Professional Documents
Culture Documents
Seminar
Community-acquired pneumonia
Aetiology
Six large-scale studies of the aetiology of CAP (table 1510) showed that S pneumoniae is still the most common cause of CAP, with respiratory viruses and Haemophilus influenzae also commonly implicated. Except for the patients studied by Woodhead and
Lancet 1998; 352: 1295302
Division of Infectious Diseases, Department of Internal Medicine, Wayne State University School of Medicine (P D Brown MD) , and Division of Infectious Diseases, Harper Hospital, 3990 John R, Detroit, MI 48201, USA (S A Lerner MD) Correspondence to: Dr Stephen A Lerner
SEMINAR
Study Location
Year
Number of Rank order microbial cause (%) patients 1 2 116 236 359 106 346 334
4 GNB 7 GNB 15 Chlamydia spp 6 GNB 8 Legionella spp 162 Mycoplasma spp 6
Unknown 35 45 33 33 194 45
5 6 7 8 9 10
Paris, France Nottingham, UK Pittsburgh, USA Adelaide, Australia Beer-Sheva, Israel Leiden, Netherlands
Legionella spp 4 S aureus 1 Gram-negative bacilli 6 Mycoplasma spp 8 Viral 101 Chlamydia spp 3
series. Torres and colleagues13 also summarised data from five series of severe CAP. In all five series, S pneumoniae was the most common pathogen; and in three of the five L pneumophila was the second most common isolate. In the other two studies, M pneumoniae and Klebsiella pneumoniae were the second most frequently isolated pathogens.13 In an analysis of 11 studies of the microbiology of CAP in the elderly, Woodhead16 showed that in 785 patients over 65 years old S pneumoniae was again the most common cause of CAP. H influenzae, gramnegative bacilli, respiratory viruses, and Staphylococcus aureus accounted for more cases of pneumonia in the elderly than in people under the age of 65. The atypical pathogens, especially M pneumoniae, accounted for a smaller proportion of pneumonias in people over 65. However, Marston and colleagues4 showed a much higher incidence of M pneumoniae and C pneumoniae in elderly patients with CAP than was reported in previous studies. Accurate information on the incidence of various pathogens in elderly patients is especially important for the selection of appropriate antimicrobial therapy, since more than 90% of deaths caused by pneumonia occur in the elderly.16 Few studies have analysed seasonal variation in the incidence of common pneumonia pathogens. In a prospective study of 346 patients with CAP admitted to hospital over 1 year, Lieberman and colleagues17 found that most pathogens showed no seasonal variation, except for the respiratory viruses, which were more common in winter and spring and were rare in autumn, and for M pneumoniae, which was most common in spring. However, this study was done in southern Israel, which has less climatic variation than Europe and North America. No specific cause is found in 2550% of patients with CAP. As a result, many patients with CAP must be treated empirically.
the elderly, or from a true physiological effect of ageing, is unknown. Fever occurs in 80% of patients; 80% have crackles on auscultation and signs of consolidation are present in 30% of patients.1
Clinical presentation
Fever with cough, sputum production, dyspnoea, and pleuritic chest pain, are the presenting symptoms of pneumonia. In the past, many clinicians thought that they could differentiate between pneumonia caused by one of the atypical pathogens and typical pneumonia caused by S pneumoniae and other bacteria, because the two types had different clinical presentations. However, it is not possible to predict microbial aetiology reliably by use of presenting signs and symptoms.7,12 Extrapulmonary symptoms, including headache, myalgia, arthralgia, and gastrointestinal symptoms, are reported in 1030% of patients with CAP.1 Elderly patients report fewer symptoms than patients under 65 years of age, even after control for increased morbidity and severity of illness.18 Whether this tendency results from a diminished subjective response to symptoms in 1296
SEMINAR
Society22 state that the presence of a predominant organism in a Grams stain of a good quality specimen is a specific but not sensitive test which provides presumptive diagnostic information. Guidelines for the management of CAP from the Infectious Diseases Society of America also call for sputum gram stain, but admit that the recommendation is based mainly on expert opinion without strong supporting evidence.23 We feel strongly that an attempt to obtain sputum for gram stain and culture should be made in all patients with CAP who are admitted to hospital. Results of gram stains are useful in the initial selection of antimicrobial therapy, and culture results can confirm or alter the initial diagnostic impression and help to refine an appropriate therapy. Culture and antimicrobial susceptibility results also aid the compilation of data on trends in the prevalence and susceptibility patterns of various pathogens in local communities. A gram stain positive for pneumonia should have more than 25 polymorphonuclear leucocytes and fewer than ten epithelial cells in each low-power field.24 The presence of a predominant organism (at least eight to ten organisms in each high-power field) that is morphologically compatible with a likely pulmonary pathogen is acceptably specific for diagnosis of CAP.25 Culture confirmation should always be sought, given that antimicrobial resistance is increasing. However, many of the pathogens that cause pneumonia may colonise the respiratory tract without causing disease, and thus culture results must be interpreted together with the results of the gram stain. Some patients with CAP produce either no sputum at all or no specimen of adequate quality. Previous antimicrobial therapy may also affect the gram-stain results. The clinician or clinical microbiologist must be experienced in analysis of sputum gram stains. Inexperienced clinicians can make interpretative errors that can have adverse effects on patient care.26 The start of antibiotic therapy should not be delayed unduly if an adequate sputum specimen cannot be obtained at first. Meehan and colleagues27 found that in elderly patients with pneumonia 30-day mortality was lower after administration of antibiotics within 8 h of arrival at hospital than after delayed treatment.27 At our institution, we advise that the start of therapy is delayed for no longer than 6 h by attempts to obtain an adequate sputum sample for diagnostic studies. Fibreoptic bronchoscopy with protected brush culture can be of diagnostic value in CAP, but diagnostic success may be significantly reduced in patients who have been on antibiotic therapy for several days.28 This invasive procedure should generally be reserved for critically ill patients or for those who are severely immunosuppressed. In CAP caused by Legionella spp, M pneumoniae, and C pneumoniae, the best strategies for diagnosis are uncertain at present. Serological diagnosis can be made for all three pathogens but it is of limited practical use, since it gives a diagnosis only in retrospect. Sputum culture for Legionella spp has 8090% sensitivity and 100% specificity, but it requires special media and selective techniques that may not be available in all laboratories. Immunofluorescence techniques have a sensitivity of 5070%, and a DNA probe for the detection of antigen in sputum has a sensitivity of 2575%.29 Urinary antigen detection by
radioimmunoassay has a sensitivity of 8099% and a specificity of 99%;29 the sensitivity is not greatly decreased even after antimicrobial therapy starts. At present, antigen-detection tests can detect only L pneumophila serogroup 1, although this serogroup is estimated to cause 7090% of legionella cases. M pneumoniae also requires special techniques for culture, but results may take a week or more to process, so clinical use is limited. Rapid antigen-detection tests are not currently available for widespread clinical use. C pneumoniae is an obligate intracellular pathogen, and therefore culture is difficult. A PCR enzyme immunoassay may eventually allow more rapid diagnosis.30 At present, we do not recommend tests for one of the atypical pathogens as part of the routine investigation of all patients with CAP. Edelstein29 recommends tests for legionella in patients who do not respond to -lactam antibiotics, in areas with a high prevalence of community-acquired legionella, in cases of epidemic-associated pneumonia, and in patients with a recent travel history or occupational exposure to water, especially if a sputum gram stain shows many polymorphonuclear cells and no apparent pathogen. CAP patients not treated in hospital should have chest radiography and laboratory tests to assess severity of the disorder and to help assess the need for a hospital stay. If possible, sputum should be obtained for gram stain and culture.
Mortality
For patients not admitted to hospital, the mortality from CAP is less than 1%.1 In a meta-analysis of studies of outcome in CAP,31 the overall mortality for hospitaladmitted patients was 137%, that for elderly patients 176%, and that for bacteraemic patients 196%. The mortality of CAP patients who needed admission to an intensive-care unit was 365%. There have been several studies of risk factors for mortality in CAP; poor prognostic factors that would influence the decision to admit a patient with CAP to hospital are listed in the panel.32 Fine and colleagues33 analysed data on more than 14 000 patients with CAP to derive a prediction rule based on age, comorbidity, abnormal physical findings,
Risk factors in patients with CAP* Age >65 years Comorbidity Diabetes, renal failure, heart failure, chronic lung disease, alcoholism, hospital admission within previous year, immunosuppression, neoplastic disease Clinical findings Respiratory rate >30 breaths/min Systolic blood pressure <90 mm Hg or diastolic pressure <60 mm Hg Body temperature >383C Altered mental status Evidence of extrapulmonary sites of infection Laboratory findings White cell count <4 or >30109 L pO2 798 kPa on room air Renal insufficiency Multilobar involvement or significant pleural effusion Packed-cell volume <30%
*Adapted from Bartlett and Mundy.32
1297
SEMINAR
and laboratory abnormalities, which enables patients to be stratified among five risk categories with respect to 30-day mortality. The prediction rule was validated with retrospective data from two additional cohorts of patients with CAP. Although the prediction rule may prove valuable in the future to guide decisions about the need for hospital treatment, it has not been evaluated prospectively. The decision to admit to hospital must still be a clinical judgment, aided by clinical assessment and laboratory data that show a poor prognosis in CAP. In addition to treatment guidelines, many institutions have developed clinical pathways for CAP management. However, there are not enough data available for definite conclusions to be drawn about the effects of treatment guidelines and management pathways on clinical outcomes and cost of care.
Antibiotic therapy
Although the susceptibility profile of S pneumoniae, the main pathogen involved in CAP, is changing, the susceptibilities of the other important CAP pathogens remain fairly predictable. Thus, it is important to find out whether S pneumoniae is the main pathogen as soon as a patient with CAP presents to medical attention.
in S pneumoniae. Lower, but increasing, rates of penicillin non-susceptibility have been reported elsewhere in Europe, including Germany42 and Switzerland.43 Colonisation and infection with non-susceptible S pneumoniae are more common in some groups of people than in others. Higher rates of penicillin nonsusceptibility have been reported in children,36,44 in white than in African-American patients,36,44 in residents of nursing homes, and in HIV-positive people.45 These differences are probably related to greater exposure to antibiotics among these categories of people and, presumably, to increased selection of antibiotic-resistant strains. Therefore, it is important that S pneumoniae strains isolated from patients in different settings within every community are tested for susceptibility, so that current patterns can be monitored and appropriate therapy designed. In a prospective study in Spain, where high bacterial resistance to penicillin is common, ClavoSanchez and colleagues46 found by multivariate analysis that -lactam treatment within the previous 3 months, alcoholism, and isolation of S pneumoniae from sputum but not from a normally sterile body site were risk factors for penicillin resistance in the isolated strain.
Susceptibility to penicillin Over the past 30 years, strains of S pneumoniae with diminished susceptibility to penicillin have emerged and spread worldwide.34 These strains have retained their virulence, and they cause infections indistinguishable from those caused by susceptible isolates. Isolates of S pneumoniae are categorised as penicillin-susceptible (minimum inhibitory concentration [MIC] 01 g/mL) or non-susceptible (>01 g/mL). The strains in the latter category are further subdivided into intermediate (10 g/mL) and resistant (20 g/mL). The prevalence of S pneumoniae isolates in these penicillin-susceptibility categories varies widely between nations, between communities, and even among different populations of patients within a community. The results of surveillance of S pneumoniae isolates by the Centers for Disease Control and Prevention throughout the USA in 197987 showed that only 5% of strains were penicillin-intermediate, and there was virtually no penicillin resistance.35 By 199394, 109% of strains were penicillin-intermediate and 32% were penicillinresistant.36 Similar work in Canada in 19949537 showed that 84% of strains were penicillin-intermediate, and 33% of strains were penicillin-resistant, although earlier studies had not reported resistant strains. In a study of S pneumoniae bacteraemia in 199194 in Ohio, USA, Plouffe and colleagues38 showed that the proportion of penicillin-intermediate isolates rose progressively from 31% in 1991 to 116% in 1994 and the proportion of penicillin-resistant strains rose from 09% to 24%. In Spain, decreasing bacterial susceptibility to penicillin was recognised earlier than in most of the rest of Europe and North America. Isolates from a 10-year prospective study of S pneumoniae pneumonia at a medical centre in Barcelona showed increases in penicillin nonsusceptibility from 13% penicillin-intermediate strains in 198488 to 20% in 198993, with the proportion of resistant isolates increasing from 6% to 15% during 198493.39 In particular, South Africa40 and Hungary41 have very high prevalence of penicillin non-susceptibility
1298
Susceptibility to cephalosporins Although strains of S pneumoniae with lowered susceptibility to penicillin generally show cross-resistance to cephalosporins, third-generation cephalosporins such as cefotaxime and ceftriaxone are still generally effective against S pneumoniae. The activity of these thirdgeneration drugs against most penicillin-intermediate and resistant strains is still higher than that of penicillin.37,47,48 However, mutational alterations of penicillin-binding proteins that produce resistance to -lactam antibiotics may have differential effects on resistance to penicillins and cephalosporins.4951 As a result, in some strains the degree of resistance to cephalosporins exceeds that of resistance to penicillins, so extrapolation from the penicillin susceptibility of a strain to its response to cephalosporins is unwise. Cross-resistance to other antibiotics Cross-resistance to other antipneumococcal antibiotics has been shown in many strains of S pneumoniae that have diminished susceptibility to penicillins and cephalosporins.37,40,41,48,52 The cross-resistance is not complete, and the mechanisms are not understood. Nonetheless, cross-resistance is sufficiently common to compromise the potential use of substitutes for -lactams in the treatment of -lactam-resistant S pneumoniae infections. These substitute drugs include erythromycin, the newer macrolides (clarithromycin, azithromycin), clindamycin, doxycycline and other tetracyclines, and co-trimoxazole. Alternative antibiotics Other antibiotics do retain their activity against -lactam-resistant pneumococci. All strains of S pneumoniae, including those fully resistant to penicillin, are susceptible to vancomycin at present.37,53 Although the MICs of imipenem are higher in penicillin-resistant S pneumoniae, almost all of these strains remain clinically susceptible to imipenem.37,48,53 In addition, the activity of the fluoroquinolones against strains of S pneumoniae appears not to vary with penicillin susceptibility.37,43,48,54
SEMINAR
Preferred treatment
Outpatient (oral therapy) S pneumoniae Phenoxymethylpenicillin Amoxicillin H influenzae Cefuroxime Amoxycillin/clavulanate S aureus Cloxacillin Dicloxacillin Hospital ward (parenteral therapy) S pneumoniae Benzylpenicillin
H influenzae
Cefuroxime
S aureus
Nafcillin
Gram-negative bacilli
Cephalosporin Imipenem Vancomycin Ampicillin/sulbactam Cephalosporin|| Quinolone First-generation cephalosporin Clindamycin Vancomycin Ceftazidime or imipenum, with or without aminoglycoside Imipenem Vancomycin Quinolone Ampicillin/sulbactam Cephalosporin|| Quinolone First-generation cephalosporin Clindamycin Vancomycin Imipenem, with or without aminoglycoside Quinolone
H influenzae
Cefuroxime
preclude effective therapy of pneumococcal pneumonia and sepsis with high-dose penicillin.39,68,69 For S pneumoniae strains with higher levels of penicillin resistance, it is not clear whether high-dose penicillin therapy is adequate. Third-generation cephalosporins such as cefotaxime or ceftriaxone are appropriate alternatives to penicillin, at least when their MICs are 2 g/mL or less. Highly penicillin-resistant S pneumoniae can be treated with imipenem and meropenem, although as penicillin resistance rises further, MICs of these carbapenems might eventually reach levels that make standard doses ineffective. Other options include vancomycin, and the antipneumococcal quinolones levofloxacin, sparfloxacin, grepafloxacin, and trovafloxacin. Medical centres must monitor the susceptibility of local isolates of S pneumoniae; further increase of penicillin and cephalosporin MICs above 2 g/mL would indicate a shift from these -lactams to other agents for the treatment of pneumococcal infection. Physicians must be aware of the susceptibility pattern of pneumococci in the community that they serve.
S aureus
Nafcillin
Gram-negative bacilli
*Antipneumococcal quinolone (levofloxacin, sparfloxacin, grepafloxacin, trovafloxacin). High-dose (12 million units per day). Cefotaxime or ceftriaxone. Levofloxacin or trovafloxacin, ||Cefotaxime, ceftriaxone, or ceftizoxime.
Table 2: Initial antibiotic treatment for CAP when the aetiological agent is evident from sputum gram stain
Nonetheless, the fluoroquinolones differ in their intrinsic activity against S pneumoniae. Ciprofloxacin has relatively poor activity against some strains, but the newer quinolones are more active generally against pneumococci (activity of trovafloxacin>grepafloxacin sparfloxacin>levofloxacin in vitro).5456 There are few reports of pneumococcal resistance to trovafloxacin and grepafloxacin, owing to their more recent introduction into clinical use. Quinolones tend to cause the selection of resistance to themselves and to other quinolones in most bacteria that have been studied. Thus, the use of quinolones should be limited, and clinicians should be alert to the possible emergence of quinolone resistance in S pneumoniae.
Antibiotic susceptibility of other CAP pathogens The other main typical bacterial pathogen in CAP, H influenzae, is generally susceptible to cefuroxime, to third-generation cephalosporins (cefotaxime, ceftriaxone, ceftizoxime), and to the fluoroquinolones. H influenzae is less susceptible to the newer macrolides (activity of azithromycin>clarithromycin). The macrolides, including erythromycin,57,58 and the fluoroquinolones5867 also have in-vitro activity and clinical efficacy against the atypical CAP pathogens M pneumoniae, C pneumoniae, and legionella. Treatment options for penicillin-resistant S pneumoniae At present, penicillin resistance in strains of S pneumoniae (MICs generally up to 2 g/mL) can be overcome with high-dose intravenous benzylpenicillin (at least 12106 U per day).53 Current levels of resistance to penicillin and cephalosporins in S pneumoniae do not
Initial therapy of CAP Our recommended approach to the initial therapy of CAP is shown in tables 2 and 3. For the treatment of pneumococcal pneumonia in patients not admitted to hospital, an antipneumococcal quinolone (levofloxacin, sparfloxacin, grepafloxacin, trovafloxacin) could be used if multidrug resistance in S pneumoniae is sufficiently prevalent in the local area to preclude the routine use of a penicillin for mild infection. However, we would not use such a drug routinely, because widespread use might lead to selection of quinolone resistance among S pneumoniae, other CAP pathogens, and other organisms colonising the patient. Erythromycin is the preferred macrolide in cases with no diagnostic sputum gram stain because of its low cost, although azithromycin or clarithromycin are acceptable options if the sideeffects of erythromycin are intolerable. Azithromycin might also be preferred for convenience (5 days of oncedaily therapy, compared with 710 days of multiple daily doses of other drugs). Again, a quinolone could be used empirically in such cases when there is a high prevalence of multidrug-resistant S pneumoniae. Since S pneumoniae may be resistant to penicillins, macrolides, and doxycycline, outpatients treated with these drugs empirically or for suspected S pneumoniae must be told to return for further assessment if response to therapy is poor. If the patient is admitted to a general ward and a gram-stained smear of sputum or empyema fluid shows S pneumoniae, high-dose benzylpenicillin should be adequate, as long as laboratory data show that the penicillin MICs of isolates in the local community are 2 g/mL or less. If the patient is allergic to penicillin, a
Treatment setting Preferred treatment Other options
Outpatient (oral therapy) Macrolide, doxycycline Hospital ward (parenteral therapy) Intensive-care unit (parenteral therapy)
Levofloxacin, sparfloxacin, grepafloxacin, or trovafloxacin Cefotaxime or ceftriaxone Levofloxacin or trovafloxacin +erythromycin Cefotaxime or ceftriaxone Imipenemaminoglycoside aminoglycoside +erythromycin +erythromycin Levofloxacin or trovafloxacin
Table 3: Initial empirical antibiotic treatment for CAP when diagnostic sputum gram-stain is unavailable
1299
SEMINAR
cephalosporin (cefotaxime, ceftriaxone) could be used if the allergic reaction is not anaphylactic. Acceptable substitutes for benzylpenicillin or a cephalosporin for -lactam-allergic patients would be intravenous vancomycin or a quinolone. Levofloxacin and trovafloxacin are available for parenteral and oral use. If the prevalence of high-level resistance to penicillin (MIC 4 g/mL) and cephalosporins (MIC 4 g/mL) is above 5%, penicillins or cephalosporins cannot be used routinely, so vancomycin, a quinolone, or imipenem would have to be used. If the sputum gram stain is non-diagnostic or if no sputum is available for examination, treatment should aim not only at S pneumoniae but also more broadly. In such cases, we recommend treatment with a high-dose regimen of a cephalosporin (cefotaxime, ceftriaxone) and with a macrolide such as erythromycin. Alternatively, quinolone monotherapy can be used. If a CAP patient needs intensive care and the sputum gram stain indicates S pneumoniae, we would treat with high-dose cephalosporin, or with imipenem, vancomycin, or a quinolone, if resistance to cephalosporins is too high to permit their routine use. If the gram-stained smear of sputum or empyema fluid is not diagnostic (table 3), we recommend the addition of erythromycin to the treatment regimen of high-dose cephalosporin with or without an aminoglycoside. Alternatively, if there is concern about the possibility of P aeruginosa in patients with severe underlying structural lung disease such as cystic fibrosis or bronchiectasis, imipenem and erythromycin with or without an aminoglycoside, or quinolone monotherapy could be used. Since pharmacokinetic studies of azithromycin have shown that most of the drug is cleared quickly from the circulation, intravenous azithromycin may not be appropriate in patients who might be bacteraemic. If diagnostic information becomes available that shows a specific pathogen (eg, a culture isolate from sputum, blood, or empyema, or a urine antigen or sputum fluorescent-antibody test positive for legionella), susceptibility results, or both, the treatment regimen should be narrowed accordingly.
Conclusion
In light of the prevalence of CAP and the evolution of resistance in the most common bacterial CAP pathogen, we strongly advise that physicians obtain specimens for culture of CAP pathogens and analyse patterns of susceptibility, especially of S pneumoniae, in their communities, that they use antibiotics appropriately and prudently, according to prevailing susceptibilities when empirical treatment is called for, and that they immunise their susceptible patients with pneumococcal and influenza vaccines.
References
1 2 Marrie TJ. Community-acquired pneumonia. Clin Infect Dis 1994; 18: 50105. Guest JF, Morris A. Community acquired pneumonia: the annual cost to the National Health Service in the UK. Eur Respir J 1998; 10: 153034. Centers for Disease Control and Prevention. Premature deaths, monthly mortality, and monthly physician contactsUnited States. MMWR Morb Mortal Wkly Rep 1997; 46: 556. Marston BJ, Plouffe JF, File TM, et al. Incidence of communityacquired pneumonia requiring hospitalizations: results of a population-based active surveillance study in Ohio. Arch Intern Med 1997; 157: 170918. Lvy M, Dromer F, Brion N, Leturdu F, Carbon C. Communityacquired pneumonia: importance of initial noninvasive bacteriologic and radiographic investigations. Chest 1988; 92: 4348. Woodhead MA, Macfarlane JT, McCracken JS, Rose DH, Finch RG. Prospective study of the aetiology and outcome of pneumonia in the community. Lancet 1987; i: 67174.
Subsequent therapy Once the patients condition is clearly improving in response to therapy (eg, normalising temperature, improved respiratory status, resolved leucocytosis), and once he or she is haemodynamically stable and able to ingest and absorb oral medication, treatment can be switched to the oral route.70,71 This eliminates the need for intravenous access, simplifies therapy, and reduces cost. The patient could then be discharged to complete therapy at home. If the pathogen is S pneumoniae and its susceptibilities are known, the use of phenoxymethylpenicillin or amoxicillin, an oral thirdgeneration cephalosporin such as cefpodoxime, a macrolide, or a quinolone, should be considered. For H influenzae, agents shown in table 2 can be used. If the cause of the pneumonia is unknown, use of a macrolide or a quinolone might be most prudent. The total course of therapy should be 710 days, depending on the severity of the patients condition. If the patient has had evidence of sepsis and the response to therapy has been slow, treatment might be extended to 14 days. Some researchers have advocated therapy for 21 days in cases of infection due to L pneumophila.
1300
SEMINAR 7 Fang G, Fine M, Orloff J, et al. New and emerging etiologies for community-acquired pneumonia with implications for therapy: a prospective multicenter study of 359 cases. Medicine 1990; 69: 30716. Lim I, Shaw DR, Stanley DP, Lumb R, McLennan G. A prospective hospital study of the aetiology of community-acquired pneumonia. Med J Aust 1989; 151: 8791. Porath A, Schlaeffer F, Lieberman D. The epidemiology of community-acquired pneumonia among hospitalized adults. J Infect 1997; 34: 4148. Bohte R, vanFurth R, van den Brock PJ. Aetiology of communityacquired pneumonia: a prospective study among adults requiring admission to hospital. Thorax 1995; 50: 54347. Lieberman D, Schlaeffer F, Bolden I, et al. Multiple pathogens in adult patients admitted with community-acquired pneumonia: a one year prospective study of 346 consecutive patients. Thorax 1996; 51: 17984. Marrie TJ, Peeling RW, Fine MJ, Singer DE, Coley CM, Kapoor WN. Ambulatory patients with community-acquired pneumonia: the frequency of atypical agents and clinical course. Am J Med 1996; 101: 50815. Torres A, Serra-Batlles J, Ferrer A, et al. Severe community-acquired pneumonia: epidemiology and prognostic factors. Am Rev Respir Dis 1991; 144: 31218. Bartlett JG. Management of respiratory tract infections. Baltimore: Williams and Wilkins, 1997: 49. Moine P, Vercken J, Chevret S, Chastang C, Gajdos P. Severe community-acquired pneumonia: etiology, epidemiology, and prognostic factors. Chest 1994; 105: 148795. Woodhead M. Pneumonia in the elderly. J Antimicrob Chemother 1994; 34 (suppl A): 8592. Lieberman D, Lieberman D, Porath A. Seasonal variation in community-acquired pneumonia. Eur Respir J 1996; 9: 263034. Metlay JP, Schulz R, Hi-Hwei L, et al. Influence of age on symptoms at presentation in patients with community-acquired pneumonia. Arch Intern Med 1997; 157: 145359. Chalasani NP, Valdecanas AL, Gopal AK, McGowen JE, Jurado RL. Clinical utility of blood cultures in adult patients with communityacquired pneumonia without defined underlying risks. Chest 1995; 108: 93236. Sahn SA. Management of complicated parapneumonia effusions. Am Rev Respir Dis 1993; 148: 81317. American Thoracic Society. Guidelines for the initial management of adults with community-acquired pneumonia: diagnosis, assessment of severity, and initial antimicrobial therapy. Am Rev Respir Dis 1993; 148: 141826. British Thoracic Society. Guidelines for the management of community-acquired pneumonia in adults admitted to hospital. Br J Hosp Med 1993; 49: 34650. Bartless JG, Breiman RF, Mandell LA, File TM. Communityacquired pneumonia in adults: guidelines for management. Clin Infect Dis 1998; 26: 81138. Murray PR, Washington JA. Microscopic and bacteriologic analysis of expectorated sputum. Mayo Clin Proc 1975; 50: 33944. Rein MF, Gwaltmer JM, OBrien WM, et al. Accuracy of the grams stain in identifying pneumococci in sputum. JAMA 1978; 239: 267173. Fine MJ, Orloff JJ, Rihs JD, et al. Evaluation of housestaff physicians preparation and interpretation of sputum gram stains for communityacquired pneumonia. J Gen Intern Med 1991; 6: 18998. Meehan TP, Fine MJ, Krunholz HM, et al. Quality of care, process and outcomes in elderly patients with pneumonia. JAMA 1997; 278: 208084. Ortquist A, Kelin M, Lejdeborn L, Lundberg B. Diagnostic fiberoptic bronchoscopy and protected brush culture in patients with community-acquired pneumonia. Chest 1990; 97: 57682. Edelstein PH. Legionnaires disease. Clin Infect Dis 1993; 16: 74149. Gaiydos CA, Eiden JJ, Oldach D, et al. Diagnosis of Chlaymdia pneumoniae infection in patients with community acquired pneumonia by polymerase chain reaction enzyme immunoassay. Clin Infect Dis 1994; 19: 15760. Fine MJ, Smith MA, Carson CA, et al. Prognosis and outcomes of patients with community-acquired pneumonia: a meta-analysis. JAMA 1996; 275: 13441. Bartlett JG, Mundy LM. Community-acquired pneumonia. N Engl J Med 1995; 333: 161823. Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community acquired pneumonia. N Engl J Med 1997; 336: 24350. Austrian R. Confronting drug-resistant pneumococci. Ann Intern Med 1994; 121: 80709. Spika JS, Facklam RR, Plikaytis BD, Oxtoby MJ. Antimicrobial resistance of Streptococcus pneumoniae in the United States, 19791987: the pneumococcal surveillance working group. J Infect Dis 1991; 163: 127378. Butler JC, Hofmann J, Cetron MS, Elliott JA, Facklam RR, Breiman RF. The continued emergence of drug-resistant Streptococcus pneumoniae in the United States: an update from the Centers for Disease Control and Prevention Pneumococcal Sentinel Surveillance System. J Infect Dis 1996; 174: 98693. Simor AE, Louie M, Canadian Bacterial Surveillance Network, Low DE. Canadian national survey of prevalence of antimicrobial resistance among clinical isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother 1996; 40: 219093. Plouffe JF, Breiman RF, Facklam RR. Bacteremia with Streptococcus pneumoniae: implications for therapy and prevention. JAMA 1996; 275: 19498. Pallares R, Linares J, Vadillo M, et al. Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain. N Engl J Med 1995; 333: 47480. Klugman KP. Pneumococcal resistance to antibiotics. Clin Microbiol Rev 1990; 3: 17196. Marton A. Pneumococcal antimicrobial resistance: the problem in Hungary. Clin Infect Dis 1992; 15: 10611. Reinert RR, Lutticken R, Kaufhold A. Aktuelle Daten zur Antibiotikempfindlich-keiten von Streptococcus pneumoniae (Pneumokokken): die Bedeutung von penicillin resistenten Isolaten. Med Klin 1993; 88: 35761. Moreillon P, Wenger A. Antibiotic resistance in pneumococci. Schweiz Med Wochenschr 1996; 126: 25563. Hofmann J, Cetron MS, Farley MM, et al. The prevalence of drugresistant Streptococcus pneumoniae in Atlanta. N Engl J Med 1995; 333: 48186. Crewe-Brown HH, Karstaedt AS, Saunders GL, et al. Streptococcus pneumoniae blood culture isolates from patients with and without human immunodeficiency virus infection: alterations in penicillin susceptibilities and in serogroups or serotypes. Clin Infect Dis 1997; 25: 116572. Clavo-Sanchez AJ, Giron-Gonzalez JA, Lopez-Prieto D, et al. Multivariate analysis for infection due to penicillin-resistant and multidrug-resistant Streptococcus pneumoniae: a multicenter study. Clin Infect Dis 1997; 24: 105259. Linares J, Alonso T, Prez JL, et al. Decreased susceptibility of penicillin-resistant pneumococci to twenty-four beta-lactam antibiotics. J Antimicrob Chemother 1992; 30: 27988. Thomson KS, Chartrand SA, Sanders CC, Block SL. Trovafloxacin, a new fluoroquinolone with potent activity against Streptococcus pneumoniae. Antimicrob Agents Chemother 1997; 41: 47880. Coffey TJ, Daniels M, McDougal LK, Dowson CG, Tenover FC, Spratt BG. Genetic analysis of clinical isolates of Streptococcus pneumoniaeith high-level resistance to expanded-spectrum cephalosporins. Antimicrob Agents Chemother 1995; 39: 130613. Krauss J, van der Linden M, Grebe T, Hakenbeck R. Penicillinbinding proteins 2x and 2b as primary PBP targets in Streptococcus pneumoniae. Microb Drug Resist 1996; 2: 18386. Krauss J, Hakenbeck R. A mutation in the D,D-carboxypeptidase penicillin-binding protein 2 of Streptococcus pneumoniae contributes to cefotaxime resistance of the laboratory mutant C604. Antimicrob Agents Chemother 1997; 41: 93642. Goldstein FW, Acar JF. Antimicrobial resistance among lower respiratory tract isolates of Streptococcus pneumoniae: results of a 199293 western Europe and USA collaborative surveillance study: The Alexander Project Collaborative Group. J Antimicrob Chemother 1996; 38 (suppl A): 7184. Friedland IR , McCracken GH. Management of infections caused by antibiotic-resistant Streptococcus pneumoniae. N Engl J Med 1994; 331: 37782. Brueggemann AB, Kugler KC, Doern GV. In vitro activity of BAY 12-8039, a novel 8-methoxyquinolone, compared to activities of six fluoroquinolones against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Antimicrob Agents Chemother 1997; 41: 159497. Ernst ME, Ernst EJ, Klepser ME. Levofloxacin and trovafloxacin: the next generation of fluoroquinolones? Am J Health Syst Pharm 1997; 54: 256983. Wagstaff AJ, Balfour JA. Grepafloxacin. Drugs 1997; 53: 81724. Tarlow MJ, Block SL, Harris J, Kolokathis A. Future indications for macrolides. Paediatr Infect Dis J 1997; 16: 45762. Schrock J, Hackman BA, Plouffe JF. Susceptibility of ninety-eight clinical isolates of Legionella to macrolides and quinolones using the E test. Diagn Microbiol Infect Dis 1997; 28: 22123. File TM Jr, Segreti J, Dunbar L, et al. A multicenter, randomized study comparing the efficacy and safety of intravenous and/or oral levofloxacin versus ceftriaxone and/or cefuroxime axetil in treatment of adults with community-acquired pneumonia. Antimicrob Agents Chemother 1997; 41: 196572.
36
37
10
38
11
39
12
40 41 42
13
14 15
43 44
16 17 18
45
46
19
47
20 21
48
49
22
23
50
24 25
51
52
26
27
53
28
54
29 30
55
31
56 57 58
32 33
59
34 35
1301
SEMINAR 60 Sparfloxacin and levofloxacin. Med Lett Drugs Ther 1997; 39: 4143. 61 Ortqvist A, Valtonen M, Cars O, Wahl M, Saikku P, Jean C. Oral empiric treatment of community-acquired pneumonia: a multicenter, double-blind, randomized study comparing sparfloxacin with roxithromycin. Chest 1996; 110: 1499506. 62 Aubier M, Lode H, Gialdroni-Grassi G, et al. Sparfloxacin for the treatment of community-acquired pneumonia: a pooled data analysis of two studies. J Antimicrob Chemother 1996; 37 (suppl A): 7382. 63 Donowitz GR, Brandon ML, Salisbury JC, et al. Sparfloxacin versus cefaclor in the treatment of patients with community-acquired pneumonia: a randomized, double-masked, comparative multicenter study. Clin Ther 1997; 19: 93653. 64 Topkis S, Swarz H, Breisch SA, Maroli AN. Efficacy and safety of grepafloxacin 600 mg daily for 10 daily in patients with communityacquired pneumonia. Clin Ther 1997; 19: 97578. 65 Grepafloxacina new fluoroquinolone. Med Lett Drugs Ther 1998; 40: 1718. 66 Gooding B-B, Jones RN. In vitro antimicrobial activity in CP-99,219, a novel azabicyclo-naphthyridone. Antimicrob Agents Chemother 1993; 37: 34953. 67 Trovafloxacin. Med Lett Drugs Ther 1998; 40: 3031. 68 Friedland IR, Klugman KP. Antibiotic-resistant pneumococcal disease in South African children. Am J Dis Child 1992; 146: 92023. 69 Tan TQ, Mason EO Jr, Kaplan SL. Systemic infections due to Streptococcus pneumoniae relatively resistant to penicillin in a childrens hospital: clinical management and outcome. Pediatrics 1992; 90: 92833. 70 Mandell LA, Bergeron MC, Gribble MJ, et al. Sequential antibiotic therapy: effective management and patient care. Can J Infect Dis 1995; 6: 306. 71 Ramirez JS, Srinath L, Ahkee S, Huang A, Raff MJ. Early switch from intravenous to oral cephalosporins in the treatment of hospitalized patients with community-acquired pneumonia. Arch Intern Med 1995; 155: 127376. 72 Sims RV, Steinmann WC, McConville JH, King LR, Zwick WC, Schwartz JS. The clinical effectiveness of pneumococcal vaccine in the elderly. Ann Intern Med 1988; 108: 65357. 73 Shapiro ED, Berg AT, Austrian R, et al. The protective efficacy of polyvalent pneumococal polysaccharide vaccine. N Engl J Med 1991; 325: 145460. 74 Koivula I, Sten M, Makela PH. Clinical efficacy of pneumococcal vaccine in the elderly: a randomized, single-blind population-based trial. Am J Med 1997; 103: 28190. 75 Fine MJ, Smith MA, Carson CA, et al. Efficacy of pneumococcal vaccination in adults: a meta-analysis of randomized controlled trials. Arch Intern Med 1994; 154: 266677. 76 Centers for Disease Control and Prevention. Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep 1997; 46: 124. 77 Ely EW. Pneumonia in the elderly: diagnostic and therapeutic challenges. Infect Med 1997; 14: 64354. 78 Centers for Disease Control and Prevention. Update on adult immunization: recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep 1997; 40: 194. 79 Centers for Disease Control and Prevention. Pneumococcal and influenza vaccination levels among adults aged > or =65 years United States, 1995. MMWR Morb Mortal Wkly Rep 1997; 46: 91319. 80 Centers for Disease Control and Prevention. Missed opportunities for pneumo-coccal and influenza vaccination of Medicare pneumonia inpatients12 western states. MMWR Morb Mortal Wkly Rep 1997; 46: 91923. Gleckman R, DeVita J, Hibert D, et al. Sputum gram stain assessment in community-acquired bacteriemic pneumonia. J Clin Microbiol 1988; 26: 84649. Tuomanen EI, Austrian R, Masure HR. Pathogenesis of pneumococcal infection. N Engl J Med 1995; 332: 128084. Stout JE, Yu VL. Legionellosis. N Engl J Med 1997; 337: 68287. Bryant RE, Salmon CJ. Pleural empyema. Clin Infect Dis 1996; 22: 74762.
Further reading
Mundy LM, Auwaerter PG, Oldach D, et al. Community-acquired pneumonia: impact of immune status. Am J Respir Crit Care Med 1995; 152: 130915. Riquelme R, Torres A, El-Ebiary M, et al. Community-acquired pneumonia in the elderly: a multivariate analysis of risk and prognostic factors. Am J Respir Crit Care Med 1996; 154: 145055.
1302