the treatment of infections due to N gonorrhea (Caine et al, 1984). E. SYNERGISM 1. In vitro studies have been performed to evaluate the synergy which occurs when ampicillin is combined with sulbactam. Marked lowering of the inhibitory concentrations of ampicillin/sulbactam was observed, even when the organism was resistant to either agent alone (Aswapokee & Neu, 1978). Synergy was remarkable against S aureus and S epidermidis which were resistant to ampicillin and sulbactam when these agents were used in combination. Similar observations have been reported (Retsema et al, 1986). The same effect was also observed with isolates of S epidermidis. The in vitro activity of ampicillin/sulbactam against many beta-lactamaseproducing organisms, including gram-positive cocci, was evaluated (Jones et al, 1983). Ampicillin/sulbactam converted the resistant Staphylococci to susceptible organisms and significantly reduced the MICs of resistant strains.

 2. Synergy of ampicillin/sulbactam against many gram-negative organisms has also been demonstrated. The in vitro activity of ampicillin/sulbactam against hospital bacterial isolates, including many gram-negative pathogens, was evaluated (Retsema et al, 1986). Over 90% of the Hemophilus influenzae, Moraxella catarrhalis (formerly called Branhamella catarrhalis), Neisseria gonorrhea, Klebsiella spp, E coli, E aerogenes, Proteus spp, and Acinetobacter calcoaceticus were inhibited by a concentration of 16/8 mcg/mL ampicillin/sulbactam. The combination was potent against betalactamase-producing strains of H influenzae and Moraxella catarrhalis. In addition, ampicillin/sulbactam was more active than amoxicillin/clavulanic acid against beta-lactamase-producing H influenzae (Jones et al, 1983). Ampicillin/sulbactam was also more inhibitory than amoxicillin/clavulanic acid against Enterobacteriaceae. It was noted that the synergy of ampicillin/sulbactam was marked against Enterobacteriaceae (Aswapokee & Neu, 1986). 3. In addition to extending the activity of ampicillin against gram-positive and gram-negative organisms, sulbactam combined with ampicillin considerably extends ampicillin's anaerobic spectrum (Aswapokee & Neu, 1978; Retsema et al, 1980). Especially noteworthy is the activity of the combination against B fragilis and Bacteroides spp. In vitro, ampicillin/sulbactam has been shown to be 4 to 16 times more potent than cefoxitin and moxalactam against these anaerobes (Retsema et al, 1986; Pers Comm, 1987). Ampicillin/sulbactam was tested for activity against 272 clinical isolates of anaerobic bacteria, including those commonly resistant to ampicillin (Pers Comm, 1987). The combination of ampicillin/sulbactam, at a concentration of 16 mcg/mL and 8 mcg/mL, respectively, inhibited 99.6% of all the strains tested. Against the B fragilis group, addition of sulbactam increased the activity of ampicillin by four-fold. This activity against anaerobic organisms, as well as S aureus and other gram-positive and gram-negative organisms, suggests that this combination may be useful in the treatment of mixed aerobic-anaerobic infections. F. MINIMUM INHIBITORY CONCENTRATIONS 1. Organisms with a minimum inhibitory concentration of less than or equal to 8 mg/L (based on the ampicillin component in the presence of sulbactam at a constant ratio of 1 part sulbactam to 2 parts ampicillin) are considered susceptible to ampicillin/sulbactam. A minimum inhibitory concentration greater than 16 mg/L indicates resistance (Prod Info Unasyn(R), 1995). 2. The following are MIC-90 (minimum concentration required to inhibit 90% of isolates tested) (Kucers & Bennett, 1979); Campoli-Richards & Brogden, 1987; Retsema et al, 1986); minimum inhibitory concentrations are expressed in terms of ampicillin (AMP) alone, a sulbactam concentration equal to the ampicillin concentration (1:1), and a sulbactam concentration that is one-half that of ampicillin (1:2):
ORGANISM AMP MIC (mcg/mL) 1:1 1:2

---------------------------------------B catarrhalis 12.5 0.4 0.8 (betalactamasepositive) B fragilis 4-256+ 1.6-8 B melanino0.5-4 genicus B pertussis 0.39-1.56 Brucella 0.25-0.8 Citrobacter 128+ 32 E coli 5-128+ 16 16-32 Enterobacter 128 16 aerogenes Enterobacter 128-256+ 16 32-128 H influenzae 3-500+ 1 2 (resistant) K oxytoca 128+ 16 K pneumoniae 1.25-128+ 8 8 Listeria 0.08-0.32 monocytogens N gonorrhoease 0.02-0.6 N meningitidis 0.05 P mirabilis 1.25 P vulgaris 5-128+ 8 8 P aeruginosa 256+ 256 S typhi 0.25 S typhimurium 1-5 Serratia 128+ 32 32 Sh flexneri 1.25 Sh sonnei 1-10 Staph aureus 128+ 2 4 (resistant) Staph aureus 128-256+ 16 16-32 (methicillinresistant) Staph epidermidis 16-64 2 4 Staph epidermidis 128 32 (methicillinresistant)

G. REVIEW ARTICLES 1. Comprehensive reviews of ampicillin/sulbactam and its clinical use are available (Campoli-Richards & Brogden, 1987; Kerins, 1991). 4.5 THERAPEUTIC USES A. ACINETOBACTER INFECTION 1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no EFFICACY: Adult, possibly effective DOCUMENTATION: Adult, fair

2. SUMMARY: Ten intensive-care-unit patients with Acinetobacter infections resistant to many antibiotics including imipenem were treated with ampicillin/sulbactam for 5 to 28 days. All patients showed clinical

improvement; however, only 6 of the 10 patients were microbiologically cured. The dose of ampicillin/sulbactam was most commonly 3 grams every 6 to 8 hours (Urban et al, 1993). B. BONE AND JOINT INFECTIONS 1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no EFFICACY: Pediatric, possibly effective DOCUMENTATION: Pediatric, fair

2. SUMMARY:

- Ampicillin/sulbactam may be useful in the treatment of osteomyelitis or septic arthritis

3. PEDIATRIC: a. In a limited series of 9 children, parenteral ampicillin/sulbactam and oral sultamicillin (an ester of ampicillin and sulbactam) were used sequentially for the treatment of OSTEOMYELITIS and/or SEPTIC ARTHRITIS (Aronoff et al, 1986). All bacterial isolates were sensitive to ampicillin/sulbactam; all of the Staphylococcus aureus isolates and 1 of the H influenzae type b isolates were beta-lactamase producing. All patients improved clinically during the course of parenteral therapy. After follow up periods ranging from 4 to 6 months, all children were cured clinically and there was no evidence of relapse. Adverse effects were minimal. C. DIVERTICULITIS 1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no EFFICACY: Adult, possibly effective DOCUMENTATION: Adult, poor

2. SUMMARY:

- Ampicillin/sulbactam has been used in the treatment of moderate to severe cases of diverticulitis

3. ADULT: See Drug Consult DIVERTICULITIS" D. EPIGLOTTITIS 1. OVERVIEW:

reference:

"ANTIBIOTIC

THERAPY

OF

FDA APPROVAL: Adult, no; pediatric, no EFFICACY: Pediatric, effective DOCUMENTATION: Pediatric, fair

2. SUMMARY: In an open non-comparative trial, 31 children between the ages of 15 months and 7 years were admitted with the diagnosis of acute epiglottitis; 84% had H influenzae type b recovered from blood culture, and 27% of these isolates were beta-lactamase producing and resistant to ampicillin. All patients received therapy with sulbactam 30 milligrams/kilogram/day plus ampicillin 200 milligrams/kilogram/day administered by intravenous bolus four times daily. Twenty-five patients (96%) responded rapidly to treatment. Adverse effects were infrequent (Wald et al, 1986).

E. GYNECOLOGIC INFECTIONS
FDA Labeled Indication FDA APPROVAL: Adult, yes; pediatric, no EFFICACY: Adult, effective DOCUMENTATION: Adult, excellent

1. OVERVIEW:

2. SUMMARY: Several prospective randomized comparative trials have demonstrated that ampicillin/sulbactam is comparable in efficacy to cefoxitin, clindamycin/gentamicin, and metronidazole/gentamicin in the treatment of obstetric and gynecologic infections (Bruhat et al, 1986; Senft et al, 1986; Gunning, 1986; Crombleholme et al, 1986; Hemsell, 1986). 3. ADULT: a. In a review of the prospective, randomized, comparative clinical trials evaluating ampicillin/sulbactam in the treatment of polymicrobial pelvic infections, the combination of ampicillin and sulbactam was clinically effective in curing more than 90% of women treated for acute pelvic infections, with a bacteriologic efficacy of 96.6% (Hemsell, 1986). A total of 168 women in these trials received ampicillin/sulbactam for the treatment of a variety of acute pelvic infections including pelvic cellulitis after hysterectomy, endomyometritis after cesarean section, acute pelvic inflammatory disease, and postoperative wound infection. One hundred sixteen women received comparative regimens including the combinations of metronidazole/gentamicin or clindamycin/gentamicin, or monotherapy with cefoxitin. Standard approved doses were used. Three hundred fiftyeight potential pathogens were cultured from women given ampicillin/sulbactam; 346 of these pathogens (96.6%) were eradicated. In comparison, the bacteriological efficacy observed with comparative regimens was 91.5% (236/258 isolates). Clinical efficacy paralleled bacteriological efficacy; 97 of 105 evaluable women (92.4%) administered ampicillin/sulbactam were reported to be clinically cured. Women receiving comparative agents (78 of 82 evaluable cases) had a clinical cure rate of 95.1%. b. For More Information: See Drug Consult reference: "PELVIC INFLAMMATORY DISEASE - CDC GUIDELINES" F. INTRA-ABDOMINAL INFECTIONS
FDA Labeled Indication

1. OVERVIEW:

FDA APPROVAL: Adult, yes; pediatric, no EFFICACY: Adult, effective DOCUMENTATION: Adult, excellent

2. SUMMARY: Ampicillin/sulbactam is indicated for the treatment of abdominal infections caused by Escherichia coli, Klebsiella spp, Bacteroides spp, and Enterobacter spp (Prod Info Unasyn(R), 1997). 3. ADULT:

 a. The Study Group of Intra-abdominal Infections (Anon, 1986) has reported preliminary data suggesting that ampicillin/sulbactam is at least as effective as gentamicin/clindamycin in the treatment of intra-abdominal infections. One hundred twenty-three patients have been entered into this blinded, randomized comparative trial; 62 were randomized to receive ampicillin/sulbactam and 61 were randomized to receive gentamicin/clindamycin. Among the 46 assessable patients in the ampicillin/sulbactam group, 36 (78%) achieved clinical cure, 4 (9%) showed clinical improvement, and 6 (13%) showed no improvement. In comparison, 33 of the 37 patients receiving gentamicin/clindamycin achieved a clinical cure (89%), 3 patients improved (8%), and 1 patient (3%) showed no improvement. These differences were not statistically significant. b. In contrast, the combination of ampicillin/sulbactam was not reported to be as effective as clindamycin/gentamicin in the treatment of perforated appendicitis and gangrenous appendicitis (Yellin et al, 1985). Although both treatments had good anaerobic activity, including activity against Bacteroides fragilis organisms, infectious complications were seen in patients from whom pseudomonas species were isolated. Pseudomonas was found particularly in patients with perforated appendicitis and was not nosocomially acquired. Eight of 51 patients treated with ampicillin/sulbactam failed therapy, while none of 23 patients treated with clindamycin/gentamicin failed. This difference was statistically significant. Pseudomonas was isolated from 5 of 8 patients who failed treatment with ampicillin/sulbactam. The authors recommend that although the combination of clindamycin/gentamicin is less convenient to administer to the patient, it should still be considered the adjunct antibiotic management of choice for perforated or gangrenous appendicitis until further comparative data are available. G. MENINGITIS 1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no EFFICACY: Adult, effective; pediatric, effective DOCUMENTATION: Adult, good; pediatric, good

2. SUMMARY: Ampicillin/sulbactam is effective for the treatment of meningitis caused by susceptible organisms (Dutse et al, 1987; Rodriguez et al, 1986). 3. ADULT: a. Preliminary data suggest that ampicillin/sulbactam is effective in the treatment of meningitis caused by Neisseria meningitidis, pneumococci, or other susceptible organisms (Dutse et al, 1987). Sixty consecutive patients (10 to 40 years) with clinical signs and symptoms of meningitis were entered in a clinical trial during a meningitis epidemic in Nigeria. Each patient was administered ampicillin 1 gram/sulbactam 500 milligrams intramuscularly every 6 hours for a period of 5 to 10 days, depending on patient response. Fifty-six of sixty patients responded, with complete resolution of presenting

signs and symptoms. The remaining four patients presented with overwhelming sepsis and died within 6 hours of admission. No adverse effects could be attributed to the drug. 4. PEDIATRIC: a. Ampicillin/sulbactam is similar in efficacy to chloramphenicol/ampicillin in the treatment of meningitis in infants and children (Rodriguez et al, 1986). In an open randomized study, 81 patients (aged 1 month to 14 years) with meningitis were randomized to receive 10 days of therapy with either sulbactam 50 milligrams/kilogram/day plus ampicillin 400 milligrams/kilogram/day (41 patients), or chloramphenicol 100 milligrams/kilogram/day plus ampicillin 400 milligrams/kilogram/day; all medications were intravenous. Pathogens were isolated from the cerebrospinal fluid of 80% of the 81 patients. Of 63 patients who had positive cerebrospinal fluid cultures and assessable pathogens 7 (11%) died; 1 of 29 (3%) in the ampicillin/sulbactam group and 6 of 34 (18%) in the chloramphenicol/ampicillin group. Neurologic complications of meningitis were similar in both groups, with 12% in the ampicillin/sulbactam and 18% in the chloramphenicol/ampicillin group. The authors concluded that ampicillin/sulbactam was as ef fective as chloramphenicol/ampicillin in the treatment of meningitis. H. PERITONITIS 1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no EFFICACY: Adult, effective DOCUMENTATION: Adult, fair

2. SUMMARY:

- Used with an aminoglycoside for peritonitis in peritoneal-dialysis patients with success rates comparable to those with vancomycin and other antibiotic regimens

3. ADULT: a. Intraperitoneal use of ampicillin/sulbactam (A/S) 1 gram every 6 hours may provide an effective and safe alternative for treating episodes of peritonitis in chronic ambulatory peritoneal dialysis (CAPD) patients (Ersoy et al, 1998). The study evaluated 75 episodes of peritoneal-dialysis-related peritonitis in 36 CAPD patients; for comparison purposes amicacin or netilmicin were added to the regimen in 37 and 38 episodes, respectively. The overall cure rate with A/S with an aminoglycoside for treating grampositive organisms was 89% and for gram-negative organisms was 50%; this breaks down to 84% with A/S-amicacin and to 71% with A/S-netilmicin. Treatment was not successful in 17 cases (23%). Abdominal pain and discomfort resolved in all patients who had good response to treatment. I. PNEUMONIA 1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no EFFICACY: Adult, effective; pediatric, effective

DOCUMENTATION: Adult, good; pediatric, good

2. SUMMARY: Ampicillin/sulbactam is effective for the treatment of pneumonia caused by susceptible organisms (Oviasu & Obasohan, 1987; Syriopoulou et al, 1986). 3. ADULT: a. A preliminary uncontrolled trial has suggested that ampicillin/sulbactam administered intramuscularly is effective in the treatment of LOBAR PNEUMONIA (Oviasu & Obasohan, 1987). Ampicillin 1 gram plus sulbactam 500 milligrams intramuscularly was administered 3 times daily for 7 days to 20 patients with lobar pneumonia caused by a variety of organisms. Within 24 hours of initiation of therapy, temperatures fell to normal. Chest radiographs showed complete clearing of infiltrates within 14 days for 17 patients. 4. PEDIATRIC: a. The clinical efficacy of ampicillin/sulbactam in pediatric infections was evaluated (Syriopoulou et al, 1986). Twenty-three children were admitted to this open trial; 11 children had urinary tract infections, 8 had pus-forming cervical adenitis following upper respiratory tract infection, and 4 had lobar pneumonia. Seventeen children were treated with 50 milligrams sulbactam/kilogram/day plus 100 or 150 milligrams ampicillin/kilogram/day, while 6 received sulbactam (same dosage) plus 100,000 or 150,000 International Units penicillin/kilogram/day. All isolates were resistant to either ampicillin or penicillin alone. By the end of therapy, all 18 patients with initial positive cultures demonstrated eradication of the pathogen. Twentytwo of 23 children had a favorable clinical response. J. PROPHYLAXIS - GYNECOLOGIC INFECTIONS 1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no EFFICACY: Adult, effective DOCUMENTATION: Adult, good

2. SUMMARY: Ampicillin-sulbactam has significantly reduced INTRAAMNIOTIC INFECTION in pregnancies complicated by meconium-stained amniotic fluid (Adair et al, 1996). In a randomized, double-blind trial, at-risk patients with intrapartum meconium-stained amniotic fluid (n=120) received either ampicillin-sulbactam or placebo intravenously every six hours from diagnosis of meconium until delivery. The ampicillin-sulbactam combination reduced both intra-amniotic infection (23.3% versus 6.7%) and POSTPARTUM ENDOMETRITIS (16.7% versus 8.3%), although only the former difference was statistically significant. Other than a 7-day hospitalization for septic complications following cesarean delivery for arrest of descent, no adverse events were reported by patients in either group, and neonatal outcomes were unremarkable. K. SKIN AND SOFT TISSUE INFECTIONS
FDA Labeled Indication

1. OVERVIEW:

FDA APPROVAL: Adult, yes; pediatric, yes EFFICACY: Adult, effective; pediatric, effective DOCUMENTATION: Adult, excellent; pediatric, good

2. SUMMARY: Ampicillin/sulbactam has been effective in the treatment of skin and soft tissue infections. Several studies with small numbers of patients have suggested that ampicillin/sulbactam is at least as effective as clindamycin/tobramycin, or cefotaxime (Loffler et al, 1986; Stromberg et al, 1986; Nichols et al, 1985). 3. ADULT: a. Sulbactam plus either ampicillin or penicillin appears effective in treating skin and soft tissue infections. The combination of sulbactam/ampicillin or penicillin G was studied in the treatment of patients admitted with serious soft tissue infections (Nichols et al, 1985). Patients were treated intravenously at 6-hour intervals with sulbactam (0.5 to 1 gram) plus either penicillin G (0.5 to 1 gram) or ampicillin (0.5 to 1 gram). Staphylococcus aureus was the most common pathogen (48 isolations), followed by the coliforms (30 isolations); 90% of the isolates were beta-lactamase producing. Overall, 86% of the infections were either well-controlled or cured; 59% of patients showed complete remission of symptoms, while 27% showed a marked improvement. These data suggest that sulbactam plus either penicillin or ampicillin is effective in the treatment of soft tissue infections caused by penicillin-resistant and penicillin-sensitive organisms. However, since this study lacked a control group it is difficu lt to determine the relative efficacy of the addition of sulbactam. b. The combination of sulbactam and ampicillin appears to enhance bacterial susceptibility. In a prospective randomized double-blind trial, the comparable effectiveness of ampicillin/sulbactam and clindamycin plus tobramycin was reported for treatment of soft tissue infections (Stromberg et al, 1986). Sixty patients were enrolled in the trial, with 31 patients randomized to the ampicillin/sulbactam group and 29 patients randomized to the clindamycin/tobramycin group. Patients received 2 g ampicillin/1 g sulbactam every 6 hours, or 600 mg clindamycin every 6 hours plus 1.5 mg/kg tobramycin every 8 hours. Clinical cure was reported in 93% of patients receiving ampicillin/sulbactam; only 33% of patients receiving ampicillin/sulbactam had any organisms that were found on culture at the end of the study. In comparison, 81% of patients receiving clindamycin/tobramycin were considered cured, with 65% of patients showing persistent organisms at the end of therapy. This difference was statistically significant. Duration of hospital stay was also significantly different between the two groups. The addition of sulbactam to ampicillin was shown to enhance the susceptibility of bacteria to ampicillin significantly; overall, the resistance of bacteria to ampicillin was reduced from 57% to 25%. c. In an open, randomized, comparative trial involving 22 patients, the combination of sulbactam plus ampicillin was at least as effective as

cefotaxime in the initial treatment of serious soft tissue, and bone and joint, infections (Loffler et al, 1986). Larger controlled trials are needed to define the role of sulbactam plus ampicillin in therapy for bone/joint and soft tissue infections. L. SURGICAL PROPHYLAXIS DURING APPENDECTOMY 1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no EFFICACY: Pediatric, effective DOCUMENTATION: Pediatric, good

2. SUMMARY: Data from a randomized, comparative study of ampicillin/sulbactam versus metronidazole/cefotaxime suggests that ampicillin/sulbactam is at least as effective as metronidazole plus cefotaxime in preventing sepsis following appendectomy (Foster et al, 1986). Seventy-three patients between the ages of 5 and 15 years undergoing emergency appendectomy were administered either ampicillin (15 milligrams/kilogram)/sulbactam (7.5 milligrams/kilogram) intravenously or metronidazole (7.5 milligrams/kilogram) plus cefotaxime (25 milligrams/kilogram) intravenously, with the first dose administered at the time of induction of anesthesia. Single doses of antibiotic were given unless the appendix was gangrenous or perforated, in which case drugs were administered for 72 hours. The overall infection rate at 10 days to 6 weeks after appendectomy was 9% in the ampicillin/sulbactam group and 14% in the metronidazole/cefotaxime group. This difference was not significant (Foster et al, 1986). M. SURGICAL PROPHYLAXIS DURING COLORECTAL SURGERY 1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no EFFICACY: Adult, effective DOCUMENTATION: Adult, good

2. SUMMARY: Ampicillin/sulbactam appears to be at least as effective as cefoxitin in prophylaxis for COLORECTAL SURGERY. 3. ADULT: a. Ampicillin plus sulbactam or cefoxitin were compared as prophylaxis in LARGE BOWEL SURGERY. One hundred four patients were included in this open study, and were randomized to receive 4 intravenous bolus injections of ampicillin 1 gram/sulbactam 1 gram, or cefoxitin 2 grams at 6hour intervals starting with the induction of anesthesia (de la Hunt, 1986). After correcting for patients who received additional postoperative antibiotic therapy (for reasons other than wound sepsis), the corrected major woundsepsis rate was 8.3% for ampicillin/sulbactam and 10.3% for cefoxitin (not statistically significant). b. In an uncontrolled trial, ampicillin/sulbactam was administered to 21 patients undergoing colorectal surgery. Patients received an initial intravenous dose of 500 milligrams ampicillin/500 milligrams sulbactam administered at the induction of anesthesia. This was followed by 6

subsequent doses of 500 mg ampicillin/500 mg sulbactam at 8-hour intervals. No other antibiotics were given. Ampicillin/sulbactam resulted in no measurable alteration of aerobic fecal microflora. In contrast, anaerobic cocci, gram-negative rods, and bacteroides were decreased. After 2 weeks, anaerobic fecal flora normalized in all patients. All strains were susceptible to ampicillin/sulbactam (minimum inhibitory concentration 0.05 to 12.5 micrograms/milliliter). These data show that ampicillin/sulbactam prophylaxis has a greater effect on anaerobic bowel flora than on aerobic bowel flora (Kager et al, 1982). N. SURGICAL PROPHYLAXIS DURING GENITOURINARY SURGERY 1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no EFFICACY: Adult, effective DOCUMENTATION: Adult, good

2. SUMMARY: Ampicillin/sulbactam appears to be as effective as cefoxitin in preventing urinary tract infections after GENITOURINARY SURGERY (Dorflinger & Madsen, 1985). 3. ADULT: a. Ampicillin/sulbactam was compared with cefoxitin in the prevention of urinary tract infections during and following TRANSURETHRAL SURGERY (Dorflinger & Madsen, 1985). One hundred and three patients were included in this double-blind study and randomly received ampicillin 1 gram/sulbactam 0.5 gram, or cefoxitin 1 gram intramuscularly 30 to 90 minutes prior to surgery and then intravenously every 8 hours for 3 additional doses. During the first postoperative week, 4 of 52 patients treated with ampicillin/sulbactam developed urinary tract infections, compared with 2 of 51 patients in the cefoxitin group (not statistically significant). One month following surgery, 1 patient in the ampicillin/sulbactam group and 2 patients in the cefoxitin group were infected; again not statistical significance. O. SURGICAL PROPHYLAXIS DURING GYNECOLOGIC SURGERY 1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no EFFICACY: Adult, effective DOCUMENTATION: Adult, good

2. SUMMARY: Ampicillin sulbactam was as effective as ampicillin/metronidazole in preventing infections after gynecologic surgery (Houang et al, 1984). 3. ADULT: a. During a single-blind, randomized, placebo-controlled trial, a single dose of ampicillin/sulbactam reportedly reduced the incidence of early postoperative endometritis after first-trimester abortion (Krohn, 1986). Three hundred five healthy women in the first trimester of pregnancy were randomized to receive either ampicillin 1 gram plus sulbactam 0.5 gram intravenously or normal saline placebo. Within the first week after

therapeutic abortion, 4 of 145 patients (2.8%) receiving ampicillin/sulbactam and 11 of 140 patients (7.9%) receiving placebo developed endometritis; the statistical significance of this difference was not reported. b. Ampicillin/sulbactam appears to be as effective as ampicillin plus metronidazole in the prophylaxis of infection following gynecologic surgery (Houang et al, 1984). In a randomized, double-blind, placebo- controlled trial, 295 patients undergoing abdominal hysterectomy, vaginal hysterectomy, or other gynecologic surgeries received either a single dose of ampicillin 500 mg/sulbactam 500 mg after anesthesia, a single metronidazole 1 g suppository 2 hours before the operation plus ampicillin 500 mg after anesthesia, or a placebo suppository 2 hours before the operation. Although there was a statistically significant difference in the number of wound infections and febrile mortality between both treatment groups and the placebo group, there was no significant difference between the two active treatment groups. No adverse effects were reported with either treatment. P. URINARY TRACT INFECTIONS 1. OVERVIEW:
FDA APPROVAL: Adult, no; pediatric, no EFFICACY: Adult, ineffective; pediatric, ineffective DOCUMENTATION: Adult, fair; pediatric, fair

2. SUMMARY: A single dose of ampicillin/sulbactam was ineffective for the treatment of urinary tract infections in a small study of 13 women (Bailey & Peddie, 1985). 3. ADULT: a. Ampicillin/sulbactam as single-dose therapy in patients with uncomplicated urinary tract infections was reported (Bailey & Peddie, 1985). In an initial open non-comparative study, 13 women (19 to 50 years of age) with bacterial CYSTITIS received 1 gram sulbactam combined with 2 grams ampicillin administered intravenously over 15 minutes. Seven days after treatment, only 3 of 13 patients were cured (ie, sterile urine). Based on this limited data, the combination of ampicillin/sulbactam does not appear sufficiently effective as single-dose therapy of uncomplicated urinary tract infections. 4. PEDIATRIC: a. The clinical efficacy of ampicillin/sulbactam in pediatric infections was evaluated (Syriopoulou et al, 1986). Twenty-three children were admitted to this open trial; 11 children had urinary tract infections (UTI), 8 had pusforming cervical adenitis following upper respiratory tract infection, and 4 had lobar pneumonia. Seventeen children were treated with 50 mg sulbactam/kg/day plus 100 or 150 mg ampicillin/kg/day, while 6 received sulbactam (same dosage) plus 100,000 or 150,000 IU penicillin/kg/day. All isolates were resistant to either ampicillin or penicillin alone. By the end of therapy, all 18 patients with initial positive cultures demonstrated eradication of the pathogen. Twenty-two of 23 children had a favorable clinical

response; 2 patients with UTI relapsed 4 and 12 days after completion of therapy. In both relapses, the new bacterial isolate was an E coli strain resistant to ampicillin/sulbactam. 4.6 COMPARATIVE EFFICACY AND EVALUATION WITH OTHER SIMILAR THERAPEUTIC AGENTS A. AMPICILLIN 1. MENINGITIS a. Ampicillin/sulbactam has been reported to be similar in efficacy to chloramphenicol/ampicillin in the treatment of meningitis in infants and children (Rodriguez et al, 1986). In an open, randomized study, 81 patients (aged 1 month to 14 years) with meningitis were randomized to receive 10 days of therapy with either sulbactam 50 mg/kg/day plus ampicillin 400 mg/kg/day (41 patients), or chloramphenicol 100 mg/kg/day plus ampicillin 400 mg/kg/day; all medications were intravenous. Pathogens were isolated from the cerebrospinal fluid of 80% of the 81 patients. Neurologic complications of meningitis were similar in both groups, with 12% in the ampicillin/sulbactam and 18% in the chloramphenicol/ampicillin group. The authors concluded that ampicillin/sulbactam was as effective as chloramphenicol/ampicillin in the treatment of meningitis. 2. SURGICAL PROPHYLAXIS a. Ampicillin/sulbactam appears to be as effective as ampicillin plus metronidazole in the prophylaxis of infection following gynecologic surgery (Houang et al, 1984). In a randomized, double-blind, placebo-controlled trial, 295 patients undergoing abdominal hysterectomy, vaginal hysterectomy, or other gynecologic surgeries received either a single dose of ampicillin 500 mg/sulbactam 500 mg after anesthesia, a single metronidazole 1 g suppository 2 hours before the operation plus ampicillin 500 mg after anesthesia, or a placebo suppository 2 hours before the operation. Although there was a statistically significant difference in the number of wound infections and febrile mortality between both treatment groups and the placebo group, there was no significant difference between the two active treatment groups. No adverse effects were reported with either treatment. B. CEFAMANDOLE 1. LOWER RESPIRATORY TRACT INFECTION a. Seventy-five patients with community-acquired PNEUMONIA were randomized to receive either cefamandole (1 to 2 grams every 6 hours) or ampicillin/sulbactam (1.5 to 3 grams every 6 hours). The clinical cure rate was significantly higher for ampicillin/sulbactam than for cefamandole, 97% versus 81%, respectively. The most common causes of the infection were Streptococcus pneumoniae and Haemophilus parainfluenzae (Williams et al, 1994). C. CEFAZOLIN 1. SURGICAL PROPHYLAXIS

 a. Ampicillin/sulbactam was compared to cefazolin in preventing infections after biliary tract surgery. Patients randomly received 2 g ampicillin/1 g sulbactam or 1 g cefazolin intravenously after induction of surgery. Overall, the rate of infection was not significantly different between the two groups. However, in jaundiced patients, a higher incidence of wound infections occurred when cefazolin was used (Morris et al, 1989). D. CEFIXIME 1. SHIGELLOSIS a. Cefixime was found to be superior to ampicillin/sulbactam in treating shigellosis in children in one study (Helvaci et al, 1998). Both drugs were given orally for 5 days, cefixime at a dosage of 8 milligrams/kilogram once daily (n=31) and ampicillin/sulbactam at a dosage of 100 mg/kg three times daily (n=34) in a prospective, randomized, double-blind trial. Patients in the cefixime group had a shorter duration of fever and bloody stools, more rapid cessation of diarrhea, and less time hospitalized during the 5 days of treatment than those in the ampicillin/sulbactam group (p less than 0.01 in all above comparisons). E. CEFOTAXIME 1. BONE AND SOFT TISSUE INFECTIONS a. In an open, randomized, comparative trial, the combination of sulbactam plus ampicillin was at least as effective as cefotaxime in the initial treatment of serious soft tissue, and bone and joint, infections (Loffler et al, 1986). Twenty-two patients were randomized to receive ampicillin 2 g/sulbactam 1 g intravenously 3 times daily, or cefotaxime 2 g intranveously 3 times daily for 2 weeks. Two weeks after the completion of therapy, clinical cure or improvement was observed in 13 of 13 patients treated with sulbactam and 7 of 9 patients treated with cefotaxime. 2. SURGICAL PROPHYLAXIS a. The combination of sulbactam and ampicillin appears suitable for prophylaxis in appendicitis in children. The combination was compared with that of metronidazole and cefotaxime as prophylaxis against postoperative wound infection in children undergoing emergency appendectomy (Foster et al, 1986). Patients randomly received either sulbactam 7.5 mg/kg plus ampicillin 15 mg/kg, or metronidazole 7.5 mg/kg plus cefotaxime 25 mg/kg; the first dose was administered intravenously prior to surgery, and if the appendix was felt to be perforated or gangrenous, the combinations were continued for a further 72 hours (every eight hours) for metronidazole/cefotaxime and every six hours for sulbactam/ampicillin). Of 51 children assigned to receive sulbactam and ampicillin, 19 were given the 72-hour course; 20 of 49 children receiving metronidazole/cefotaxime were given the 72-hour course. F. CEFOXITIN 1. GYNECOLOGIC INFECTIONS

 a. In a review of the prospective, randomized, comparative clinical trials evaluating ampicillin/sulbactam in the treatment of polymicrobial pelvic infections, the combination of ampicillin 2 g and sulbactam 1 g coadministered intravenously was clinically effective in curing more than 90% of women treated for acute pelvic infections, with a bacteriologic efficacy of 96.6% (Hemsell, 1986). A total of 168 women in these trials received ampicillin/sulbactam for the treatment of a variety of acute pelvic infections including pelvic cellulitis after hysterectomy, endomyometritis after cesarean section, acute pelvic inflammatory disease, and postoperative wound infection. One hundred sixteen women received comparative regimens including the combinations of metronidazole/gentamicin or clindamycin/gentamicin, or monotherapy with cefoxitin. Three hundred fiftyeight potential pathogens were cultured from women given ampicillin/sulbactam; 346 of these pathogens (96.6%) were eradicated. In comparison, the bacteriological efficacy observed with comparative regimens was 91.5% (236/258 isolates). Clinical efficacy paralleled bacteriological efficacy; ninety-seven of 105 evaluable women (92.4%) administered ampicillin/sulbactam were reported to be clinically cured. Women receiving comparative agents (78 of 82 evaluable cases) had a clinical cure rate of 95.1%. Adverse reactions were similar with ampicillin/sulbactam and comparative regimens, and no serious reactions were observed for any of the regimens. Skin disorders were the most frequent adverse reaction with ampicillin/sulbactam (4.8%), while gastrointestinal disorders were the most frequent with the comparative regimens (15.5%). The overall incidence of reactions was 13.1% and 12.1% with ampicillin/sulbactam and comparative regimens, respectively. 2. ABDOMINAL INFECTION a. A cost analysis comparing the beta-lactamase-inhibitor ampicillin/sulbactam and the broad-spectrum cephalosporin cefoxitin that included as outcome measures costs of nosocomial infections, adverse drug events, and treatment failures as well as clinical cure and failure reported an approximately 9% greater failure frequency with cefoxitin, which although not significant increased its cost of treatment (Messick et al, 1998). This retrospective analysis covered 196 evaluable patients from various institutions who, as part of a prospective, randomized, double-blind clinical trial, received either ampicillin/sulbactam 3 grams or cefoxitin 2 grams intravenously every 6 hours for intra-abdominal infections. Costs of drug acquisition were based on 1997 costs specific to each institution and, when only those costs were considered, potential savings of $37 per patient could be realized by using ampicillin/sulbactam rather than cefoxitin. When considering all outcomes of interest, potential cost savings from use of ampicillin/sulbactam rather than cefoxitin totaled $890 per patient. Given assumptions of the Monte Carlo model, this analysis predicted with 78%

certainty that use of ampicillin/sulbactam will be less expensive than use of cefoxitin. b. When ampicillin/sulbactam 3 g every 6 hours were compared to cefoxitin 2 g every 6 hours in a randomized double-blind trial of 197 surgical patients with abdominal infections, effects were similar. The clinical and microbiological cure rate for patients receiving ampicillin/sulbactam were 86% and 85%, respectively. For patients receiving cefoxitin the rate of clinical and microbiological cure was 78% and 83%, respectively. These differences were not statistically significant. Adverse effects were similar between the 2 groups (Walker et al, 1993). 3. SOFT TISSUE INFECTIONS a. Ampicillin/sulbactam and cefoxitin were equally safe and effective for treating CUTANEOUS and other SOFT TISSUE INFECTIONS in patients with or without a history of injection drug abuse. In a randomized, doubleblind study, ampicillin/sulbactam 2 grams/1 gram or cefoxitin 2 grams were administered intravenously every 6 hours for at least 3 days. At the end of therapy, 44 of 49 (90%) patients treated with ampicillin/sulbactam and 44 of 47 (94%) of patients treated with cefoxitin were cured or had improvement in their clinical condition (not statistically different). Median time to complete resolution of clinical symptoms was 10.5 days for ampicillin/sulbactam treatment and 15.5 days for cefoxitin (not statistically different). All pathogens were eradicated in 100% of evaluable patients treated with ampicillin/sulbactam and 96.2% of evaluable treated with cefoxitin (not different). Although pathogen profiles were somewhat different for drug users and nonusers, efficacy of either drug was not affected by the history of drug abuse (Talan et al, 2000). 4. SURGICAL PROPHYLAXIS a. Sulbactam plus ampicillin appears to be an effective and safe alternative to cefoxitin for prophylaxis in colorectal surgery; however, 24-hour prophylaxis appears to be inadequate in stoma patients. When four intravenous bolus infections of ampicillin 1 g plus sulbactam 1 g were compared with cefoxitin 2 g at 6-h intervals starting with anesthesia as prophylaxis in large bowel surgery, there were no significant differences between the 2 groups for risk factors preoperatively or operatively (de la Hunt et al, 1986). No serious side effects were recorded in either group; candidiasis was reported in 3 sulbactam patients and 2 cefoxitin patients. b. Ampicillin/sulbactam appears to be as effective as cefoxitin in the preventing urinary tract infections after transurethral surgery. Ampicillin/sulbactam was compared with cefoxitin in the prevention of urinary tract infections during and following transurethral surgery (Dorflinger & Madsen, 1985). During the first postoperative week, 4 of 52 patients treated with ampicillin/sulbactam developed urinary tract infections, compared with 2 of 51 patients in the cefoxitin group (not statistically significant). One month following surgery, 1 patient in the

ampicillin/sulbactam group and 2 patients in the cefoxitin group were infected; again no statistical significance. c. During a single-blind, randomized, placebo-controlled trial, a single dose of ampicillin/sulbactam reportedly reduced the incidence of early postoperative endometritis after first-trimester abortion (Krohn, 1986). Within the first week after therapeutic abortion, 4 of 145 patients (2.8%) receiving ampicillin/sulbactam and 11 of 140 patients (7.9%) receiving placebo developed endometritis; the statistical significance of this difference was not reported. d. When cefoxitin 2 g was compared to ampicillin-sulbactam 3 g for prophylaxis in abdominal surgery patients considered to be high risk, the authors concluded that both regimens were efficacious (Paladino et al, 1994). From an economic perspective, the authors concluded that the drug with the lowest acquisition cost should be used since the incidental costs for both regimens was the same. G. CEFUROXIME 1. SKIN INFECTION a. Ampicillin/sulbactam demonstrated efficacy comparable to that of cefuroxime in the treatment of pediatric skin infections. Pediatric patients (n=234) requiring hospitalization for the treatment of skin and/or skinstructure infections were studied in a randomized, multi-center, comparative, open-label trial. One hundred fifty-four patients received intravenous ampicillin/sulbactam 150 to 300 milligrams/kilogram/day (mg/kg/day) in 4 equally-divided daily doses, while 80 patients were treated with equally divided, 3-times or 4-times daily doses of intravenous or intramuscular cefuroxime 50 to 100 mg/kg/day. The maximum treatment duration was not to exceed 14 days; patients were subsequently discharged from the hospital, and could be provided with oral anti-microbial therapy at the discretion of their physician. Clinical and bacteriologic efficacies were evaluated following the conclusion of parenteral therapy, oral therapy (if warranted), and 14 days following the last administered treatment dose. Ampicillin/sulbactam was found to eradicate 95.5% of recovered pathogens, compared with 98.1% eradication by cefuroxime. There were no significant differences between clinical efficacies of the two study drugs at the end of the evaluation periods, nor were significant differences found in bacteriologic efficacy. Ampicillin/sulbactam and cefuroxime were both found to be clinically effective in pathogen eradication, including those microorganisms testing positive for beta- lactamase activity. Both ampicillin/sulbactam and cefuroxime were well-tolerated, with the most common adverse events comprising diarrhea, nausea/vomiting and rash (Azimi et al, 1999). H. CHLORAMPHENICOL 1. MENINGITIS

 a. Ampicillin/sulbactam is reported to be similar in efficacy to chloramphenicol/ampicillin in the treatment of meningitis in (Rodriguez et al, 1986). infants and children In an open, randomized study, 81 patients (aged 1 month to 14 years) with meningitis were randomized to receive 10 days of therapy with either sulbactam 50 mg/kg/day plus ampicillin 400 mg/kg/day (41 patients), or chloramphenicol 100 mg/kg/day plus ampicillin 400 mg/kg/day; all medications were intravenous. Pathogens were isolated from the cerebrospinal fluid of 80% of the 81 patients. Of 63 patients who had positive cerebrospinal fluid cultures and assessable pathogens 7 (11%) died; 1 of 29 (3%) in the ampicillin/sulbactam group and 6 of 34 (18%) in the chloramphenicol/ampicillin group. Neurologic complications of meningitis were similar in both groups, with 12% in the ampicillin/sulbactam and 18% in the chloramphenicol/ampicillin group. The authors concluded that ampicillin/sulbactam was as effective as chloramphenicol/ampicillin in the treatment of meningitis. I. CLINDAMYCIN 1. GYNECOLOGIC INFECTIONS a. In a review of the prospective, randomized, comparative clinical trials evaluating ampicillin/sulbactam in the treatment of polymicrobial pelvic infections, the combination of ampicillin and sulbactam was clinically effective in curing more than 90% of women treated for acute pelvic infections, with a bacteriologic efficacy of 96.6% (Hemsell, 1986). A total of 168 women in these trials received ampicillin/sulbactam for the treatment of a variety of acute pelvic infections including pelvic cellulitis after hysterectomy, endomyometritis after cesarean section, acute pelvic inflammatory disease, and postoperative wound infection. One hundred sixteen women received comparative regimens including the combinations of metronidazole/gentamicin or clindamycin/gentamicin, or monotherapy with cefoxitin. Three hundred fifty-eight potential pathogens were cultured from women given ampicillin/sulbactam; 346 of these pathogens (96.6%) were eradicated. In comparison, the bacteriological efficacy observed with comparative regimens was 91.5% (236/258 isolates). Clinical efficacy paralleled bacteriological efficacy; ninety-seven of 105 evaluable women (92.4%) administered ampicillin/sulbactam were reported to be clinically cured. Women receiving comparative agents (78 of 82 evaluable cases) had a clinical cure rate of 95.1%. Adverse reactions were similar with ampicillin/sulbactam and comparative regimens, and no serious reactions were observed for any of the regimens. Skin disorders were the most frequent adverse reaction with ampicillin/sulbactam (4.8%), while gastrointestinal disorders were the most frequent with the comparative regimens (15.5%). The overall incidence of reactions was 13.1% and 12.1% with ampicillin/sulbactam and comparative regimens, respectively. 2. ENDOMYOMETRITIS

 a. Ampicillin/sulbactam (2 g/1 g intravenously every 6 hours) was found to be equally efficacious compared to clindamycin (900 mg intravenously every 8 hours) in the treatment of postpartum endometritis. Cure rates were 83% and 88% respectively (Martens et al, 1990). b. Similarly, ampicillin/sulbactam 2 g/1 g intravenously every 6 hours was as effective as the traditional clindamycin/gentamicin 900 mg/1.5 mg/kg intravenously every 8 hours for treating postpartum endometritis (Gall & Koukol, 1996). Clinical cures were reported to be 82% for ampicillin/sulbactam and 84% for clinadmycin/gentamicin; bacterial eradication rates were 86% and 84%, respectively. 3. INTRA-ABDOMINAL INFECTIONS a. The Study Group of Intra-abdominal Infections (Anon, 1986) has reported data suggesting that ampicillin/sulbactam is at least as effective as gentamicin/clindamycin in the treatment of intra-abdominal infections. One hundred twenty-three patients have been entered into this blinded, randomized, comparative trial. Among the 46 assessable patients in the ampicillin/sulbactam group, 36 (78%) achieved clinical cure, 4 (9%) showed clinical improvement, and 6 (13%) showed no improvement. In comparison, 33 of the 37 patients receiving gentamicin/clindamycin achieved a clinical cure (89%), 3 patients improved (8%), and 1 patient (3%) showed no improvement. These differences were not statistically significant. b. In contrast, the combination of ampicillin/sulbactam was not as effective as clindamycin plus gentamicin in the treatment of perforated appendicitis and gangrenous appendicitis (Yellin et al, 1985). Although both treatments had good anaerobic activity, including activity against Bacteroides fragilis organisms, infectious complications were seen in patients from whom pseudomonas species were isolated. Pseudomonas was found particularly in patients with perforated appendicitis and was not nosocomially acquired. Eight of 51 patients treated with ampicillin/sulbactam failed therapy, while none of 23 patients treated with clindamycin/gentamicin failed. This difference was statistically significant. Pseudomonas was isolated from 5 of 8 patients who failed treatment with ampicillin/sulbactam. The authors recommend that although the combination of clindamycin plus gentamicin is less convenient to administer to the patient, it should still be considered the adjunct antibiotic management of choice for perforated or gangrenous appendicitis until further comparative data are available. 4. SOFT TISSUE INFECTIONS a. The combination of sulbactam and ampicillin appears to enhance bacterial susceptibility. In a prospective randomized double-blind trial, ampicillin/sulbactam was compared to clindamycin plus tobramycin in the treatment of soft tissue infections (Stromberg et al, 1986). Sixty patients were enrolled in the trial, with 31 patients randomized to the ampicillin/sulbactam group and 29 patients randomized to the clindamycin/tobramycin group. Clinical cure was defined as eradication of

organisms and complete resolution of clinical signs of infection, while improvement was defined as clinical resolution of signs of infection but with some persistent organisms. Clinical cure was reported in 93% of patients receiving ampicillin/sulbactam; only 33% of patients receiving ampicillin/sulbactam had any culturable organisms at the end of the study. In comparison, 81% of patients receiving clindamycin/tobramycin were considered cured, with 65% of patients showing persistent organisms at the end of therapy. This difference was statistically significant. Duration of hospital stay was also significantly different between the 2 groups. The addition of sulbactam to ampicillin was shown to enhance the susceptibility of bacteria to ampicillin significantly; overall, the resistance of bacteria to ampicillin was reduced from 57% to 25%. Staphylococcus aureus, K pneumoniae, Acinetobacter anitratus, Citrobacter freundii, and Cornebacterium were the organisms demonstrating the most markedly enhanced susceptibility to ampicillin when sulbactam was added. J. GENTAMICIN 1. INTRA-ABDOMINAL INFECTIONS a. The Study Group of Intra-abdominal Infections (Anon, 1986) has reported data suggesting that ampicillin/sulbactam is at least as effective as gentamicin/clindamycin in the treatment of intra-abdominal infections. One hundred twenty-three patients have been entered into this blinded, randomized, comparative trial. Among the 46 assessable patients in the ampicillin/sulbactam group, 36 (78%) achieved clinical cure, 4 (9%) showed clinical improvement, and 6 (13%) showed no improvement. In comparison, 33 of the 37 patients receiving gentamicin/clindamycin achieved a clinical cure (89%), 3 patients improved (8%), and 1 patient (3%) showed no improvement. These differences were not statistically significant. b. In contrast, the combination of ampicillin/sulbactam was not as effective as clindamycin plus gentamicin in the treatment of perforated appendicitis and gangrenous appendicitis (Yellin et al, 1985). Although both treatments had good anaerobic activity, including activity against Bacteroides fragilis organisms, infectious complications were seen in patients from whom pseudomonas species were isolated. Pseudomonas was found particularly in patients with perforated appendicitis and was not nosocomially acquired. Eight of 51 patients treated with ampicillin/sulbactam failed therapy, while none of 23 patients treated with clindamycin/gentamicin failed. This difference was statistically significant. Pseudomonas was isolated from 5 of 8 patients who failed treatment with ampicillin/sulbactam. The authors recommend that although the combination of clindamycin plus gentamicin is less convenient to administer to the patient, it should still be considered the adjunct antibiotic management of choice for perforated or gangrenous appendicitis until further comparative data are available. 2. GYNECOLOGIC INFECTIONS

 a. In a review of the prospective, randomized, comparative clinical trials evaluating ampicillin/sulbactam in the treatment of polymicrobial pelvic infections, the combination of ampicillin and sulbactam was clinically effective in curing more than 90% of women treated for acute pelvic infections, with a bacteriologic efficacy of 96.6% (Hemsell, 1986). A total of 168 women in these trials received ampicillin/sulbactam for the treatment of a variety of acute pelvic infections including pelvic cellulitis after hysterectomy, endomyometritis after cesarean section, acute pelvic inflammatory disease, and postoperative wound infection. One hundred sixteen women received comparative regimens including the combinations of metronidazole/gentamicin or clindamycin/gentamicin, or monotherapy with cefoxitin. Three hundred fifty-eight potential pathogens were cultured from women given ampicillin/sulbactam; 346 of these pathogens (96.6%) were eradicated. In comparison, the bacteriological efficacy observed with comparative regimens was 91.5% (236 of 258 isolates). Clinical efficacy paralleled bacteriological efficacy; ninety-seven of 105 evaluable women (92.4%) administered ampicillin/sulbactam were reported to be clinically cured. Women receiving comparative agents (78 of 82 evaluable cases) had a clinical cure rate of 95.1%. Adverse reactions were similar with ampicillin/sulbactam and comparative regimens, and no serious reactions were observed for any of the regimens. Skin disorders were the most frequent adverse reaction with ampicillin/sulbactam (4.8%), while gastrointestinal disorders were the most frequent with the comparative regimens (15.5%). The overall incidence of reactions was 13.1% and 12.1% with ampicillin/sulbactam and comparative regimens, respectively. K. IMIPENEM/CILASTATIN 1. DIABETIC FOOT INFECTION a. Ninety-six limb-threatening diabetic foot infections were treated with either imipenem/cilastatin (500 mg every 6 hours) or ampicillin/sulbactam (3 grams every 6 hours) with similar rates of clinical and microbiological cures. This well-designed study compared empiric treatment with either ampicillin/sulbactam or imipenem/cilastatin in combination with surgical debridement or amputation when necessary. The doses of antibiotic were adjusted in patients with renal dysfunction. Clinical cure occurred in 81% of patients receiving ampicillin/sulbactam and 85% of patients receiving imipenem/cilastatin. Microbiological cure rates were not significantly different with eradication occurring in 67% of patients receiving ampicillin/sulbactam and 75% of patients receiving imipenem/cilastatin. Adverse effects were also similar between the 2 groups (Grayson et al, 1994). A retrospective economic analysis of this trial revealed that mean per patient treatment costs were lower in the ampicillin/sulbactam group than in the imipenem/cilastatin group, mainly owing to lower drug and hospitalization costs and less-severe adverse effects in the former group (McKinnon et al, 1997).

L. METRONIDAZOLE 1. APPENDECTOMY a. The combination of sulbactam and ampicillin appears suitable for prophylaxis in appendicitis in children (Foster et al, 1986). The combination was compared with that of metronidazole and cefotaxime as prophylaxis against postoperative wound infection in children undergoing emergency appendectomy. Patients randomly received either sulbactam 7.5 mg/kg plus ampicillin 15 mg/kg, or metronidazole 7.5 mg/kg plus cefotaxime 25 mg/kg; the first dose was administered IV prior to surgery, and if the appendix was felt to be perforated or gangrenous, the combinations were continued for a further 72 hours (every 8 hours or metronidazole/cefotaxime and every 6 hours for sulbactam/ampicillin). Of 51 children assigned to receive sulbactam and ampicillin, 19 were given the 72-hour course; 20 of 49 children receiving metronidazole/cefotaxime were given the 72-hour course. 2. GYNECOLOGIC INFECTIONS a. In a review of the prospective, randomized, comparative clinical trials evaluating ampicillin/sulbactam in the treatment of polymicrobial pelvic infections, the combination of ampicillin and sulbactam was clinically effective in curing more than 90% of 168 women treated for acute pelvic infections, with a bacteriologic efficacy of 96.6% (Hemsell, 1986). The overall incidence of adverse effects was comparable to other regimens. 3. SURGICAL PROPHYLAXIS a. Ampicillin/sulbactam appears to be as effective as ampicillin plus metronidazole in the prophylaxis of infection following gynecologic surgery (Houang et al, 1984). In a randomized, double-blind, placebo-controlled trial, 295 patients undergoing abdominal hysterectomy, vaginal hysterectomy, or other gynecologic surgeries received either a single dose of ampicillin 500 mg/sulbactam 500 mg after anesthesia, a single metronidazole 1 g suppository 2 hours before the operation plus ampicillin 500 mg after anesthesia, or a placebo suppository 2 hours before the operation. Although there was a statistically significant difference in the number of wound infections and febrile mortality between both treatment groups and the placebo group, there was no significant difference between the two active treatment groups. No adverse effects were reported with either treatment. b. Data from a randomized, comparative study of ampicillin/sulbactam versus metronidazole plus cefotaxime suggests that ampicillin/sulbactam is at least as effective as metronidazole plus cefotaxime in preventing sepsis following appendectomy (Foster et al, 1986). Seventy-three patients between the ages of 5 and 15 years undergoing emergency appendectomy were administered either ampicillin (15 mg/kg)/sulbactam (7.5 mg/kg) intravenously or metronidazole (7.5 mg/kg) plus cefotaxime (25 mg/kg) intravenously, with the first dose administered at the time of induction of anesthesia. Single doses of antibiotic were given unless the appendix was gangrenous or perforated, in which case drugs were administered for 72

hours. The overall infection rate at 10 days to 6 weeks after appendectomy was 9% in the ampicillin/sulbactam group and 14% in the metronidazole/cefotaxime group. This difference was not significant (Foster et al, 1986). M. TOBRAMYCIN 1. SOFT TISSUE INFECTIONS a. The combination of sulbactam and ampicillin appears to enhance bacterial susceptibility. In a prospective randomized double-blind trial, the comparable effectiveness of ampicillin/sulbactam and clindamycin plus tobramycin was reported for treatment of soft tissue infections (Stromberg et al, 1986). Sixty patients were enrolled in the trial, with 31 patients randomized to the ampicillin/sulbactam group and 29 patients randomized to the clindamycin/tobramycin group. Patients received 2 g ampicillin/1 g sulbactam every 6 hours, or 600 mg clindamycin every 6 hours plus 1.5 mg/kg tobramycin every 8 hours. Clinical cure was reported in 93% of patients receiving ampicillin/sulbactam; only 33% of patients receiving ampicillin/sulbactam had any culturable organisms at the end of the study. In comparison, 81% of patients receiving clindamycin/tobramycin were considered cured, with 65% of patients showing persistent organisms at the end of therapy. This difference was statistically significant. Duration of hospital stay was also significanly different between the two groups. The addition of sulbactam to ampicillin was shown to enhance the susceptibility of bacteria to ampicillin significantly (p less than 0.01); overall, the resistance of bacteria to ampicillin was reduced from 57% to 25%. 6.0 REFERENCES 1. Adair CD, Ernest JM, Sanchez-Ramos L et al: Meconium-stained amniotic fluid-associated infectious morbidity: a randomized, double-blind trial of ampicillin-sulbactam prophylaxis. Obstet Gynecol 1996; 88:216-220. 2. Akinwande K, Hales-McDonald R, Frederick E et al: Ampicillin/sulbactam: efficacy and cost comparison of 1.5- and 3-gram doses. Formulary 1998; 33(4):369-376. 3. Ali HM: Reduced ampicillin bioavailability following oral coadministration with chloroquine. J Antimicrob Chemother 1985; 15:781-784. 4. Anon: A randomized controlled trial of ampicillin plus sulbactam vs gentamicin plus clindamycin in the treatment of intraabdominal infections: a preliminary report. Study Group of Intraabdominal Infections. Rev Infect Dis 1986; 8(suppl 5):S583-S588. 5. Anon: Boston Collaborative Drug Surveillance Program: excess of ampicillin rashes associated with allopurinol or hyperuricemia. N Engl J Med 1972; 286:505. 6. Anon: Excess of amphicillin rashes associated with allopurinol or hyperuricemia. N Engl J Med 1972; 386:505-507. 7. Anon: Salmonella infections. Med Lett Drugs Ther 1968; 10:50.

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Original publication: 03/1987 Most recent revision: 03/2004 List of contributors: 1. DRUGDEX(R) Editorial Staff For further information on contributing authors, see editorial board listings.

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