Infect Dis Clin N Am 18 (2004) 513531

Antibacterial agents in pediatrics

Karen L. Bowlware, MD, Terrence Stull, MD*
Division of Pediatric Infectious Diseases, Department of Pediatrics, The University of Oklahoma Health Sciences Center, 940 NE 13th Street, Room 2B2308, Oklahoma City, OK 73104, USA

This article focuses on antibacterial agents used in children. Antibiotics are among the most widely prescribed therapeutic agents among pediatrics patients, and otitis media is the most common diagnosis leading to antibiotic prescriptions [1]. Because of the crisis of antibiotic resistance in the United States and the resultant promotion of judicious use of antibiotics, the number of prescriptions for antibiotics in the pediatric population has decreased [1,2]. In addition, recent legislation addressing Food and Drug Administration (FDA) approved clinical trials will ensure development of information about the use of new medications in children. It is hoped that these trends will reduce the emergence of resistant organisms and lead to more precise use of anti-infective agents for pediatrics. This article provides insight into specic applications of antibacterial agents in children. The rst section focuses on the principles of pharmacokinetics and pharmacodynamics among the pediatric population. Subsequently, the most commonly used antibacterial agents in pediatrics are discussed. Pharmacokinetics and pharmacodynamics in pediatrics Pharmacokinetics and pharmacodynamics of certain antibacterial agents are key in determining ecacy of selected agents. They must be taken into consideration when choosing agents, especially in pediatric patients. Pharmacokinetics describes the absorption, distribution, and elimination of a certain agent. Pharmacodynamics describes the eects, activity, or toxicity of the agent within the body. Factors aecting these parameters include gestational and chronologic age, underlying disease, drug interactions, and tissue distribution. In addition, the principals of bactericidal activity may determine when certain antibacterial agents are eective. Two
* Corresponding author. E-mail address: terrence-stull@ouhsc.edu (T. Stull). 0891-5520/04/$ - see front matter 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.idc.2004.04.009

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patterns of bactericidal activity exist. Bacterial killing by such antibiotics as aminoglycosides and uoroquinolones is concentration-dependent (ie, higher drug concentration leads to a greater rate and extent of bacterial killing). Such antibiotics as b-lactams, vancomycin, clindamycin, and macrolides demonstrate time-dependent killing (ie, longer time with the drug concentration above the minimum inhibitory concentration (MIC) of the target organism increases bacterial killing) [3]. Age-related factors The wide variability of ages and dierent stages of development among pediatric patients are associated with marked variability in the pharmacokinetics and pharmacodynamics of antibiotics. Developmental changes in hepatic and renal function result in variability in drug metabolism. Similarly, dierences in body water content and body surface area result in variability in volume of distribution [4]. The newborn period is an excellent example of the eect of these dierences when dosing certain antibacterial agents (Table 1). Because of the immaturity of hepatic enzyme expression at birth, bilirubin excretion is reduced, resulting in elevated concentrations of unconjugated serum bilirubin in newborns. Excess unconjugated bilirubin can result in kernicterus. Certain antibacterial agents (eg, ceftriaxone and sulfonamides) can exacerbate the increased levels by displacing bilirubin from albumin. Because of the risk of bilirubin encephalopathy, or kernicterus, with increased unconjugated bilirubin concentrations, these agents should be avoided in newborns. In addition to hepatic immaturity during the newborn period, kidney function is also relatively reduced. Reduced glomerular ltration and tubular secretion profoundly aect the clearance of certain antibiotic agents. b-Lactams, vancomycin, and aminoglycosides are examples of such agents and require adjustments in dose and frequency of administration. Monitoring of renal function and serum drug concentrations is frequently indicated. Underlying illnesses Certain chronic conditions may aect the pharmacokinetics and pharmacodynamics of an agent. For example, patients with cystic brosis have an increased volume of distribution and more rapid elimination of antibiotics commonly used in this disease. b-Lactams, aminoglycosides, and quinolones all demonstrate altered pharmacokinetics in these patients, compared with patients without cystic brosis (Table 2). Drug interactions Coadministration of certain drugs with antibiotics may alter levels of one or both agents. For example, macrolides compete with theophylline for

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Table 1 Dosages of common antibiotics in newborn period Body weight \2000 g Antibiotics Ampicillin Augmentin Cefazolin Cefotaxime Ceftazidime Meropenem Nafcillin, oxacillin Penicillin G Procaine Penicillin G Clindamycin Routes of Administration IV, PO IV, IV, IV, IV IV IV IM IM IM IM 07 days old 100 div q 12 h 40 div q 12 h 100 div q 12 h 100 div q 12 h 40 div q 12 h 50 div q 12 h 100,000 U div q 12 h 50,000 U q 24 h 10 div q 12 h 828 days old 150 div q 8 h 40 div q 12 h 150 div q 8 h 150 div q 8 h 60 div q 8 h 75 div q 8 h 225,000 U div q8h 50,000 U q 24 h 15 div q 8 h Body weight > 2000 g 07 days old 150 div q 8 h 30 div q 12 h 40 div q 12 h 100 div q 12 h 100 div q 12 h 40 div q 12 h 75 div q 8 h 150,000 U div q8h 50,000 U q 24 h 15 div q 8 h 828 days old 200 div q 6 h 30 div q 12 h 60 div q 8 h 150 div q 8 h 150 div q 8 h 60 div q 8 h 150 div q 6 h 200,000 U div q6h 50,000 U q 24 h 20 div q 6 h >28 days old 200 div q 6 h 30 div q 12 h 60 div q 8 h 200 div q 6 h 150 div q 8 h 60 div q 8 h 150 div q 6 h 200,000 U div q6h 50,000 U q 24 h 30 div q 6 h

IM IV, IM, PO

Abbreviations: Div, divided; IM, intramuscular; IV, intravenous; PO, orally. Dosages are in milligrams per kilograms per day. Data from Bradley JS, Nelson JD. Nelsons pocket book of pediatric antimicrobial therapy. 15th edition. Philadelphia: Lippincott, Williams and Wilkins; 20022003. p. 18.

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Table 2 Gentamicin pharmacokinetics in patients with and without cystic brosis Patients with cystic brosis Creatinine clearance (mL/min/1.73 m2) Half-life (hours) Volume of distribution (L/kg) Total clearance (mL/min/1.73 m2) Recommended dose 133.5 1.62 0.15 0.339 0.030a 73.8 4.09a 710 mg/kg/d Patients without cystic brosis 131.4 1.98 0.235 40.6 37.5 13.6 0.27 0.016 4.74 mg/kg/d

Data from Kearns GL, Hilman BC, Wilson JT. Dosing implications of altered gentamicin disposition in patients with cystic brosis. J Pediatr 1982;100:3128. a Signicantly dierent between patients with and without cystic brosis.

hepatic metabolism resulting in increased theophylline levels and potential toxicity. They also have been shown to reduce the excretion of carbamazepine, cyclosporine, warfarin, and protease inhibitors [5]. Specic toxicities in children Because of the demonstrable eects of delayed bone growth and teeth staining by tetracyclines in young children, these agents are usually restricted for use in children less than 8 years of age. Even so, a tetracycline may be used when treating Rocky Mountain spotted fever or ehrlichiosis at any age in children because of the relative ecacy of tetracyclines against these pathogens [6]. Because the previously stated eects are dose-dependent and cumulative, signicant toxicity from treating tick-borne infections with these agents is unlikely. Among the tetracyclines, doxycycline is not as avidly bound to calcium and is the preferred agent in pediatrics.

b-Lactam antibiotics The b-lactam antibiotics are an integral part of the armamentarium against pediatric infections. Overall, these agents are well tolerated, safe, and ecacious against most bacterial agents pediatricians encounter in their patients. Penicillins Penicillins remain the drug of choice in many pediatric infections. Increasing resistance has limited the use of natural penicillins. The development of extended-spectrum penicillins, penicillinase-resistant derivatives, and combinations of penicillins with b-lactamase inhibitors has allowed the continued broad use of penicillins. Penicillin G and penicillin V remain rst-line therapy for infections caused by susceptible streptococci, including group A streptococcal pharyngitis. In addition, the natural penicillins are the drugs of choice in syphilis, meningococcal, Listeria, and neonatal group B streptococcal infections.

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Staphylococci, such as Staphylococcus aureus, have developed resistance to the natural penicillins by the production of penicillinase. By modifying the b-lactam ring through an addition of an acyl side chain, semisynthetic penicillins have been constructed that are resistant to disruption by penicillinase. These penicillinase-resistant agents include oxacillin, nafcillin, dicloxacillin, and methicillin. Certain factors limit the use of these agents. For instance, methicillin (not available in the United States) is rarely used because of its association with interstitial nephritis [7]. Dicloxacillin has excellent bioavailability as an oral agent, but is poorly palatable. The emergence of methicillin-resistant S aureus (MRSA), which is also resistant to the other semisynthetic penicillins, has also limited the use of these agents. Initially, limitations were in empiric therapy for nosocomial-acquired S aureus. Recently, however, many geographic areas are reporting increasing methicillin-resistance in their community-acquired S aureus isolates [8,9]. These factors must be taken into account when initiating empiric antistaphylococcal therapy. Coagulase-negative staphylococci, major pathogens in neonatal intensive care units, are also predominantly resistant to these agents. The aminopenicillins (ampicillin and amoxicillin) were developed as extended-spectrum agents with activity against gram-negative bacteria and enterococci. Initially, they were active against many gram-negative strains of bacteria including Escherichia coli, Proteus spp, Salmonella, and b-lactamasenegative Haemophilus inuenzae. Because of changes in susceptibility patterns in many geographic regions, however, aminopenicillins are no longer the drugs of choice for infections caused by many of these organisms. For example, ampicillin may no longer be appropriate rst-line therapy for Salmonella gastroenteritis or E coli urinary tract infection unless the susceptibility pattern of the organism indicates otherwise. Streptococcus pneumoniae, the most common etiologic agent of otitis media, is an important example of the development of bacterial resistance to penicillin. Through production of penicillin-binding proteins with decreased anity for penicillins, resistance of many strains of S pneumoniae has progressively increased. Because the mutations in the penicillin-binding proteins may result in only modestly reduced susceptibility, however, higher doses of aminopenicillins result in serum concentrations that exceed the MIC for a greater portion of the dosing interval, allowing eective killing [10]. For example, dosing amoxicillin at 80 to 100 mg/kg/d divided twice daily instead of 40 mg/kg/d is more ecacious when treating an otitis media or sinusitis secondary to penicillin-nonsusceptible S pneumoniae. Amoxicillin has better bioavailability compared with oral ampicillin and is the drug of choice when an oral aminopenicillin is indicated. Because of its superior absorption and more convenient twice daily dosing, many physicians use amoxicillin rather than oral penicillin in such situations as group A streptococcal pharyngitis or prevention of bacterial endocarditis associated with high-risk procedures (eg, certain dental procedures).

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With aminopenicillins as the prototypical extended-spectrum penicillin, other extended-spectrum groups were developed. These include the carboxypenicillins and ureidopenicillins. Side eects unique to these two groups include hypokalemia and hypernatremia. The principal role of these drugs in pediatrics is treating infections caused by Pseudomonas aeruginosa. The carboxypenicillins consist of carbenicillin (not available in the United States) and ticarcillin. Carbenicillin was produced similarly to ampicillin by substituting a carboxyl group in lieu of an amino group. Additional substitutions produced ticarcillin from carbenicillin. Compared with ampicillin both have enhanced activity against P aeruginosa and other gram-negative bacteria. Ticarcillin has greater antipseudomonal activity compared with carbenicillin in vitro. The aminopenicillins, however, continue to have superior activity against enterococci compared with the carboxypenicillins. The ureidopenicillins also have enhanced aerobic gram-negative activity including antipseudomonal activity. They have decreased frequency of side eects, however, and are active against Enterococcus spp. Included in this group are mezlocillin (not available in the United States); azlocillin (not available in the United States); and piperacillin. They were developed by the addition of an acyl side chain to ampicillin. Piperacillin also has the addition of a piperazine group. It is the predominantly used agent in this group. Resistance to penicillins is mediated by a variety of mechanisms depending on the target organism. A primary mechanism of penicillin resistance is b-lactamase production. Inactivation of b-lactamases may be achieved by b-lactamase inhibitors, which irreversibly bind to the site of action and prevent hydrolysis of the penicillin. b-Lactamase inhibitors, however, have little antibacterial activity. The combination of b-lactamase inhibitors with certain penicillins has enhanced the selection of antibiotic agents available for pediatric patients. Amoxicillin-clavulanate is the most widely used combination agent in pediatrics. It has an expanded activity to include methicillin-susceptible S aureus, b-lactamasepositive H inuenzae, and many anaerobes. It is an excellent agent in the treatment of otitis media and sinusitis. A new formulation with increased amoxicillin concentration allows for higher dosing of amoxicillin-clavulanate for use against S pneumoniae strains with increased MICs. The high-dose amoxicillin-clavulanate eradicated 98% of S pneumoniae isolates from the middle ears of children with acute otitis media, including 91% of the penicillin-resistant strains [11]. The common adverse eect of gastrointestinal upset associated with clavulanate was found to be similar to the original formulation [11,12]. In addition, it is excellent for treating animal or human bites and is eective therapy for many skin, soft tissue, and lower respiratory tract infections. Additional agents exist with limited indications in pediatric patients. Ampicillinsulbactam is a parenteral combination that is approved for use in children

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1 year of age and older. Its spectrum of activity is similar to amoxicillinclavulanate. Indications include adenitis, pneumonia, and urinary tract infections. It has been used successfully in pediatric patients with bacterial meningitis [13], although its bactericidal activity in an experimental meningitis model was inferior compared with ceftriaxone [14]. It is also eective in treating pediatric bone and joint infections [15]. Ticarcillinclavulanate is also approved for use in pediatric patients. It has been used successfully for empiric therapy in febrile neutropenic pediatric patients [16,17]. Safety and ecacy of piperacillin-tazobactam has not been established in pediatric patients. Cephalosporins First-generation cephalosporins The two most widely used rst-generation agents in pediatric patients are cefazolin, a parenteral agent, and cephalexin, an oral agent. They are mainly used for skin and soft tissue infections caused by streptococci and susceptible S aureus. In addition, they are useful at higher doses for treating bone and joint infections in the pediatric population. Both have proved records of safety and ecacy in children. Second-generation cephalosporins The second-generation cephalosporins have an enhanced spectrum of activity to include gram-negative bacteria. With the exceptions of the cephamycins (cefoxitin and cefotetan) they are not highly active against anaerobes. Furthermore, cefotetan is not FDA approved for use in children. Additionally, this generation of cephalosporins has poor penetration across the blood-brain barrier. Cefuroxime is the exception with demonstrable penetration into the central nervous system. Its use for treatment of bacterial meningitis was associated with delayed sterilization of the cerebrospinal uid, however, as compared with ceftriaxone and a higher incidence of hearing loss [18]. In addition to the parenteral formulation, cefuroxime is also available in an oral formulation (cefuroxime axetil) and is approved for use in children greater than or equal to 2 months of age. Indications include pharyngitis, otitis media, and lower respiratory tract infections; soft-tissue infections; and urinary tract infections. Other oral second-generation cephalosporins include cefaclor and cefprozil. Cefaclor, however, has been associated with serum sicknesslike reactions that have limited its use in pediatrics [19]. Cefprozil has a spectrum of activity similar to cefuroxime axetil, yet is more palatable. Loracarbef is a carbacephem that is structurally related to cephalosporins by replacement of a sulfur atom with a methylene group. Its mechanism of action, activity spectrum, and safety prole are similar to the

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second-generation cephalosporins. Safety and ecacy of this agent in children less than 6 months of age has not been established. Third-generation cephalosporins The most widely used parenteral third-generation cephalosporins in children are ceftriaxone, cefotaxime, and ceftazidime. These agents have enhanced activity compared with second-generation agents against the Enterobacteriaceae. In general, they have activity against penicillin nonsusceptible S pneumoniae, Haemophilus, Neisseria, and Moraxella spp. They are ineective against enterococci, Bacteroides, and Listeria. Their antistaphylococcal activity is inferior, however, to the other generations of cephalosporins and semisynthetic penicillins. Ceftriaxone has the convenience of dosing once daily for most infections. It can be given either intravenously or intramuscularly and this furthers its convenience for use in ambulatory settings. Its anity to bind albumin can cause displacement of bilirubin; it is not indicated for use in neonates with hyperbilirubinemia. Ceftriaxone achieves excellent peak serum concentrations and ecacy against most resistant nonmeningeal S pneumoniae infections. With the increase in the number of nonsusceptible isolates, however, vancomycin plus a third-generation cephalosporin is recommended when initiating antibiotic therapy for bacterial meningitis until culture and susceptibility results are available. Other agents combined with third-generation cephalosporins may also be ecacious. Recently, cefotaxime has been shown to act synergistically with levooxacin in an experimental meningitis model caused by penicillin-resistant S pneumoniae [20]. Cefotaxime has equivalent coverage compared with ceftriaxone and has no restrictive use for the newborn period. Ceftazidime is the only third-generation agent with activity against susceptible strains of P aeruginosa. Overall, these agents are well tolerated. They, like other b-lactams, can be associated with agranulocytosis, thrombocytopenia, pseudomembranous colitis, and hypersensitivity reactions. Ceftriaxone has been associated with reversible pseudolithiasis and rare cases of fatal hemolytic anemia [21,22]. Oral agents within this generation used in pediatrics include cefpodoxime, ceftibuten, cefdinir, and cexime. Cexime was a frequently used agent in pediatric urinary tract infections and the treatment of Salmonella infections; however, it is no longer being manufactured. Cefpodoxime may be dosed conveniently once or twice daily, but is poorly palatable. Cefdinir is broader-spectrum with comparable activity against S aureus and streptococci with the rst-generation agents. It may be dosed once or twice daily and has a favorable taste. Ceftibuten is another oral third-generation cephalosporin with similar coverage as cefpodoxime. It is approved for sinusitis and otitis media in children 6 months of age and older. The oral second- and third-generation cephalosporins are not likely to be ecacious against moderate to high-level penicillin-resistant pneumococci, and amoxicillin is expected to be more eective against these isolates (Table 3).

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Table 3 Minimum inhibitory concentration breakpoints and maximum serum concentrations of oral antibiotics directed against S pneumoniae Amoxicillin component of Augmentin ES-600 (600 mg/ 42.9mg/5 mL susp) 2 lg/mL 4 lg/mL !8 lg/mL At 45 mg/kg 15.7 7.7 lg/mL

S pneumoniae Susceptible Intermediate Resistant Cmax

Cefpodoxime 0.5 lg/mL 1 lg/mL !2 lg/mL At 5 mg/kg 2.1 lg/mL

Cefuroxime 1 lg/mL 2 lg/mL !4 lg/mL At 20 mg/kg 7 lg/mL

Cefdinir 0.5 lg/mL 1 lg/mL !2 lg/mL At 14 mg/kg 3.86 0.62 lg/mL

Cmax, maximum serum concentration. Data from Package inserts of each listed drug and National Committee for Clinical Laboratory Standards guidelines 2003.

Fourth-generation cephalosporins The fourth-generation cephalosporins are dipolar ionic compounds that have a lower anity for and are poor inducers of b-lactamases. They also diuse more rapidly into gram-negative bacteria. These characteristics are believed to lead to an overall lower development of resistance among gramnegative bacteria. Cefepime is the only approved agent in this generation. It has good activity against gram-positive bacteria including methicillinsusceptible S aureus, a-hemolytic streptococci, and some coagulase-negative staphylococci. Also, it has the best activity against penicillin-resistant pneumococcus among the cephalosporins [23]. Recently, a rabbit meningitis model with penicillin-resistant pneumococcus compared treatment with cefepime and the standard regimen of ceftriaxone and vancomycin. Cefepime was very eective against penicillin-resistant pneumococcal strains and comparable with the standard regimen in this experimental meningitis model [24]. In addition, its gram-negative activity against H inuenzae, Neisseria spp, and Pseudomonas spp is excellent. In a recent report by the SENTRY antimicrobial surveillance program, 10% of P aeruginosa isolates were resistant to cefepime [25]. Enterobacteriaceae are also included in cefepimes spectrum of activity. Furthermore, a SENTRY antimicrobial surveillance program demonstrated that cefepime sustained its activity against certain AmpC b-lactamase and extended-spectrum b-lactamase producing Enterobacteriaceae during 1997 to 2000 [26]. Even so, several other series indicate cefepime is less active than carbapenems against bacteria producing an extended-spectrum b-lactamase [2729]. Cefepime is approved for use in pediatric patients 2 months of age and older. It is indicated for treatment of febrile neutropenia, pneumonia, skin and soft tissue infections, and infections of the urinary tract. It has good tissue penetration, including inamed meninges. In addition, it has been shown to be as eective and safe as ceftazidime when treating fever and

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neutropenia in pediatric oncology patients with monotherapy [30,31]. Adverse eects associated with cefepime include headache, gastrointestinal manifestations, local reaction, and rash occurring in less than 2% of individuals. More serious adverse eects include encephalopathy and seizures. Carbapenems The basic structure of these agents is similar to penicillin. Certain characteristic of the structure confers their enhanced activity. For example, the alkylthio side chain allows for their antipseudomonal activity and the hydroxyethyl side chain allows for resistance to most b-lactamase enzymes. The carbapenems provide the broadest spectrum of activity of currently approved antibiotics. They are active against gram-positive bacteria, excluding MRSA and Enterococcus faecium. They provide broad anaerobic coverage. They also have broad activity against gram-negative bacteria, including most extended-spectrum b-lactamase producers. In fact, out of 10 antibacterial agents tested, meropenem was found to have the highest susceptibility rates among gram-negative isolates. In addition, the same surveillance demonstrated over the past several years there has been an increase in the percentage of meropenem-susceptible P aeruginosa isolates [32]. Despite their excellent record against gram-negative organisms, they are not active against Stenotrophomonas maltophilia. The rst carbapenem approved for use in adults was imipenem-cilastatin. The limited data and its association with seizures in children with meningitis, however, have limited its use in pediatric patients [33]. Meropenem is approved for use in pediatric patients 3 months of age and older. It has greater activity against P aeruginosa compared with imipenem, but is less active against gram-positives. Potential clinical uses of this agent include meningitis, febrile neutropenia, pneumonia, intra-abdominal infections, and skin and bone infections. In pediatric patients, meropenem remains the drug of choice against extended-spectrum b-lactamase producers and producers of AmpC b-lactamases. These agents require judicious use and should be limited to the most serious of infections because use of these agents has been associated with development of infection with multidrug-resistant organisms [34,35]. Monobactams The last group of b-lactams is the monobactams. Aztreonam is the only monocyclic b-lactam available. Because of its chemical structure it binds preferentially to certain penicillin-binding proteins of gram-negative bacteria. Its spectrum of activity resembles the aminoglycosides. It has good activity against most gram-negative bacteria, including P aeruginosa. Grampositive organisms and anaerobes are resistant.

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Aztreonam is widely distributed in body uids, and penetrates into cerebrospinal uid in the presence of inamed meninges [36]. It is approved for use in children 9 months of age and older. Its indications include lower respiratory tract infections, urinary tract infections, septicemia, and intraabdominal infections caused by susceptible organisms. Use in newborns is contraindicated because of the presence of arginine in its formulation and the occurrence of arginine-induced hypoglycemia in this patient population [37]. It is a useful alternative to aminoglycosides in combination with other agents because it is less nephrotoxic and has no ototoxicity. Lastly, it may be used as a substitute for other b-lactams because less than 1% of individuals with allergy to b-lactams experience a hypersensitivity reaction with aztreonam [38]. Macrolides Erythromycin is a naturally occurring macrolide. It is poorly bioavailable, however, and has signicant gastrointestinal eects. Subsequent structural modications of this parent compound resulted in the development of erythromycin salts with enhanced bioavailability. Further modications led to the newer macrolides, azithromycin and clarithromycin, which are better tolerated and more conveniently dosed. In the past erythromycin was the choice alternative therapy for penicillin-allergic children with streptococcal pharyngitis, sinusitis, or acute otitis media. Recent increases in macrolide-resistant S pneumoniae and H inuenzae have been reported [39]. In addition, azithromycin has been demonstrated to perform no better than placebo in the treatment of acute otitis media caused by penicillin-nonsusceptible bacteria [40]. The macrolides have activity against susceptible strains of Streptococcus pneumoniae, Staphylococcus aureus, Moraxella catarrhalis, and Streptococcus pyogenes and the newer macrolides against Haemophilus inuenzae. Azithromycin has the best gram-negative activity of the group with ecacy against Shigella and Salmonella [41,42]. Traditionally, erythromycin has been the rst-line agent in the treatment of pertussis and chlamydia infections in the newborn infant. Its association with an increased risk of hypertrophic pyloric stenosis, however, has prompted some clinicians to use azithromycin instead [43,44]. Because of azithromycins slow release from tissues, it has an extremely long half-life [45]. A 5-day course of azithromycin or a 7-day course of clarithromycin is better tolerated and may be comparable with 14 days of erythromycin when treating pertussis [46]. Other organisms covered by the macrolides include atypical pathogens, such as Mycoplasma pneumoniae, Legionella spp, Chlamydia spp, Ureaplasma urealyticum, and Listeria spp. Clarithromycin and azithromycin have activity against many nontuberculous mycobacteria. In summary, the macrolides have limited use in the most common bacterial infections encountered in pediatrics with the exception of group A

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b-hemolytic Streptococcus pharyngitis. Infants and young children with acute otitis media, sinusitis, or community-acquired pneumonia are unlikely to be infected with atypical bacteria; macrolide use in pediatric patents with these infections should be limited to patients with signicant penicillin allergy. Even so, they remain excellent agents against atypical pathogens. The newer macrolides, azithromycin and clarithromycin, have an expanded spectrum and, because of enhanced absorption, a more convenient dosing schedule. Azithromycin may also be given parenterally. Lincosamides Clindamycin is a semisynthetic inhibitor of protein synthesis. It provides gram-positive and anaerobic coverage; however, it does not provide aerobic gram-negative coverage. Clindamycin penetrates well into body uids, tissues, and bone. Its association with antibiotic-associated pseudomembranous colitis has limited its use in past years. Antibiotic-associated pseudomembranous colitis is more commonly associated with b-lactam antibiotics, however, because of their more frequent use in pediatric patients [47]. Clindamycin use is on the rise by many pediatric infectious disease specialists because of the increase in community-acquired MRSA infections. Although, there is some geographic variability in the degree of inducible clindamycin resistance among these isolates, several reports indicate it is less than 10% at certain centers [48,49]. Clindamycin is also eective in treating children with invasive disease caused by these isolates [50]. With community-acquired MRSA approaching 50% of the S aureus isolates in many communities, clindamycin may become a rst-line empiric agent against presumptive staphylococcal infections. Aminoglycosides The aminoglycosides are bactericidal inhibitors of protein synthesis. They are predominantly used to treat gram-negative bacterial infections. They have some activity, however, against S aureus and are synergistic against Enterococcus spp when used with penicillin or vancomycin. Their grampositive activity, however, is limited. In pediatrics they remain a key agent directed at gram-negative bacteria resulting in neonatal sepsis, complicated urinary tract infections, intra-abdominal infections, infections in cystic brosis, and empiric therapy in febrile neutropenic patients. The three most commonly used aminoglycosides in children are gentamicin, tobramycin, and amikacin. In general, tobramycin, has greater antipseudomonal activity and amikacin is more active against resistant gram-negatives. Amikacin and, rarely, streptomycin are used in the initial therapy of pediatric tuberculosis and have activity against other Mycobacteria spp. Also, paromomycin is used in the intestinal phase of amebiasis. Ototoxicity and nephrotoxicity are the most notable adverse eects. Studies have failed to demonstrate a consistent correlation, however,

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between aminoglycosides and hearing loss in pediatric patients [5153]. Even so, it is common to evaluate hearing in children on prolonged courses of aminoglycosides. In addition, the risk of nephrotoxicity in pediatric patients has also been demonstrated as low [54]. Because these are concentration-dependent antibiotics, their bactericidal eect is dependent on an adequate peak concentration. Adult studies have shown enhanced bactericidal eect and minimized toxicity with once-daily dosing of aminoglycosides. Even though there have been questions about the prevalence of aminoglycoside-associated toxicity in children, pediatric studies of oncedaily dosing have been conducted and support this dosing regimen [55,56]. Vancomycin Vancomycin is a glycopeptide that is active primarily against grampositive bacteria. It predominantly inhibits synthesis of the bacterial cell wall. In general it is well tolerated but reported adverse eects include gastrointestinal, hypotension, and cardiovascular eects with rapid infusion; drug-mediated skin reactions; thrombophlebitis; and rarely ototoxicity. Also, earlier preparations of vancomycin were associated with nephrotoxicity that infrequently occurs with the newer preparation [57]. Red mans syndrome (ie, hypotension and ushing of the face, neck, and chest) is another side eect that occurs with rapid vancomycin infusion. Red mans syndrome is probably histamine-mediated and responds to antihistamine or corticosteroid administration and slowing of the infusion rate. Vancomycin is most commonly used in infections caused by MRSA, coagulase-negative staphylococci, ampicillin-resistant enterococci, and Bacillus and Corynebacterium spp. It has become an important agent used in combination with other antibiotics when initiating therapy in biologic hardware infections (central venous catheters, ventriculoperitoneal shunts, and so forth) because of its activity against coagulase-negative staphylococci; bacterial meningitis because of its activity against penicillin-nonsusceptible S pneumoniae; and selected episodes of febrile neutropenia because of resistant viridans streptococci [58]. Oral vancomycin may be used to treat pseudomembranous colitis caused by Clostridium dicile. This use should be considered only after failure with metronidazole, however, and is to be discouraged because of the potential for selection of vancomycinresistant enterococci [59]. Judicious use of vancomycin should be exercised and limited to clinically indicated situations to limit the rate of emerging resistance. Unfortunately, in the United States there are increasing reports of vancomycin-resistant enterococci and now reported isolated strains of vancomycin-resistant S aureus [60,61]. New agents: oxalidinones and streptogramins Because of the emergence of multidrug-resistant organisms, such as vancomycin-resistant enterococci, new antibacterial agents are being

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developed to target such isolates, and two are currently available. Dalfopristin-quinupristin is a streptogramin approved for use in patients age 16 years and older. It is active against MRSA, coagulase-negative staphylococci, penicillin-resistant pneumococci, and vancomycin-resistant E faecium. It has no activity, however, against Enterococcus faecalis. It is available for parenteral use. Adverse eects include infusion site reactions (pain, edema, and so forth); nausea and vomiting; diarrhea; headache; myalgias; and arthralgias. The other group of new agents targeted against multidrug-resistant organisms is the oxazolidinones. Linezolid is currently the only approved agent in this class. It is approved for use in pediatric patients with safety data available in infants [62]. Its unique mechanism of action is through inhibition of ribosomal protein synthesis; it exhibits no cross-resistance with other drug classes. It is available in parenteral and oral formulations. Its spectrum of activity includes MRSA, vancomycin-resistant enterococci, coagulase-negative staphylococci, and penicillin-resistant pneumococci. The most common adverse events in pediatric trials were diarrhea, vomiting, and nausea [62]. Future development of oxazolidinones with enhanced gramnegative and mycobacterial activity is in progress. Although linezolid is a new agent, resistant Enterococcus spp has already been isolated [63]. The ecacy of these agents should be preserved by limiting their use to treating multidrug-resistant pathogens. Quinolones The uoroquinolones are bactericidal agents that are derivatives of nalidixic acid. They are inhibitors of DNA replication by binding to topoisomerases of their target bacteria. They are broad-spectrum agents with activity against gram-positive organisms, including some penicillinnonsusceptible pneumococci and MRSA. They exhibit excellent activity against gram-negative bacteria, including the Enterobacteriaceae, M catarrhalis, b-lactamaseproducing H inuenzae, Shigella and Salmonella spp, and Neisseria spp. In addition, they have activity against P aeruginosa with ciprooxacin being the most active. Atypical organisms, including Mycoplasma and Chlamydia spp, Legionella pneumophila, U urealyticum, and strains of mycobacterium are also susceptible. Emerging resistant strains of pneumococcus and MRSA have been reported, however, with varying rates geographically [64,65]. These agents currently are not approved for use in pediatric patients. Their restriction is caused by quinolone-associated arthropathies demonstrated in animal models. The prospect of approval of these agents in children, a group with high colonization rates of resistant pneumococcus, has also raised much concern [66]. Nevertheless, these agents are used when necessary in pediatric patients. Recently, the annual number of prescriptions for the uoroquinolone ciprooxacin in children less than 18 years of age

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was estimated at 150,000 with 20% prescribed for children less than 1 year of age [67]. In addition, The American Academy of Pediatrics Committee on Infectious Diseases has outlined clinical situations in which these agents should be considered: bronchopulmonary infections in cystic brosis patients, complicated urinary tract infections, chronic suppurative otitis media, multidrug-resistant gram-negative bacterial infections in those with immune compromise requiring prolonged oral therapy, salmonellosis or shigellosis caused by resistant species, and resistant mycobacterial infections [68]. Safety data for these agents, predominantly ciprooxacin, are available in pediatric patients. Case reports and retrospective cohort studies, mostly in children with cystic brosis, have failed to demonstrate an association with irreversible arthropathy [69,70]. Despite the outcome with regards to FDA approval of these agents in pediatric patients, they continue to be used in this population. It is imperative that their use be tempered and judicious as outlined by the American Academy of Pediatrics to preserve their ecacy as broad-spectrum agents in children.

Summary Antibacterial agents are among the most commonly prescribed pediatric therapeutic agents. Their proper use requires knowledge of the pharmacokinetics, pharmacodynamics, and toxicities unique to the pediatric population. Overall, antibacterial agents used in children are well tolerated. It is hoped that the promotion of judicious antibiotic use subsequent to increasing antibacterial resistance will preserve the ecacy of many agents. With new legislation to ensure the inclusion of pediatric subjects in FDAapproved clinical drug trials, the armamentarium against pediatric infections is likely to expand.

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