Empiric Therapy for Pneumonia

Gerald R. Donowitz and Gerald L. Mandell From the Division of Infectious Diseases, Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, Virginia

Bacterial pneumonia remains a serious infectious disease even in the modern era of an

tibiotics and still causes significant morbidity and mortality. Because of the large Downloaded from https://academic.oup.com/cid/article/5/Supplement_1/S40/378958 by guest on 02 October 2021 number of organisms that may cause pulmonary disease, the inexactness of commonly used diagnostic techniques, and the serious consequences of untreated disease, empiric therapy has become accepted practice. Empiric therapy should be designed for treat ment of the most likely etiologic organisms while minimizing the potential adverse effects of "shotgun" therapy: drug toxicity, superinfection, and excessive cost. The recognition of common pneumonia syndromes helps narrow the spectrum of possible etiologic agents and consequently aids in the design of rational empiric antibiotic therapy.

Even in the modern era of antibiotics, pneumonia to antibiotic therapy to avoid the dangers of drug remains a common life-threatening infectious toxicity, superinfection, and excessive cost asso disease and still accounts for significant morbidity ciated with "shotgun" therapy. Empiric therapy and mortality. Although the presence of pneu should be used in the initial 48-72 hr of the course monia is indicated by a carefully taken medical of the disease while results from appropriate cul history and physical examination of the patient, tures or other specific tests are pending. However, definition of the specific etiology remains a clini if these procedures do not produce a diagnosis (as cal challenge. Part of the difficulty is the extensive is often the case), a full course of empiric therapy list of organisms that can cause treatable pulmo should be administered. nary infection (table 1). Furthermore, the efficacy The recognition of pneumonia syndromes helps of common diagnostic techniques has been ques narrow the spectrum of possible etiologic agents tioned [2-5]. Problems in interpretation of gram and, therefore, helps the clinician develop a ra stains, difficulty in laboratory isolation of some of tional regimen of antibiotic therapy. the more fastidious (but commonly occurring) pulmonary pathogens, and difficulty in distin Acute, Community-Acquired Pneumonia guishing pulmonary infection from colonization are recognized problems in making a determina The syndrome of acute community-acquired tion of the specific etiology of pneumonia. Where pneumonia has been well studied. Large reviews as newer techniques for obtaining and processing have provided a characteristic epidemiologic and clinical material have been developed, questions clinical profile [6-9]. Typically, patients are in concerning their accuracy remain [5]. BeGause of their mid-50s and become ill in the mid- to late these problems, and because of the persistently winter or early spring. Although the onset of high morbidity and mortality of acute pulmonary symptoms of pneumonia is acute and represents a infection, institution of therapy prior to definite marked change in health, most patients have one etiologic identification has become generally or more underlying chronic diseases, which may accepted. include chronic obstructive lung disease, cardio The basic goals of empiric therapy are (1) to vascular disease, diabetes, or alcoholism. adequately treat the most likely etiologic agents in The rapid development of signs of respiratory order to avoid morbidity and mortality from un toxicity in association with sustained elevation of treated disease and (2) to use a selective approach temperature and cough productive of purulent sputum are clinical hallmarks of acute, com munity-acquired pneumonia. An elevated white Please address requests for reprints to Dr. Gerald R. Dono witz, University of Virginia School of Medicine, Department blood cell count, a chest roentgenogram revealing of Medicine, Box 385, Charlottesville, Virginia 22908. parenchymal infiltrate in a bronchopneumonic

S40 Empiric Therapy for Pneumonia S41

Table 1. Etiologic agents (treatable pathogens) of acute pneumonia. Type of pneumonia Pathogen(s)

Bacterial Common Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, mixed aerobes and anaerobes Less common Actinomyces and Arachnia species, Bacillus anthracis Enterobacteriaceae:

Klebsiella pneumoniae and Klebsiella species, Escherichia coli, Salmonella species, Enterobacter Downloaded from https://academic.oup.com/cid/article/5/Supplement_1/S40/378958 by guest on 02 October 2021 species, Serratia species, Proteus species, Yersinia pestis Francisella tularensis Legionella pneumophila Legionella micdadei Neisseria meningitidis Nocardia Pasteurella multocida Pseudomonas aeruginosa Pseudomonas pseudomallei Streptococcus pyogenes Rickettsial Coxiella burnet;; Mycoplasmal Mycoplasma pneumoniae Miscellaneous Chlamydia species

NOTE. Information in table is adapted from [1].

pattern, and a gram stain of sputum revealing true infection from colonization is difficult. As an numerous neutrophils and bacteria (with a single estimate, 2070-18070 of cases of acute community organism predominating) are the laboratory ab acquired pneumonia may be due to H. injluenzae normalities most often associated with the syn [6, 8, 18, 19]. Staphylococcus aureus may account drome [10, lOa]. for 2070-10070 of cases of acute, community In the preantibiotic era, >95070 of such cases of acquired pneumonia, with mixed aerobic-anaero community-acquired pneumonia were attributed bic infections and non-Haemophilus, gram-nega to Streptococcus pneumoniae [11]. More recently, tive pathogens causing the remainder [20]. several studies have documented S. pneumoniae as Specific note should be taken of bacterial pneu the etiologic agent in 55%-76% of acute com monia occurring during outbreaks of influenza. munity-acquired pneumonia [4, 7, 8]. Some of Patients are usually younger and have underlying these figures may be low estimates, since some disease less frequently than do patients with non cases of pneumonia of unknown etiology, which influenza-related, community-acquired pneumonia. account for 17%-43070 of cases, are probably due Clinical signs and symptoms of viral influenza are to pneumococci. Efficient isolation of pneumo present in the patients with influenza-related cocci requires rapid processing of cultures and, at pneumonia but stabilize or appear to resolve over times, special culture procedures. Previous anti several days. After a variable period of time rang biotic therapy may decrease the yield of sputum ing from two to 14 days, symptoms suddenly reap cultures [12, 13]. pear or become more severe, with the onset of Haemophilus injluenzae has become increasing shaking chills, pleuritic chest pain, and cough pro ly recognized as a cause of pneumonia in adults ductive of purulent sputum. Elevated white blood [14-17]. The true incidence of H. inJluenzae pneu cell counts with increased numbers of juvenile monia is not clear, since the organism may be dif forms, physical signs of pulmonary consolidation, ficult to isolate from sputum; most recent studies and roentgenographic evidence of focal paren have depended on the isolation of the organism chymal disease appear. The gram stain of sputum from blood, pleural fluid, or transtracheal as is consistent with a diagnosis of bacterial pneu pirates for diagnosis. In some older studies, these monia. Although S. pneumoniae still represents strict criteria were not used, and distinguishing the most common etiologic agent, staphylococcal S42 Donowitz and Mandell

disease occurs with a higher frequency than that of H. inf/uenzae, although a significant inoculum noted for noninfluenza-related, community-ac effect has been observed with the former drug quired pneumonia [21-25]. [46], and isolated cases of resistance have been re Penicillin and its cogeners remain the drugs of ported with the latter [47-49]. choice for treatment of disease caused by pneu Cefamandole and the third-generation cepha mococci. In the United States, no major changes losporins offer in vitro potential for treatment of in sensitivity of S. pneumoniae to penicillins have H. inJluenzae infections, although clinical experi occurred; penicillin G has an MIC of 0.003-0.042 ence is somewhat limited. Low MICs of cefaman JAg/ml for this organism, and ampicillin has an dole (~0.25 J.lg/ml) have been demonstrated for Downloaded from https://academic.oup.com/cid/article/5/Supplement_1/S40/378958 by guest on 02 October 2021 MIC of 0.01-0.04 JAg/ml [26, 27]. Penicillin-resis most strains of H. inJluenzae [37]. However, some tant strains of S. pneumoniae, e.g., those found in observers have noted MBCs significantly greater South Africa (MIC, 0.12-4 JAg/ml [28], New than MICs in ~14OJo of (3-lactamase-negative Guinea (MIC, 0.16-0.6 JAg/ml) [24], and Australia strains and unacceptably high MICs for certain (3- (MIC, 0.5 JAg/ml) [29, 30] have been seen in this lactamase-positive strains [50, 51]. Furthermore, country only sporadically [31-33]. Reports of an inoculum effect has been noted [52]. The clini S. pneumoniae resistant to chloramphenicol, eryth cal significance of these findings is unclear since romycin, and tetracycline have been made, though cefamandole has been used effectively in therapy usually in pediatric patients [34-36]. At present, for H. inJluenzae pneumonia. However, failure of first-generation cephalosporins with MICs of cefamandole in therapy for ampicillin-resistant 0.1-0.8 JAg/ml and erythromycin, with an MIC of H. inJluenzae pneumonia has been reported [53]. 0.001-0.04 JAg/ml, remain adequate alternative Moxalactam, cefotaxime, and cefoperazone have regimens to penicillin therapy in patients with extremely low MICs and MBCs to both (3-lacta presumed pneumococcal pneumonia. Therapy rnase-positive and -negative strains of H. inf/uen with the first-, second-, and third-generation zae without a marked inoculum effect [54, 55]. cephalosporins results in serum levels high enough Clinical experience with these drugs used specifi to inhibit all strains of penicillin-sensitive pneu cally against H. inJluenzae pneumonia is limited. mococci. However, the activities of cefoxitin Choice of empiric therapy for patients with (mean MIC, 0.125-0.5 J.lg/ml) [37] and moxalac acute, community-acquired pneumonia depends tam (mean MIC, 2- 4 J.lg/ml) [38, 39] are markedly in part on the situation in which pneumonia oc less than that of penicillin G. curs. In the simplest situation, that of occurrence The issue of therapy for suspected H. inf/uen of pneumonia in a patient who has no prior signs zae pneumonia is more difficult to resolve. Al and symptoms of chronic bronchitis and in whom though in the past H. inf/uenzae has been uniform the sputum shows gram-positive diplococci, peni ly susceptible to ampicillin, ampicillin-resistant cillin would be the most rational choice of antibi strains have been noted since 1974 [40-42]. Am otic, since the majority of such cases are in fact picillin resistance is usually due to (3-lactamase caused by pneumococci. If the pneumonia devel production. Resistance to ampicillin was reported ops in a patient with chronic obstructive pulmo recently in a strain of H. inf/uenzae that was nega nary disease, chronic bronchitis, or cigarette abuse, tive for (3-lactamase by the standard assay but pro where colonization of the airways with H. inf/uen duced a novel type of (3-lactamase [43]. Ampicillin zae as well as S. pneumoniae is likely, empiric an resistance has been noted in 5%-31 % of strains in tibiotic coverage against both of these organisms the United States, although wide geographic varia is necessary. In some locations, ampicillin offers tion in resistance of strains exists [44, 45]. Most of adequate coverage for both. S. pneumoniae and the data on prevalence of ampicillin-resistant H. inJluenzae. In centers where ampicillin-resis strains of H. inf/uenzae are derived from patho tant H. inJluenzae is of concern, chloramphenicol gens isolated from children, with the majority of represents the drug for which there is the greatest isolates coming from cerebrospinal fluid and clinical experience with therapy for life-threaten blood. Effective regimens of antibiotic therapy for ing H. inJluenzae infection. Cefamandole and tri ampicillin-resistant strains exist. Trimethoprim methoprim-sulfamethoxazole have been success sulfamethoxazole and chloramphenicol offer ade ful in therapy for serious H. inf/uenzae infections. quate coverage against (3-lactamase-positive strains Third-generation cephalosporins are promising Empiric Therapy jor Pneumonia S43

but have not yet proved predictably effective size and location of the aspirated material [63,64]. against ampicillin-resistant H. injluenzae. True bacterial pneumonia caused by aspiration oc When pneumonia occurs during an outbreak of curs after the aspiration of oropharyngeal materi influenza, S. aureus must be considered a com al into the lung. These syndromes are not mutually mon potential pathogen, in addition to S. pneu exclusive; lung tissue injured by acid aspiration moniae and H. injluenzae. In these cases, cefa appears more vulnerable to infection with bac mandole or a combination of nafcillin plus chlor teria. Twenty-five percent to 50070 of cases of gas amphenicol provide adequate coverage against all tric acid aspiration are followed by bacterial infec three of these pathogens. In patients whose tion, most likely due to oropharyngeal organisms Downloaded from https://academic.oup.com/cid/article/5/Supplement_1/S40/378958 by guest on 02 October 2021 sputum shows no gram-negative organisms, a pen "washed down" into the lung at the time of aspira icillinase-resistant penicillin would be the empiric ~ion [65, 66]. Obstruction that occurs after aspira therapy of choice. tion of particulate material usually results in bac terial infection if the obstruction persists for sever al weeks [67, 68]. Pneumonia Occurring as a Result of Aspiration Unlike the other syndromes associated with Pneumonia occurring as a result of aspiration aspiration, which usually cause acute symptoms, should be suspected when normal host defenses bacterial pneumonia caused by aspiration is insidi have been compromised by alterations in con ous in onset, with symptoms occurring days after sciousness or abnormalities of the normal pharyn the episode of aspiration. The bacteriology of geal and gag reflexes. Stroke, seizures, drug in aspiration pneumonia reflects the flora of the toxication, anesthesia, alcohol abuse, disorders of oropharynx. The important role of periodontal the central nervous system, intubation, tracheoto disease in increasing bacterial numbers in the my, nasogastric suction, and protracted vomiting oropharynx and the likelihood of infection follow should therefore be considered as conditions pre ing aspiration has been recognized [62]. In com disposing the patient to aspiration. munity-acquired disease, f\.J5007o of patients have Special note should be made of alcohol abuse in only anaerobes isolated; Peptostreptococcus spe this regard. Alcoholism has been the most fre cies, Bacteroides melaninogenicus, and Fusobac quent predisposing factor in studies of patients terium nucleatum are the predominant organisms. with pneumonia due to aspiration [56, 57]. Alco Mixed aerobic-anaerobic infections occur in hol-induced depression of consciousness and im f\.J4507o of cases [57, 69]. High-dose penicillin has pairment of normal pulmonary host defenses [58] been the antibiotic regimen of choice for commu are the major factors involved in this association. nity-acquired pneumonia due to aspiration; how Alcoholism has been prevalent among patients ever, some data suggest that clindamycin may be with both gram-positive and gram-negative pneu equally, if not more, effective [70, 71]. Cefoxitin monia. Though strictly designed epidemiologic has also been effective, but metronidazole should studies have not confirmed the association of al not be used as single-drug therapy because of its coholism with the development of pneumonia, unacceptably high failure rate, probably due to its this association is strongly suggested by clinical lack of activity against aerobes [72, 73]. experience. It is important to recognize that four major syn Atypical Pneumonia Syndrome dromes, only one of which is infectious, mayoc cur as a consequence of aspiration [59-61]. The atypical pneumonia syndrome is a complex of Chemical pneumonitis occurs following aspiration symptoms produced by a variety of agents, the of material directly toxic to lung tissues, including most common of which is Mycoplasma pneu acid (pH <2.5), hydrocarbons, or mineral oil moniae. In contrast to the more common bacterial [59]. Reflex closure and obstruction of airways pneumonias, atypical pneumonia is most often as may occur after aspiration of inert substances sociated with the older child (>5 years of age), the such as water, saline, tube feedings, or buffered adolescent, or the young adult. Increased inci gastric acid [62]. Partial or complete obstruction dence of disease and true epidemics have been of both upper and lower airways may occur after documented in relatively enclosed populations of aspiration of particulate matter, depending on the young adults at military bases, colleges, and S44 Donowitz and Mandell

boarding schools [74-76]. Mycoplasmal infection Legionella pneumophila Pneumonia occurs throughout the year, although a relative in Pneumonia caused by Legionella pneumophila crease in incidence is noted in the late summer and presents a syndrome that shares certain features of fall. both acute, community-acquired pneumonia and The clinical presentation of mycoplasmal pneu atypical pneumonia. Although the disease has monia is characterized by constitutional symp been described in the very young [87 -S9], most toms that predominate over specific respiratory cases occur in middle-aged patients (median age, tract symptoms. A nonproductive cough in associ

55 years) who have a history of cigarette and/or Downloaded from https://academic.oup.com/cid/article/5/Supplement_1/S40/378958 by guest on 02 October 2021 ation with fever, malaise, and headache is most alcohol abuse and an underlying chronic disease, commonly found, though a cough productive of usually chronic pulmonary disease [90, 91]. Initial purulent sputum may be noted in up to one-third symptoms resemble those associated with atypi of cases [77]. Patchy infiltrates in the lower lobe cal pneumonia, predominantly malaise, myalgia, seen in chest roentgenograms are more extensive and headache. In comparing clinical features of than the physical examination would indicate. L. pneumophila pneumonia with those of pneu Progression of the infiltrate on the chest roent mococcal pneumonia and mycoplasmal pneu genogram may be seen, despite a stable clinical monia, one notes that unexplained encephalo picture. The clinical course of mycoplasmal pneu pathy (or encephalopathy disproportionate to the monia in most cases is self-limited and benign. A amount of temperature elevation), the presence of diminution of constitutional symptoms is usually hematuria, and elevation of serum aspartate ami noted in the first and second weeks, although notransferase (SOOT) appear to occur more com cough and roentgenographic changes may persist monly in L. pneumophila pneumonia than in the for three weeks. Unusually severe cases of this other two types of pneumonia [92]. Abdominal disease have been seen in patients with sickle cell pain, "nausea, vomiting, and diarrhea are de disease [78, 79], and cases of adult respiratory dis scribed in L. pneumophila pneumonia but may tress syndrome in association with mycoplasmal also be seen in patients with pneumococcal and pneumonia have been reported [SO]. mycoplasmal pneumonia [92a]. Roentgenograms Effective antibiotic therapy for pneumonia due of persons with L. pneumophila pneumonia com to M. pneumoniae has been known since 1961, monly show unilateral lower-lobe disease, usually when it was shown in a double-blind study that with an alveolar or mixed alveolar-interstitial pat tetracycline hastened the resolution of fever, tern [92, 93]. Effusions may be seen in 200/0-60% cough, rales, fatigue, and roentgenographic ab of cases [92, 94]. Roentgenograms indicate that normalities in U. S. Marine recruits with serologic progression of disease occurs significantly more or microbiologic evidence of disease [SI]. Subse often in L. pneumophila pneumonia than in pneu quent evaluation established the similar efficacy mococcal and mycoplasmal pneumonia [92]. of erythromycin [82, 83] and a related new macro Because of the difficulty in isolation of the or lide antibiotic, josamycin [84]. While other anti ganism and the reliance on fluorescent stain of biotics have shown in vitro efficacy similar to that clinical material or serologic rises in antibody titer of erythromycin or tetracycline, clinical experi for diagnosis, empiric therapy of suspected ence with these antibiotics has been limited or has L. pneumophila infection is indicated. Erythro yielded negative results [S5, 86]. mycin, at a dosage of 0.5-1.0 g every 6 hr, remains The other etiologic agents involved in the atypi the therapy of choice. Since L. pneumophila cal pneumonia syndrome include Chlamydia psit pneumonia may not initially be clearly distinguish taci (psittacosis), Coxiella burnetii (Q fever), para able from other common types of pneumonia, em influenza virus, Epstein-Barr virus, respiratory piric therapy of L. pneumophila pneumonia may syncytial virus, and adenovirus. However, the be part of a two- or three-drug regimen. contribution of each of these agents to the total in cidence of atypical pneumonia is extremely small, Hospital-Acquired Pneumonia and therefore they will not be considered in deter mination of empiric therapy for the atypical pneu A different microbiologic picture is present in monia syndrome. cases of pneumonia that develop in the hospital; Empiric Therapy for Pneumonia S45

therefore, hospital-acquired pneumonia requires monary [103]. In patients with acute leukemia, an approach to empiric therapy different from 64070 of fatal bacteremias of known source origi that used to treat community-acquired disease. nate in the lung [l 04]. Of these pulmonary infec Approximately 60070 of cases of nosocomial pneu tions, 65070 are caused by gram-negative organisms monia are caused by aerobic, gram-negative rods, [104, 105]. Twelve percent to 42% of renal trans and members of the family Enterobacteriaceae plant recipients develop pneumonia at some time account for the majority of these cases. Staphylo during their course of treatment; 60% of these coccus causes rv 11 070 of cases of nosocomial pneu cases of pneumonia are a result of gram-negative monia, and S. pneumoniae causes only rv5OJo-a organisms [106-108]. Fifty percent of bone mar Downloaded from https://academic.oup.com/cid/article/5/Supplement_1/S40/378958 by guest on 02 October 2021 marked reversal of the pattern noted with com row transplant recipients develop pneumonia, and munity-acquired disease [95]. gram-negative organisms are the most common Since most cases of pneumonia are due to mi bacterial pathogens involved [109, 110]. croorganisms that comprise the oropharyngeal Of the gram-negative organisms involved in flora, the importance of nosocomial oropharyn pneumonia in the immunosuppressed host, two geal colonization with enteric gram-negative rods large groups predominate: the Enterobacteri as a predisposing factor for nosocomial pneu aceae, especially Escherichia coli and Klebsiella monia deserves emphasis. Only 6070-18070 of pneumoniae; and the pseudomonads, especially healthy people carry gram-negative enteric orga P. aeruginosa. In some studies, these three nisms in their oropharynx, and this phenomenon organisms account for rv50OJo of all infectious appears to be a transient occurrence [96, 97]. In episodes; mixed gram-negative infections account contrast, 75% of severely ill patients become for another 20070 [111, 112]. Other important, colonized by enteric gram-negative organisms though less frequent, gram-negative pathogens in after several days of hospitalization [97]. Serious the immunosuppressed host include species of Ser underlying disease, preexisting pulmonary disease, ratia, Enterobacter, Citrobacter, Proteus, Salmo previous use of broad-spectrum antibiotics, use of nella, and Legionella. Occasionally anaerobes respiratory equipment, exposure to endogenous may be important pathogens, especially in cases in hospital flora, and instrumentation that bypasses which aspiration has occurred. normal pulmonary host-defense mechanisms all Since gram-negative organisms colonize the facilitate colonization of the oropharynx of the oropharynx of severely ill patients, it is difficult in hospitalized patient with enteric gram-negative any given patient to determine whether bacteria rods and thereby potentiate the development of grown in sputum cultures or seen in gram stains lower respiratory tract disease due to enteric gram represent contaminants, commensals, or true negative rods [98, 99]. pathogens. In the immunosuppressed patient, Enteric gram-negative rods, including Pseudo symptoms commonly associated with pulmonary monas aeruginosa, account for the majority of infection may be subtle or entirely absent [113], cases of nosocomial pneumonia at most centers. roentgenographic changes may be nonspecific, In the last several years, Serratia marcescens has and the diagnostic tests that would be used in the been recognized as a major cause of hospital normal host are unhelpful or dangerous. Since acquired pneumonia [100, 101]. Although H. in pneumonia may progress rapidly without immedi fluenzae has been reported as having an important ate therapeutic intervention, and since mortality role in nosocomial infection in England [102], it remains high even with therapy, empiric antibiotic does not appear to be of major importance in this therapy must be used. country. In general, multiple- rather than single-drug As a special subset of nosocomial pneumonia, regimens are recommended for (1) treating pa the consideration of pneumonia in the immuno tients infected with pathogens that may be rela suppressed patient deserves special emphasis. As tively resistant to antimicrobial agents; (2) de with all nosocomial pneumonia, enteric gram creasing the chance of resistance developing negative rods are the major etiologic agents in during therapy; and (3) achieving synergistic anti volved. In patients with nonlymphocytic leu microbial activity. Antibiotic trials in immunosup kemia, 25% of all documented infections are pul- pressed patients have shown that improved clinical S46 Donowitz and Mandell

response and survival are associated with the use myxin with rifampin have been effectively used of antibiotics shown to be synergistic in vitro [136, 137]. against the organisms isolated [114, 115]. It should be noted that the 'inactivation of gen Therapy for infections caused by P. aeruginosa tamicin by carbenicillin has been reported [138]. presents an excellent example of this general prin Clinically significant inactivation appears to take ciple. Early reports of persistent infections were place only if the drugs are mixed together and al noted with gentamicin used as a single agent, even lowed to remain in contact for >24 hr or if serious when gentamicin-sensitive organisms were in renal impairment necessitates the use of a single volved [116]. Marked improvement was noted daily dose of aminoglycoside, which may persist in Downloaded from https://academic.oup.com/cid/article/5/Supplement_1/S40/378958 by guest on 02 October 2021 when gentamicin and carbenicillin were used to the blood for >24 hr [139]. gether [117, 118]. Synergy between tobramycin or Controversy exists as to the "best" empiric amikacin and carbenicillin, ticarcillin, mezlocillin, therapy for nosocomial pneumonia, including or piperacillin has been similarly shown [119-121]. cases in the immunosuppressed host. The combi Although the antimicrobial spectrum of tobramy nation of an aminoglycoside plus carbenicillin or cin is similar to that of gentamicin, tobramycin is ticarcillin would not be the regimen of choice to more active against P. aeruginosa [122-124], and treat infection with K. pneumoniae or S. aureus. gentamicin is more active against S. marcescens. A cephalosporin plus an aminoglycoside would Amikacin possesses a broad spectrum of activity not be the regimen of choice to treat pseudomonas against gram-negative organisms, including many infections. However, when two-drug regimens of organisms resistant to both gentamicin and tobra aminoglycosides and carbenicillins are compared mycin [125]. In cases in which resistance to genta with a three-drug regimen including a cephalo micin and tobramycin has been demonstrated, sporin, an aminoglycoside, and carbenicillin, no amikacin would be the aminoglycoside of choice. difference in overall response rate of a wide range Tobramycin is slightly, but significantly, less of infections, including pneumonia, has been nephrotoxic than gentamicin [126]. Carbenicillin, noted [140, 141]. The finding of increased nephro ticarcillin, mezlocillin, piperacillin, moxalactam, toxicity in patients receiving cephalothin and an and cefoperazone all have antipseudomonal activ aminoglycoside [142, 143] is a factor to be con ity and are potentially useful for pseudomonal sidered. Empiric programs have included a broad infections [127-130]. Although some of these spectrum penicillin (carbenicillin, ticarcillin, mez fJ-Iactam agents have potent activity against locillin, or piperacillin) plus an aminoglycoside; Pseudomonas, they should probably be used in a third-generation cephalosporin plus an amino conjunction with an aminoglycoside as therapy glycoside; or a broad-spectrum penicillin plus for pseudomonal pneumonia. Combinations of a a cephalosporin and an aminoglycoside. No cephalosporin with an aminoglycoside act syner firm data support the superiority of any of these gistically against K. pneumoniae [131, 132] and regimens. have potential usefulness against infections caused by this organism. Nosocomial Pneumonia due to Aspiration It has been shown that combinations of a cepha losporin, carbenicillin, ticarcillin, or other penicil The predisposing factors, pathophysiology, and lins with an amino glycoside act synergistically microbiology of community-acquired aspiration against a range of gram-negative organisms, in pneumonia have been discussed previously. Sever cluding E. coli and species of Enterobacter, Pro al differences between nosocomial and communi teus, and Serratia [132-135]. Synergy cannot al ty-acquired disease exist and should be examined. ways be demonstrated in vitro, but most authors Unlike community-acquired disease, for which pa suggest the use of the combination of a (3-lactam tients first seek medical help days or weeks after antibiotic and an aminoglycoside for treatment of the episode of aspiration, nosocomial aspiration is pneumonia due to enteric gram-negative rods. In usually witnessed or at least is suspected very the case of infections due to multiple-drug resis shortly after the occurrence. The timing of antibi tant S. marcescens, combinations of sulfamethox otic therapy for nosocomial aspiration is therefore azole-trimethoprim with polymyxin and poly- brought to question. Although some studies have Empiric Therapy for Pneumonia S47

suggested treatment immediately following all epi 6. Dorff, G. J., Rytel, M. W., Farmer, S. G., Scanlon, G. sodes of nosocomial aspiration [144, 145], others Etiologies and characteristic features of pneumonias in have suggested treatment for acute symptoms with a municipal hospital. Am. J. Med. Sci. 266:349-358, 1973. respiratory support (supplemental O2 and pul 7. Macfarlane, J. T., Finch, R. G., Ward, M. J., Macrae, monary toilet) but reserving use of antibiotics un A. D. Hospital study of adult community-acquired til true infection is documented. Since little data pneumonia. Lancet 2:255-258, 1982. exist that suggest that early use of antibiotics in 8. Sullivan, R. J., Dowdle, W. R., Marine, W. M., Hier fluences the development of postaspiration bacte holzer, J. C. Adult pneumonia in a general hospital. Etiology and host risk factors. Arch. Intern. Med. Downloaded from https://academic.oup.com/cid/article/5/Supplement_1/S40/378958 by guest on 02 October 2021 rial pneumonia [146, 147], and since antibiotics 129:935-942, 1972. used in this situation may result in higher rates of 9. Ziskind, M. M. The acute bacterial pneumonias in the superinfection with resistant organisms [148], we adult. Basics of R.D. 3:1, 1974. favor the latter approach. 10. Chatard, J. A. The leucocytes in acute lobar pneumonia. In hospitalized patients in whom bacterial Johns Hopkins Hospital Report 15:89-98, 1910. lOa. Boerner, D. F., Zwadyk, P. The value of the sputum pneumonia develops after aspiration, the major Gram's stain in community-acquired pneumonia. pathogens include gram-negative enteric rods and JAMA 247:642-645, 1982. S. aureus, as well as anaerobes [51, 63]. Empiric 11. Finland, M. Pneumonia and pneumococcal infections, therapy should therefore include agents that are with special reference to pneumococcal pneumonia. Am. Rev. Respir. 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In vitro granulocytopenia and cancer. Ann. Intern. Med. 78: activity of mezlocillin and its related compounds 825-826, 1973. against aerobic and anaerobic bacteria. Antimicrob. 142. Pennington, J. E. Fever, neutropenia, and malignancy: a Agents Chemother. 15:487-490, 1979. clinical syndrome in evolution. Cancer 39: 1345-1349, 131. Bulger, R. J. In vitro effectiveness of kanamycin and 1977. kanamycin/cephalothin against Klebsiella. Compari 143. Schimpff, S. C. Therapy of infection in patients with son with other antibiotics. Ann. Intern. Med. 67:523- granulocytopenia. Med. Clin. North Am. 61:1101- 532, 1967. 1118, 1977. 132. D'Alessandri, R. M., McNeely, D. J., Kluge, R. M. Anti 144. Ribaudo, C. A., Grace, W. J. Pulmonary aspiration. biotic synergy and antagonism against clinical isolates Am. J. Med. 50:510-520, 1971. of Klebsiella species. Antimicrob. Agents Chemother. 145. Dines, D. E., Titus, J. L., Sessler, A. D. Aspiration pneu 10:889-892, 1976. monitis. Mayo Clin. Proc. 34:347-360, 1970. 133. Klastersky, J., Hensgens, C., Meunier-Charpentier, F. 146. Lewis, R. T., Burgess, J. H., Hampson, L. G. Cardio Comparative effectiveness of combinations of amika respiratory studies in critical illness. Arch. Surg. 103: cin with penicillin G and amikacin with carbenicillin in 335-340, 1971. gram-negative septicemia: double-blind clinical trial. J. 147. Cameron, J. L., Mitchell, W. H., Zuidema, G. D. Aspir Infect. Dis. 134:S433-S440, 1976. ation pneumonia. Clinical outcome following docu 134. Klastersky, J., Hensgens, C., Debusscher, L. Empiric mented aspiration. Arch. Surg. 106:49-52, 1973. therapy for cancer patients: comparative study of ticar- Discussion DR. GERALD P. BODEY. The term "empiric anti patients with Clostridium perfringens and other biotic therapy" generally has been used to indicate types of clostridial infections, which occur occa the administration of antibiotics in a situation sionally in leukemic populations. The administra where infection, or at least the infecting organism, tion of appropriate antibiotic therapy at the onset has not been definitively established. This concept of fever still has failed to alter the course of the in of empiric antibiotic therapy has not always been fection and prevent the patient's death. Even with

accepted as a general principle. When we first other types of organisms occasional patients have Downloaded from https://academic.oup.com/cid/article/5/Supplement_1/S40/378958 by guest on 02 October 2021 began presenting the results of our empiric an an overwhelming infection that spreads so rapidly tibiotic trials in the early and mid-1960s, they were in a very short period of time that the patient dies. not always well received because many physicians Hence, there are some patients who will improve did not accept this concept. However, the recogni without therapy, and there are others who will fail tion that overwhelming sepsis can occur and can to respond even with the prompt administration of lead rapidly to death in some patient populations antibiotics. led to a reassessment of the principle that anti One current problem we face is that doctors biotic therapy should be withheld in febrile pa have become careless in their administration of tients until a site of infection and, hopefully, an antibiotics on an empiric basis. Often doctors ad organism, can be identified. Dr. Klastersky has al minister antibiotics to patients who do not have luded to the fact that there have been no well impaired host defences before they establish defin controlled trials indicating that this approach to itively that the cause of the fever is an infectious treatment is appropriate. He cited one of our early process. We now have a policy that when neutro studies of pseudomonas bacteremia conducted in penic patients develop a fever, they are observed the days when the only available antibiotics were for at least 2 hr to be certain that the fever persists the polymyxins. In this study we demonstrated before antibiotic therapy is instituted. In the that mortality was quite high within the first 24 hr. mid-1960s, we found that 1'\J35OJo of our patients Indeed, 16070 of patients died within 12 hr after the had what we called "fever of unknown origin"; first blood samples that proved culture positive that is, we were never able to clearly demonstrate were obtained. We also demonstrated in a later that they had an infection. Obviously, some of study on klebsiella bacteremia in a similar patient them did have infections, which cleared as a con population that mortality was 20070 in the first 24 sequence of antibiotic therapy. But in our more re hr. However, in that study at least a portion of the cent studies we have found that we have been un patients had already been receiving appropriate able to clearly demonstrate a site of infection or an antibiotic therapy from the onset of their infection. infecting organism in 1'\J50OJo-60OJo of our patients. It is now appropriate to discuss some of the A part of this problem is inherent in the empiric problems associated with this empiric administra administration of the antibiotics. It used to be that tion of antibiotics. I would like to focus on neu when we were treating a patient with pseudomo tropenic patients, to whom antibiotics are given nas septicemia, if we were unable to culture the when there is no clearcut evidence of infection organism on day 1 of therapy, we could culture it other than the presence of fever. First of all, as has on day 2 or day 3. Now, with the administration been pointed out by Dr. Young, neutropenic pa of anti-pseudomonal penicillins and amino tients who become febrile are at a high risk of glycosides, if we are unable to isolate the organism infection. However, in our study of pseudomonas before we institute antibiotic therapy, we are not septicemia, a few patients recovered without ap likely to isolate it thereafter, and the patient is propriate antibiotic therapy, so this possibility considered to have "fever of unknown origin." does occasionally exist. Secondly, there are some Another problem associated with empiric ther patients who will die even when antibiotics are ad apy is its effect on the changing prevalence of or ministrated promptly at the onset of fever. For ex ganisms within the hospital environment. We have ample, patients who have been splenectomized seen this phenomenon in our own hospital over who develop overwhelming pneumococcal infec the years. When methicillin first became available, tions fall into this category. Another example is we used it routinely as part of our empiric regimen

S52 Discussion S53

because of the high incidence of staphylococcal in derived from the sputum culture. As Dr. Meyers fections. Subsequently, we saw an increased inci pointed out, the information obtained from the dence of pseudomonas infections. When carbeni sputum culture was very limited. For example, in cillin became available, we began using that drug Charlottesville, Virginia, we isolated Streptococ on an empiric basis. Subsequently, there has been cus pneumoniae in only 14070 of these patients with a reduction in the frequency of occurrence of these community-acquired pneumonia. We isolated infections and the emergence of Klebsiella as a enteric gram-negative organisms from the sputum predominant organism. At the present time we are of 50070 of these patients; Staphylococcus aureus faced with a more difficult problem. We no longer was isolated from 5070, and the laboratory Downloaded from https://academic.oup.com/cid/article/5/Supplement_1/S40/378958 by guest on 02 October 2021 have a predominant organism in our institution, reported normal flora in 30070. So we agree that and at times must initiate therapy in a situation in the routine sputum culture was of very little help. which a very wide range of possibilities exists. We The house staff did not pay much attention to the have seen a resurgence of infections due to Staph culture results and made a specific etiologic ylococcus aureus, as have many other institutions, diagnosis in only 15070 of these patients. They and the widespread use of iv catheters has resulted focused on infections in which pneumococci were in a fairly substantial incidence of infection due to isolated, calling these "pneumococcal pneumonia" Staphylococcus epidermidis. Infections caused by and the others "pneumonia of questionable "nonpathogens" such as diphtheroids and Bacillus etiology." cereus are not uncommon. Hence, we are dealing Subsequently, we trained several medical stu with an enormously broad spectrum of infecting dents to read gram-stained specimens, and we had organisms. Indeed, some of these are not even the students available in the emergency room 24 hr bacterial infections, but are caused by cytomega a day so that all patients being admitted with acute lovirus, Pneumocystis carinii and fungi. What is pneumonia were screened. In a prospective study particularly disturbing is the high incidence of of 55 patients with pneumonia whose sputum was fungal infections in recent years, not only in pa examined by these students, the results of sputum tients who have been hospitalized for prolonged culture were similar to those of the 160-patient periods of time, but in leukemic patients when their study even though cultures were plated promptly disease is first diagnosed. The frequency of occur and special attention was paid to the isolation of rence of fungal infections in this population is con S. pneumoniae. We isolated S. pneumoniae from stant during the entire duration of hospitalization. the sputum of only 38070 of the 55 patients. When These are just a few of the major problems that we inoculated mice with the sputum samples, we we face as we evaluate the effectiveness of our increased our rate of isolation only to 55070. Blood antibiotic regimens. Certainly the empiric admin agar plates inoculated with the sputum of 42070 of istration of antibiotics is not the ultimate solution, patients screened yielded enteric bacilli. This sup but at present time it is an important component ports the observation that many people carry among our rather limited resources. The ability to gram-negative enteric bacilli in their oropharynx identify rapidly infections by detecting circulating at the time of onset of illness. antigens and other factors in the blood may assist Careful microscopic examination of the sputum us in the future. However, the ultimate solution in was valuable. We saw a predominant flora of the compromised host is the ability to treat the gram-positive lancet-shaped diplococci in 83070 of underlying factors that predispose patients to their the 55 patients, and we felt confident in assuming infectious complications. that these patients probably had pneumococcal pneumonia. These patients were treated with low * * * * * * * * * * * * * * * * * * * * * * * * dose penicillin and did well. A few patients had positive blood cultures, but the vast majority did DR. GERALD L. MANDELL. I am a strong supporter not. Positive quellung reactions of organisms seen of the use of the gram-stain for the evaluation of a in the sputum (the resurrection of an old test men patient with pneumonia. At the University of tioned earlier by Dr. Finland) were found in 75070 Virginia, we reviewed the charts of 160 patients of the 55 patients. Enteric bacilli, interestingly, who came to the emergency room with acute did not appear on the gram-stain of sputum speci pneumonia. We first looked at the information mens from any of these patients, even though cul- S54 Discussion

tures from 42% of the patients yielded enteric ba shaped or arrow-shaped, with the long axis end cilli. This observation indicates that the bacilli to-end and the broad base abutting. Our house were present in very small numbers and thus were staff has gotten used to the idea of performing a not seen by usual gram-staining techniques. Enter quellung test by putting a drop of Omni-serum® ic gram-negative bacilli are found frequently in (Statens Seruminstitut, Copenhagen, Denmark) sputum culture but are seen rarely on gram-stain on the appropriately prepared smear and looking and seem to be unimportant in community-ac for the clearly outlined capsule that tells you with quired pneumonia. certainty that this is S. pneumoniae. Haemophilus In community-acquired pneumonia, a gram in/luenzae, which is a small, coccobacillary, gram Downloaded from https://academic.oup.com/cid/article/5/Supplement_1/S40/378958 by guest on 02 October 2021 stain that shows a predominance or >10 gram-pos negative organism, is a very important cause of itive lancet-shaped diplococci per oil-immersion community-acquired pneumonia. S. aureus has a field is a very strong indicator of the presence of characteristic appearance; it is found in grapelike S. pneumoniae in that specimen. In the appropri clusters, and the individual organisms are ate clinical circumstances, such a finding implies spherical. that therapy with low-dose penicillin would be ap The gram-stain is of limited help in managing propriate. The evaluation of a gram-stain is some patients with nosocomial pneumonia, since it is thing of an art. A smear with many epithelial cells impossible to distinguish among various gram and few polymorphonucleocytes is inadequate; it negative bacilli. may represent saliva. Pneumococci are lancet-