THE JOURNAL OF INFECTIOUS DISEASES. VOL. 135. SUPPLEMENT • the University of Chicago. All rights reserved.
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1977
© 1977 by
Empiric Treatment with Clindamycin and Gentamicin of Suspected Sepsis Due to Anaerobic and Aerobic Bacteria From the Boston Veterans Administration Hospital, and the Infectious Disease Section, Tufts-New England Medical Center, Boston, Massachusetts
John G. Bartlett, Peter V. W. Miao, and Sherwood L. Gorbach
Recent studies have called attention to the frequent occurrence of mixed aerobic-anaerobic infections in certain clinical situations [1]. Antimicrobial selection is simplified for these patients if the infecting flora is defined and if in vitro susceptibilities are known. However, in the treatment of patients who are seriously ill, the physician cannot delay chemotherapeutic decisions until bacteriological results are available. In these situations the combination of clindamycin and gentamicin may be used on the basis of predicted activity against the different components of the infection: gentamicin is used for gram-negative bacilli and clindamycin for anaerobes. This report summarizes our experience with 107 seriously ill patients who were treated for infections in which a mixed aerobic-anaerobic flora was anticipated.
and (3) there was clinical evidence that suggested a mixed aerobic-anaerobic infection. Patients who had been receiving other antimicrobial agents were included if they failed to respond to former treatment and if culture results were not known when the decision to change the therapy was made. Clinical findings, gram stains of exudate, X rays, and other diagnostic techniques were used when appropriate to facilitate identification of the focus of infection and the pathogens. Test antimicrobial agents. The antimicrobial regimen that we tested was a combination of clindamycin and gentamicin. Clindamycin was administered in a dosage of 600 mg iv, three to four times daily. The initial dose of gentamicin was 1.5-2.0 mg/kg iv or im followed by a maintenance dose of 1.5 mg/kg at 8-hr intervals if the patient had normal renal function. For patients with renal failure, the maintenance dosage of gentamicin was adjusted according to levels of serum creatinine or serum gentamicin. Bacteriological studies. Blood cultures were obtained before treatment and thereafter at periodic intervals as indicated. Exudates from infected sites were collected when available. Acceptable specimens were those appropriate for anaerobic culture, including peritonitis fluid, abo scess contents, transtracheal aspirates, and exudate from the depths of soft tissue infections. Spe-
Materials and Methods
Criteria tor inclusion. Patients were included in the study if (1) severe sepsis was present, (2) bacteriological results were not available at the time of initial selection of antimicrobial agents,
Please address requests for reprints to Dr. John G. Bartlett, Veterans Administration Hospital, 150 South Huntington Avenue. Boston, Massachusetts 02130.
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Clindamycin and gentamicin were used in combination to treat 107 patients empirically for suspected aerobic-anaerobic sepsis. All patients were seriously ill and required initiation of treatment before results of cultures could be obtained. Infections included intraabdominal sepsis, hospital-acquired aspiration pneumonia, and soft tissue infections. Exudate cultured from 65 patients showed that the prediction of a mixed aerobic-anaerobic flora was correct in 46 patients (71%). Isolates from exudate included Escherichia coli, Bacteroides tragilis, clostridia, peptostreptococci, Proteus species, Klebsiella species, and Staphylococcus aureus. In 29 patients with bacteremia, the most frequent blood culture isolate was B. [ragilis. Analysis of response to treatment showed that 92 patients were cured, five could not be evaluated adequately, and 10 failed to respond to therapy. Therapeutic failure primarily resulted from overwhelming sepsis, despite susceptibility of the pathogens to prescribed antibiotics.
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Empiric Treatment for Sepsis
Results
The group of 107 patients treated empirically with clindamycin and gentamicin had a mean age of 57 years (range, 19-90 years). The mean peak temperature prior to treatment was 103.1 F, and there were 16 patients with fever higher than 105 F. Excluding patients with hematological disorders, the mean peripheral leukocyte count prior to treatment was 17,700jmm3 ; 10 patients had initial counts of > 30,000/mm3 • Twenty-eight patients had received other antimicrobials for the current infection, and the test regimen was substituted because of an unsatisfactory response. The previous agents included cephalosporins in 16 patients and iv penicillins in 10 patients. Twenty-nine patients underwent surgical drainage of abscesses or debridement procedures during the course of treatment with clindamycin and gentamicin. Infections were categorized as intraabdominal
sepsis (57 patients), hospital-acquired aspiration pneumonia (30 patients), and skin and soft tissue infections (20 patients). Intraabdominal sepsis. The diagnoses in 57 patients with intraabdominal sepsis were intraabdominal abscess (26 patients), peritonitis (10), wound infection after exploratory laparotomy (10), diverticulitis (four), sepsis complicating colonic carcinoma (four), cholangitis (one), gastritis with septicemia (one), and septicemia after rectal biopsy (one). Data were available from cultures of 41 patients, including 27 from whom exudate could be obtained and 21 who had positive blood cultures. (Seven patients with bacteremia also had exudate available for culture.) Bacteriological studies of exudate yielded a mixed aerobic-anaerobic flora in 23 patients (85%), only anaerobes in one, and only aerobes in three (table 1). Infections with only aerobes included spontaneous Escherichia coli peritonitis, a ruptured bladder with Proteus rettgeri peritonitis, and an abscess of the appendix cultured on the second day of treatment with clindamycin and gentamicin. The predominant anaerobes in the 27 specimens of exudate were Bacteroides fragilis and clostridia, which were recovered in 19 and 11 cases, respectively (table 2). The major aerobes were E. coli) other Enterobacteriaceae, Pseudomonas aeruginosa, and enterococci. The predominant organisms in blood cultures from 21 patients with septicemia were B. [ragilis (nine patients), E. coli (four), Klebsiella species (four), and Clostridium periringens (four). Evaluation of clinical responses of 57 patients with intraabdominal sepsis showed that cure was Table 1. Bacteriological results of culture of exudate from infected sites. No. of infections (%) yielding Type of infection (no. studied) Intraabdominal sepsis (27) Hospital-acquired aspiration pneumonia (21) Skin and soft tissue infection (1 7) Total (65)
Anaerobes Aerobes only only
Anaerobes plus aerobes
1(4)
3(11)
23(85)
1(5)
9(43)
11(52)
0
5(29)
12(71 )
17(26)
46(71)
2(3)
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cimens were transported to the laboratory for processing in an anaerobic chamber within 10 min of collection. For the recovery of anaerobes, we used previously reduced brucella agar base (containing 6% sheep's blood and 10 p.g of menadione /rnl) and laked-blood agar containing 75 p.g of kanamycin/rnl and 7.5 p.g of vancomycin/ ml. These media were incubated in an anaerobic chamber and held for seven days. Anaerobic isolates were identified by the criteria of the Virginia Polytechnic Institute manual [2]. Media used for isolation of aerobes were blood agar for incubation in 10% CO 2 , and MacConkey's agar and selective enterococcus agar (Pfizer Laboratories, New York, N. Y.) for incubation in air. Aerobic isolates were identified by conventional methods [3]. Evaluation of response. The criterion for cure was resolution of signs and symptoms of infection after the course of clindamycin and gentamicin was completed. The criteria for failure were (1) lack of objective response to treatment; (2) death of the patient during treatment, with infection considered to be a contributing factor to the fatal outcome; or (3) change of antimicrobial treatment because of drug toxicity, delayed response, or in vitro resistance of an isolate from the infected site.
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Bartlett, Miao, lind Gorboch
Table 2. Results of bacteriological analysis of exudate and blood cultures from infected sites in seriously ill patients. Intraabdominal sepsis"
Organism
Hospital-acquired aspiration pneumonia']
Skin and soft tissue infection ]
19(9) 5(1) 5 8(1) 4 11(4)
2 5 5 4{I) 7
8(2) 3
21(4) 5(4) 5 5 7 0 7
9 4 3 2 4{I) 7(2} 3
Anaerobes
3
1 4(1) 5 2(1) 6 1
7 3 6(1 )
7 4
NOTE. Data are numbers of isolates from exudate, with numbers of isolates from blood culture in parentheses. *Twenty-seven specimens of exudate and 21 positive blood cultures were obtained. tTwenty-one transtracheal aspirates and three positive blood cultures were obtained. :!:Seve~teen specimens of exudate and five positive blood cultures were obtained.
achieved in 51 (89%) (table 3). One patient could not be evaluated because of a fatal gastrointestinal hemorrhage that occurred during the course of antimicrobial treatment; however, there had been definite improvement in signs of sepsis at the time of the fatal complication. There were five deaths ascribed to infection. Three of these patients had septicemia, and two were hypotensive when the antimicrobial therapy was started. Blood cultures from the patients with fatal septicemia yielded B. tragi lis, C. periringens, and Klebsiella species. An additional fatality was a patient with a perforated sigmoid colon and a peri colonic abscess involving B. [ragilis and E. coli. The fifth fatality was Table 3. Clinical results in patients treated with clindamycin.
Type of infection Intraabdominal sepsis Hospital-acquired aspiration pneumonia Skin and soft tissue infection Total
No. of patients treated"
No. of cures
No. of failures
(%)
(%)
56
51(91)
5(9)
26
23(88)
3(12)
20
I8(90)
2{IO)
102
92(90)
IO{lO)
*Number of patients treated who could be evaluated.
a patient with intraabdominal carcinomatosis complicated by peritonitis; it was decided to defer surgical intervention. Hospital-acquired aspiration pneumonia. The diagnosis of hospital-acquired aspiration pneumonia in 30 patients was made on the basis of the following features: a predisposition to aspirate due to altered consciousness or dysphagia, evidence on X ray of an infiltrate in a dependent pulmonary segment, clinical signs of sepsis including fever and purulent sputum, and no extrapulmonary source of infection. Transtracheal aspiration was done on 21 patients prior to antimicrobial treatment. Cultures of the aspirates yielded a combination of aerobic and anaerobic bacteria in 11 patients (52%), only aerobes in nine, and only anaerobes in one (table 1). The predominant isolates were Enterobacteriaceae, anaerobic gram-negative bacilli (other than B. tragilis), anaerobic gram-positive cocci, and Staphylococcus aureus (table 2). Three patients had positive blood cultures, including two with S. aureus septicemia, and one with polymicrobial bacteremia. After administration of the antibiotic regimen. symptoms resolved and chest X-rays cleared in 23 (77%) of 30 patients. Four patients could not be evaluated because of their rapid demise
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Bacteroides fragilis Bacteroides species (other) Fusobacteria Peptostreptococci Peptococci Clostridia Aerobes Escherichia coli Klebsiella species Proteus species Pseudomonas aeruginosa Gram-negative bacilli (other) Staphylococcus aureus Streptococcusfaecaus
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Empiric Treatment for Sepsis
Discussion
The selection of antimicrobial agents is based optimally on in vitro susceptibility patterns of pathogens isolated from infected sites. This principle, while theoretically desirable, poses difficulties in the treatment of patients who are seriously ill. For example, there may be a lack of infected material for culture. Even when reliable specimens are obtained, bacteriological results are not usually available when initial therapeutic decisions must be made. This difficulty particularly applies to anaerobic infections since oxygen-sensitive bacteria grow relatively slowly, the infecting flora is often complex, and several days may be required to sort out the culture results. As a practical consequence, decisions concerning antimicrobial agents must be empiric, based on suspected, rather than established pathogens. In this series of infections, the anticipated bacteriology was a mixed flora com posed of anaerobic bacteria and aerobic gram-negative bacilli. vVe predicted this pattern because of the location and clinical features of the infection. Intraabdominal infections, other than spontaneous peritonitis and biliary tract sepsis, usually involve both aerobic gram-negative bacilli and anaerobes derived from the fecal flora [4]. Previous studies from our laboratory indicate that hospital-acquired aspiration pneumonia, in contrast to community-acquired pneumonia, also is associated with a mixed aerobic-anaerobic flora [5]. Soft tissue infections are caused by a heterogeneous array of bacteria; characteristics which have proven useful in signaling the presence of anaerobes include infected foot ulcers of patients with diabetes, gangrene, gas in tissues, abscess formation, and the penetrating odor of putrefaction [6-8]. An additional clue is a gram-stained slide of exudate showing organisms with distinctive morphological features, often in the setting of a polymicrobial flora. Exudate was available for culture from 65 of the 107 patients studied. Bacteriological results confirmed the presence of anaerobic bacteria in 48 bases (74%), and a mixed aerobic-anaerobic flora in 46 cases (71~~). Of 17 specimens collected after the initiation of treatment with clindamycin and gentamicin, five yielded only aerobic bacteria. Since the cultivation of anaerobes from
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from underlying conditions during the course of treatment with clindamycin and gentamicin. The causes of death were myocardial infarction, pulmonary embolism, gastrointestinal hemorrhage, and cardiac arrhythmia. All four patients had clinical evidence of improvement of the pulmonary infection at the time of the fatal complications. There were three fatalities in which pulmonary infection was a contributing factor. Each patient was severely debilitated; multiple lobes of the lung were involved and clinical deterioration was rapid, with death occurring within three days. Transtracheal aspirates in these three patients showed mixed aerobic-anaerobic flora, and all isolates subsequently proved susceptible in vitro to the test antimicrobial agents. Skin and soft tissue infections. Of the 20 patients with infection of the skin and soft tissue, six had diabetes and foot ulcers complicated by extensive cellulitis, four had prostatic abscess, three had infection of an amputated stump of a lower extremity, two had infected traumatic wounds, one had periorbital cellulitis secondary to maxillary sinusitis, one had an infected decubitus ulcer, one had gangrene of the foot, one had a wound infection after carotid endarterectomy, and one had a wound infection following open hi p reduction. Exudate was available for culture from 17 patients; five patients had bacteremia. Cultures of exudate revealed a combination of aerobes and anaerobes in 12 cases and an exclusively aerobic flora in five (table 1). The predominant isolates in exudate were B. fragilis, anaerobic gram-positive cocci, E. coli, Proteus species, and S. aureus (table 2). Positive blood cultures from five patients yielded B. [ragilis (two patients), peptostreptococci (one), Clostridium pavaputriiicum (one), and Serratia marcescens (one). Eighteen of these 20 patients were cured, and two were considered therapeutic failures. One of the patients who failed to respond had gangrene of an amputated stump with B. fragilis bacteremia and died on the first day of treatment. The second failure was a patient with diabetes mellitus and severe cellulitis involving Proteus mirabilis and P. aeruginosa. Although both isolates were susceptible to gentamicin, there was no clinical improvement, and an amputation was performed on day 5 of treatment.
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emia, 36 had intraabdominal abscesses or generalized peritonitis, and seven had severe extremity wounds associated with vascular insufficiency. In addition, there were 30 cases of hospital-acquired pneumonia, and the mortality rate for this condition has been reported to be as high as 30% [11J. Analysis of the response to treatment with clindamycin and gentamicin showed that cure was achieved in 92 (90%) of the 102 cases. Even in the 10 therapeutic failures, virtually all pathogens were susceptible to clindamycin or gentamicin. However, the antibiotics were not effective for these patients because of the fulminant course of their illnesses, four of which were associated with bacteremia. The monitoring of patients for side effects showed a hypersensitive skin rash in one patient, although both antibiotics were continued in this individual without additional ill effects. Seven patients had increasing serum creatinine levels which may have been due to gentamicin, but this effect proved difficult to evaluate in view of the serious associated conditions. None of the patients had debilitating diarrhea or documented pseudomembranous colitis. It is our view that the regimen of clindamycin and gentamicin in combination is useful for patients in whom there is a likelihood that a mixed flora is present. Furthermore, selection of the appropriate patients to receive this regimen can usually be made clinically, based on a careful assessment of the disease process. References 1. Gorbach, S. L., Bartlett, J. G. Anaerobic infections. N. Eng!. ]. Med. 290:1177-1184, 1237-1245, 12891294,1974. 2. Holdeman, L. V., Moore, W. E. C. [cd.]. Anaerobe laboratory manual. 3rd ed. Virginia Polytechnic Institute and State University, Blacksburg, Va., 1975. 132 p. 3. Lennette, E. H., Spaulding, E. H., Truant, J. B. [ed.]. Manual of clinical microbiology. 2nd ed. American Society for Microbiology, Washington, D.C., 1974, p. 189-221,250-269. 4. Thadepalli, H., Gorbach, S. L., Broido, P. W., Norsen, j., Nyhus, L. M. Abdominal trauma, anaerobes, and antibiotics. Surg. Gynecol. Obstct. 137:270-276, 1973. 5. Bartlett, J. G., Finegold, S. M. Anaerobic infections of the lung and pleural space. Am. Rev. Respir. Dis. IlO:56-77,1974.
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infected sites seems to be rapidly reduced by the presence of clindamycin [9], the actual incidence of anaerobe-associated infections may be somewhat higher. Gentamicin is active against the vast majority of aerobic gram-negative bacilli, whereas clindamycin is effective against most anaerobic bacteria, including B. [ragilis. Analysis of the types of bacteria recovered from 83 patients with available culture data (exudate and/or blood cultures) showed that 18 had aerobic gram-negative bacilli that might be resistant to commonly used antibiotics other than gentamicin. These organisms included P. aeruginosa, indole-positive Proteus, and S. marcescens. The most frequently encountered anaerobe, B. fragilis, was recovered from exudate in 29 patients and from blood cultures in II patients; all of these strains were sensitive to clindamycin. Another possible advantage of clindamycin is its activity against S. aureus. This organism was isolated in seven patients with hospital-acquired aspiration pneumonia and in seven with soft tissue infections. Analysis of 1,050 strains of S. aureus over the past four years at our hospital showed that 1,022 strains (97%) were susceptible to clindamycin, with no apparent shift towards resistance in the more recent years (authors' unpublished observations). (Gentamicin also shows good activity against S. aureus, but there are few clinical studies to document its efficacy in serious staphylococcal infections.) In vitro tests of the organisms isolated from our patients showed that most were susceptible to either clindamycin or gentamicin. One exception was a blood culture isolate of C. paraputrificum that was resistant to clindamycin at a level of 25 fLg/ml. Signs of sepsis and bacteremia cleared in this patient during treatment with clindamycin and gentamicin, before susceptibility data were reported. Spontaneous clearing of clostridial bacteremia has been reported [1OJ. The only other resistant organism was Streptococcus [aecalis, which was recovered in 14 cases. In each instance this organism was part of a complex flora of exudate and was never encountered in blood cultures. The role of S. faecalis as a pathogen in this setting is ill-defined. All patients entered into the study were seriously ill. Twenty-nine had documented bacter-
Bartlett, Miao, and Gorbach
Empiric Treatment jor Sepsis
6. Louie, T. j., Bartlett, ]. G., Tally, F. P., Gorbach, S. L. Aerobic and anaerobic bacteria in diabetic foot ulcers. Ann. Intern. Med. 85:461-463, 1976. 7. MacLennan, J. D. The histotoxic clostridial infections of man. Bacteriol. Rev. 26:177-276,1962. 8. Altemeier, W. A. The cause of the putrid odor of perforated appendicitis with peritonitis. Ann. Surg. 107: 634-636, 1938. 9. Gorbach, S. L., Thadepalli, H. Clindamycin in pure
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and mixed anaerobic infections. Arch. Intern. Med. 134:87-92, 1974. 10. Gorbach, 5. L., Thadepalli, H. Isolation of Clostridium in human infections: evaluation of 114 cases. J. Infect. Dis. 131 (SuppI.):S81-S85, 1975. 11. O'Keefe, J. P., Bartlett, J. G., Tally, F. P., Gorbach, S. L. An heuristic approach to hospital-acquired pneumonia [abstract]. Clin. Res. 23:589A, 1975.
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Discussion Moderator: Robert Condon
don't perform proctoscopy routinely, so we can't make statements about pseudomembranous colitis. We've had very little trouble with clindamycin and therefore we like it. But on our service, if the house staff and other physicians decide to use penicillin instead, we do not disparage that choice. DR. J. G. BARTLETT. Dr. Louria, regarding the comparison study we did with penicillin and clindamycin, you mentioned that the risk factors had not been taken into account. I would agree with the risk factors you mentioned: age, chronicity of the lesion, and the size of the cavity. Although we may not have reported individual case data, we did report statistical means for each of those variables, and the two groups of antibiotic-treated patients proved to be comparable. I am not surprised that there are anecdotal experiences with lung abscess which do not respond to penicillin, but those cases appear to be relatively uncommon. Since the clinical experience with penicillin G is so extensive and the response is so good, I still think that penicillin has to be regarded as the drug of choice. DR. FINEGOLD. There are instances in which penicillin G fails. In the Western Journal of Medicine, there is a discussion of a patient with lung abscess who failed to respond despite two extended courses of penicillin G in a dosage of 10-12 X 106 units per day. Subsequently, he responded to clindamycin therapy. We are currently treating another patient with a lung abscess who also failed to respond to penicillin G but subsequently responded to chloramphenicol. Dr. Louria, I don't share your dim view of transtracheal aspiration (TTA). It is a safe procedure in the hands of those who have used it enough to be adept, provided that high-risk patients, such as those with bleeding tendencies or those having difficulty oxygenating, are excluded. DR. LaURIA. In the best of hands, there are patients who are going to die or be hurt by TTA. I am concerned about physicians who read the literature where it is suggested that TTA is the way to diagnose gram-negative pneu-
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DR. S. M. FINEGOLD. Dr. Louria, in regard to lung abscess, you commented that there were several factors that influenced prognosis, the most consistent being the size of the abscess. You seemed to imply that large abscesses often require surgical drainage. I would like to suggest that abscesses of great size often respond well to medical therapy. In fact, I believe that in most cases surgery is contraindicated since it carries the risk of the patient drowning from material spreading from the abscess cavity during positioning on the operating table. DR. D. B. LaURIA. With regard to cavity size, my point was that a fair number of studies utilized cavity size as a determinant as to whether they would likely heal on medical therapy, and this variable must be considered. We agree that the majority of patients do not require surgery. And, of course, if we're going to compare antibiotics, cavity size is just one variable to consider in terms of antimicrobial response. We have to look at duration of disease and rate of cavity closure as well. In certain cases, drainage is perhaps more efficacious than not using this technique, but I really think that's a nuance. DR. S. M. FINEGOLD. Dr. Louria, you mentioned the studies of Bartlett and Gorbach which indicate that penicillin works effectively in anaerobic pneumonia, whether or not Bacteroides fragilis is present. You pointed out that others have also had considerable experience using penicillin alone for lung abscess. My feeling is that penicillin is ordinarily the preferred drug in anaerobic pulmonary infection of any type including lung abscess, with the exception of patients with hospital-acquired aspiration pneumonia, in which case it is necessary to cover other organisms as well. Is your choice of therapy clindamycin? DR. LaURIA. As to choice, we prefer clindamycin, but I think you will concur that one really can't be dogmatic on the basis of current evidence. We feel comfortable with clindamycin and haven't had any significant toxicity. We've seen relatively little diarrhea. 'Ve do discontinue the drug as soon as any diarrhea occurs. We
Discussion
procedure for selected clinical settings such as necrotizing pneumonia, hospital-acquired pneumonia, and pulmonary infection in the compromised host. Another consideration is the patient who has an abnormality on chest X ray, and we're not certain if it represents bacterial infection. Our experience suggest that a negative result with TTA virtually excludes the possibility of bacterial infection. DR. S. L. GORBACH. To address a different subject, I would like to solicit comments concerning chloramphenicol therapy for B. fmgilis infection. We have been using clindamycin for so long in anaerobic infections that I can no longer compare it with chloramphenicol in terms of efficacy. Perhaps, the others here who have had experience with chloramphenicol might comment or provide actual data on the comparative use of these drugs. DR. R. J. FASS. Several studies have shown some cases of serious B. fragilis infections that failed to respond to chloramphenicol. One of our patients had persistently positive blood cultures of B. fragilis despite 6 g of chloramphenicol per day. This occurs less commonly with clindamycin. DR. M. E. LEVISON. Some patients with organisms ostensibly sensitive in vitro fail to respond to chloramphenicol and others to clindamycin. There does not seem to be adequate evidence to say which is the preferable agent. There are circumstances such as infections of the central nervous system in which chloramphenicol is the preferable drug. DR. CHOW. Much of our experience with chloramphenicol has been from a retrospective study of bacteriodes bacteremia. The results with clindamycin and chloramphenicol were comparable, but the numbers were small. DR. BARTLETT. \Ve have had several patients who failed to respond to chloramphenicol even though they were infected by organisms susceptible to that agent. In most cases, the pathogen was B. fmgilis, and these patients subsequently responded to clindamycin. We have also had failures with clindamycin, but the organisms have usually been resistant to the drug. DR. G. T. KEUSCH. I wonder if the panelists would agree that we can bury the issue of highdosage penicillin, in combination with an
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monia. Unfortunately, some will interpret this to mean every pneumonia. Certainly, I can't approve of doing TTA on a patient who is bringing up putrid sputum. I know what the diagnosis is. DR. R. 1\1. SWENSON. OU! approach to TTA is based on some studies we did a few years ago on patients with alcoholism. About 15% of alcoholics have significant numbers of gramnegative facultative anaerobes as part of their normal oropharyngeal flora. At least in theory, there is about a 15% chance of gram-negative rods being present in the expectorated sputum from patients with alcoholism. About 90% of the patients who develop anaerobic pulmonary infections outside of the hospital are not critically ill. We get blood cultures and a coughed specimen of sputum and begin penicillin therapy. The following day, if we find that the patients have gram-negative rods in the coughed sputum, we then do TTA to differentiate between oropharyngeal colonization and true gram-negative pneumonia. We think that TTA is desirable because the hazards of several weeks of gentamicin or kanamycin therapy probably outweigh the risks associated with TTA. DR. A. W. CHOW. The indications for doing TTA are not so much for diagnosis of anaerobic pulmonary infection, but rather for diagnosis of aerobic, gram-negative bacillary pneumonia. We have agreed that putrid sputum indicates the presence of anaerobes, but certainly it does not rule out coexisting aerobes, particularly gram-negative rods. Anaerobes can be treated with penicillin, regardless of whether the organisms are cultured. The problem is with aerobic gram-negative rods in patients with necrotizing bacillary pneumonia, a serious disease requiring potentially toxic antibiotic therapy. In that situation, as well as in hospital-acquired aspiration pneumonia and in patients who fail to respond to conventional therapy, TTA is very helpful. In addition, I think that TTA may be helpful sometimes in recovering tubercle bacilli. DR. BARTLETT. TTA is a good technique to identify the flora of the lower respiratory tract in a patient who has an ill-defined pneumonia. The suggestion that any patient who comes into the hospital with pneumonia should have TTA is not a reflection of our view. We reserve this
587
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and the usual clinical context is that drainage occurs after a rather prolonged period of antibiotic therapy, usually administered in the hope that the abscess will heal without the necessity for surgical intervention. Do you administer antibiotics to all patients who are having surgical drainage of an abscess, and do you continue that treatment once drainage is established? What criteria do you use for either continuing or stopping antibiotic therapy? DR. R. L. NICHOLS. Surgical drainage alone is better than antibiotics alone, but drainage alone, even with good initial response, can lead to septicemia in some patients. I prefer drainage plus antibiotics for deep abscesses, assuming that some small loculations may persist. The routine use of potent antimicrobial agents for superficial wound abscess seems superfluous to me, because you can adequately drain, irrigate, and clean up any superficial wound. We know there are septicemic episodes during the period of drainage, but then there is no further contamination.
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aminoglycoside for treatment of intraabdominal sepsis, or is there still a question? DR. FASS. For colon-related intraabdominal sepsis, I would not recommend this combination. For some infections, such as biliary tract sepsis, these drugs might be useful, and I generally treat such patients with ampicillin and an aminoglycoside. DR. SWENSON. In the case of diffuse peritonitis, B. fragilis is common. In that circumstance I would be uncomfortable using just penicillin and an aminoglycoside. Even large doses of carbenicillinmight not be sufficient in this situation since about 10% of B. fragilis are resistant to this drug. My impression is that the primary modality of therapy for localized abscesses is surgical drainage, and it might be difficult to show much difference among a variety of regimens in this setting. DR. R. CONDON. Dr. Nichols, in your presentation you indicated that the treatment of an abscess was both drainage and the administration of antibiotics. Conventional wisdom says that drainage is sufficient treatment for an abscess,
Discussion
~fARCH
1977
© 1977 by
Empiric Treatment with Clindamycin and Gentamicin of Suspected Sepsis Due to Anaerobic and Aerobic Bacteria From the Boston Veterans Administration Hospital, and the Infectious Disease Section, Tufts-New England Medical Center, Boston, Massachusetts
John G. Bartlett, Peter V. W. Miao, and Sherwood L. Gorbach
Recent studies have called attention to the frequent occurrence of mixed aerobic-anaerobic infections in certain clinical situations [1]. Antimicrobial selection is simplified for these patients if the infecting flora is defined and if in vitro susceptibilities are known. However, in the treatment of patients who are seriously ill, the physician cannot delay chemotherapeutic decisions until bacteriological results are available. In these situations the combination of clindamycin and gentamicin may be used on the basis of predicted activity against the different components of the infection: gentamicin is used for gram-negative bacilli and clindamycin for anaerobes. This report summarizes our experience with 107 seriously ill patients who were treated for infections in which a mixed aerobic-anaerobic flora was anticipated.
and (3) there was clinical evidence that suggested a mixed aerobic-anaerobic infection. Patients who had been receiving other antimicrobial agents were included if they failed to respond to former treatment and if culture results were not known when the decision to change the therapy was made. Clinical findings, gram stains of exudate, X rays, and other diagnostic techniques were used when appropriate to facilitate identification of the focus of infection and the pathogens. Test antimicrobial agents. The antimicrobial regimen that we tested was a combination of clindamycin and gentamicin. Clindamycin was administered in a dosage of 600 mg iv, three to four times daily. The initial dose of gentamicin was 1.5-2.0 mg/kg iv or im followed by a maintenance dose of 1.5 mg/kg at 8-hr intervals if the patient had normal renal function. For patients with renal failure, the maintenance dosage of gentamicin was adjusted according to levels of serum creatinine or serum gentamicin. Bacteriological studies. Blood cultures were obtained before treatment and thereafter at periodic intervals as indicated. Exudates from infected sites were collected when available. Acceptable specimens were those appropriate for anaerobic culture, including peritonitis fluid, abo scess contents, transtracheal aspirates, and exudate from the depths of soft tissue infections. Spe-
Materials and Methods
Criteria tor inclusion. Patients were included in the study if (1) severe sepsis was present, (2) bacteriological results were not available at the time of initial selection of antimicrobial agents,
Please address requests for reprints to Dr. John G. Bartlett, Veterans Administration Hospital, 150 South Huntington Avenue. Boston, Massachusetts 02130.
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Clindamycin and gentamicin were used in combination to treat 107 patients empirically for suspected aerobic-anaerobic sepsis. All patients were seriously ill and required initiation of treatment before results of cultures could be obtained. Infections included intraabdominal sepsis, hospital-acquired aspiration pneumonia, and soft tissue infections. Exudate cultured from 65 patients showed that the prediction of a mixed aerobic-anaerobic flora was correct in 46 patients (71%). Isolates from exudate included Escherichia coli, Bacteroides tragilis, clostridia, peptostreptococci, Proteus species, Klebsiella species, and Staphylococcus aureus. In 29 patients with bacteremia, the most frequent blood culture isolate was B. [ragilis. Analysis of response to treatment showed that 92 patients were cured, five could not be evaluated adequately, and 10 failed to respond to therapy. Therapeutic failure primarily resulted from overwhelming sepsis, despite susceptibility of the pathogens to prescribed antibiotics.
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Empiric Treatment for Sepsis
Results
The group of 107 patients treated empirically with clindamycin and gentamicin had a mean age of 57 years (range, 19-90 years). The mean peak temperature prior to treatment was 103.1 F, and there were 16 patients with fever higher than 105 F. Excluding patients with hematological disorders, the mean peripheral leukocyte count prior to treatment was 17,700jmm3 ; 10 patients had initial counts of > 30,000/mm3 • Twenty-eight patients had received other antimicrobials for the current infection, and the test regimen was substituted because of an unsatisfactory response. The previous agents included cephalosporins in 16 patients and iv penicillins in 10 patients. Twenty-nine patients underwent surgical drainage of abscesses or debridement procedures during the course of treatment with clindamycin and gentamicin. Infections were categorized as intraabdominal
sepsis (57 patients), hospital-acquired aspiration pneumonia (30 patients), and skin and soft tissue infections (20 patients). Intraabdominal sepsis. The diagnoses in 57 patients with intraabdominal sepsis were intraabdominal abscess (26 patients), peritonitis (10), wound infection after exploratory laparotomy (10), diverticulitis (four), sepsis complicating colonic carcinoma (four), cholangitis (one), gastritis with septicemia (one), and septicemia after rectal biopsy (one). Data were available from cultures of 41 patients, including 27 from whom exudate could be obtained and 21 who had positive blood cultures. (Seven patients with bacteremia also had exudate available for culture.) Bacteriological studies of exudate yielded a mixed aerobic-anaerobic flora in 23 patients (85%), only anaerobes in one, and only aerobes in three (table 1). Infections with only aerobes included spontaneous Escherichia coli peritonitis, a ruptured bladder with Proteus rettgeri peritonitis, and an abscess of the appendix cultured on the second day of treatment with clindamycin and gentamicin. The predominant anaerobes in the 27 specimens of exudate were Bacteroides fragilis and clostridia, which were recovered in 19 and 11 cases, respectively (table 2). The major aerobes were E. coli) other Enterobacteriaceae, Pseudomonas aeruginosa, and enterococci. The predominant organisms in blood cultures from 21 patients with septicemia were B. [ragilis (nine patients), E. coli (four), Klebsiella species (four), and Clostridium periringens (four). Evaluation of clinical responses of 57 patients with intraabdominal sepsis showed that cure was Table 1. Bacteriological results of culture of exudate from infected sites. No. of infections (%) yielding Type of infection (no. studied) Intraabdominal sepsis (27) Hospital-acquired aspiration pneumonia (21) Skin and soft tissue infection (1 7) Total (65)
Anaerobes Aerobes only only
Anaerobes plus aerobes
1(4)
3(11)
23(85)
1(5)
9(43)
11(52)
0
5(29)
12(71 )
17(26)
46(71)
2(3)
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cimens were transported to the laboratory for processing in an anaerobic chamber within 10 min of collection. For the recovery of anaerobes, we used previously reduced brucella agar base (containing 6% sheep's blood and 10 p.g of menadione /rnl) and laked-blood agar containing 75 p.g of kanamycin/rnl and 7.5 p.g of vancomycin/ ml. These media were incubated in an anaerobic chamber and held for seven days. Anaerobic isolates were identified by the criteria of the Virginia Polytechnic Institute manual [2]. Media used for isolation of aerobes were blood agar for incubation in 10% CO 2 , and MacConkey's agar and selective enterococcus agar (Pfizer Laboratories, New York, N. Y.) for incubation in air. Aerobic isolates were identified by conventional methods [3]. Evaluation of response. The criterion for cure was resolution of signs and symptoms of infection after the course of clindamycin and gentamicin was completed. The criteria for failure were (1) lack of objective response to treatment; (2) death of the patient during treatment, with infection considered to be a contributing factor to the fatal outcome; or (3) change of antimicrobial treatment because of drug toxicity, delayed response, or in vitro resistance of an isolate from the infected site.
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Bartlett, Miao, lind Gorboch
Table 2. Results of bacteriological analysis of exudate and blood cultures from infected sites in seriously ill patients. Intraabdominal sepsis"
Organism
Hospital-acquired aspiration pneumonia']
Skin and soft tissue infection ]
19(9) 5(1) 5 8(1) 4 11(4)
2 5 5 4{I) 7
8(2) 3
21(4) 5(4) 5 5 7 0 7
9 4 3 2 4{I) 7(2} 3
Anaerobes
3
1 4(1) 5 2(1) 6 1
7 3 6(1 )
7 4
NOTE. Data are numbers of isolates from exudate, with numbers of isolates from blood culture in parentheses. *Twenty-seven specimens of exudate and 21 positive blood cultures were obtained. tTwenty-one transtracheal aspirates and three positive blood cultures were obtained. :!:Seve~teen specimens of exudate and five positive blood cultures were obtained.
achieved in 51 (89%) (table 3). One patient could not be evaluated because of a fatal gastrointestinal hemorrhage that occurred during the course of antimicrobial treatment; however, there had been definite improvement in signs of sepsis at the time of the fatal complication. There were five deaths ascribed to infection. Three of these patients had septicemia, and two were hypotensive when the antimicrobial therapy was started. Blood cultures from the patients with fatal septicemia yielded B. tragi lis, C. periringens, and Klebsiella species. An additional fatality was a patient with a perforated sigmoid colon and a peri colonic abscess involving B. [ragilis and E. coli. The fifth fatality was Table 3. Clinical results in patients treated with clindamycin.
Type of infection Intraabdominal sepsis Hospital-acquired aspiration pneumonia Skin and soft tissue infection Total
No. of patients treated"
No. of cures
No. of failures
(%)
(%)
56
51(91)
5(9)
26
23(88)
3(12)
20
I8(90)
2{IO)
102
92(90)
IO{lO)
*Number of patients treated who could be evaluated.
a patient with intraabdominal carcinomatosis complicated by peritonitis; it was decided to defer surgical intervention. Hospital-acquired aspiration pneumonia. The diagnosis of hospital-acquired aspiration pneumonia in 30 patients was made on the basis of the following features: a predisposition to aspirate due to altered consciousness or dysphagia, evidence on X ray of an infiltrate in a dependent pulmonary segment, clinical signs of sepsis including fever and purulent sputum, and no extrapulmonary source of infection. Transtracheal aspiration was done on 21 patients prior to antimicrobial treatment. Cultures of the aspirates yielded a combination of aerobic and anaerobic bacteria in 11 patients (52%), only aerobes in nine, and only anaerobes in one (table 1). The predominant isolates were Enterobacteriaceae, anaerobic gram-negative bacilli (other than B. tragilis), anaerobic gram-positive cocci, and Staphylococcus aureus (table 2). Three patients had positive blood cultures, including two with S. aureus septicemia, and one with polymicrobial bacteremia. After administration of the antibiotic regimen. symptoms resolved and chest X-rays cleared in 23 (77%) of 30 patients. Four patients could not be evaluated because of their rapid demise
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Bacteroides fragilis Bacteroides species (other) Fusobacteria Peptostreptococci Peptococci Clostridia Aerobes Escherichia coli Klebsiella species Proteus species Pseudomonas aeruginosa Gram-negative bacilli (other) Staphylococcus aureus Streptococcusfaecaus
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Empiric Treatment for Sepsis
Discussion
The selection of antimicrobial agents is based optimally on in vitro susceptibility patterns of pathogens isolated from infected sites. This principle, while theoretically desirable, poses difficulties in the treatment of patients who are seriously ill. For example, there may be a lack of infected material for culture. Even when reliable specimens are obtained, bacteriological results are not usually available when initial therapeutic decisions must be made. This difficulty particularly applies to anaerobic infections since oxygen-sensitive bacteria grow relatively slowly, the infecting flora is often complex, and several days may be required to sort out the culture results. As a practical consequence, decisions concerning antimicrobial agents must be empiric, based on suspected, rather than established pathogens. In this series of infections, the anticipated bacteriology was a mixed flora com posed of anaerobic bacteria and aerobic gram-negative bacilli. vVe predicted this pattern because of the location and clinical features of the infection. Intraabdominal infections, other than spontaneous peritonitis and biliary tract sepsis, usually involve both aerobic gram-negative bacilli and anaerobes derived from the fecal flora [4]. Previous studies from our laboratory indicate that hospital-acquired aspiration pneumonia, in contrast to community-acquired pneumonia, also is associated with a mixed aerobic-anaerobic flora [5]. Soft tissue infections are caused by a heterogeneous array of bacteria; characteristics which have proven useful in signaling the presence of anaerobes include infected foot ulcers of patients with diabetes, gangrene, gas in tissues, abscess formation, and the penetrating odor of putrefaction [6-8]. An additional clue is a gram-stained slide of exudate showing organisms with distinctive morphological features, often in the setting of a polymicrobial flora. Exudate was available for culture from 65 of the 107 patients studied. Bacteriological results confirmed the presence of anaerobic bacteria in 48 bases (74%), and a mixed aerobic-anaerobic flora in 46 cases (71~~). Of 17 specimens collected after the initiation of treatment with clindamycin and gentamicin, five yielded only aerobic bacteria. Since the cultivation of anaerobes from
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from underlying conditions during the course of treatment with clindamycin and gentamicin. The causes of death were myocardial infarction, pulmonary embolism, gastrointestinal hemorrhage, and cardiac arrhythmia. All four patients had clinical evidence of improvement of the pulmonary infection at the time of the fatal complications. There were three fatalities in which pulmonary infection was a contributing factor. Each patient was severely debilitated; multiple lobes of the lung were involved and clinical deterioration was rapid, with death occurring within three days. Transtracheal aspirates in these three patients showed mixed aerobic-anaerobic flora, and all isolates subsequently proved susceptible in vitro to the test antimicrobial agents. Skin and soft tissue infections. Of the 20 patients with infection of the skin and soft tissue, six had diabetes and foot ulcers complicated by extensive cellulitis, four had prostatic abscess, three had infection of an amputated stump of a lower extremity, two had infected traumatic wounds, one had periorbital cellulitis secondary to maxillary sinusitis, one had an infected decubitus ulcer, one had gangrene of the foot, one had a wound infection after carotid endarterectomy, and one had a wound infection following open hi p reduction. Exudate was available for culture from 17 patients; five patients had bacteremia. Cultures of exudate revealed a combination of aerobes and anaerobes in 12 cases and an exclusively aerobic flora in five (table 1). The predominant isolates in exudate were B. fragilis, anaerobic gram-positive cocci, E. coli, Proteus species, and S. aureus (table 2). Positive blood cultures from five patients yielded B. [ragilis (two patients), peptostreptococci (one), Clostridium pavaputriiicum (one), and Serratia marcescens (one). Eighteen of these 20 patients were cured, and two were considered therapeutic failures. One of the patients who failed to respond had gangrene of an amputated stump with B. fragilis bacteremia and died on the first day of treatment. The second failure was a patient with diabetes mellitus and severe cellulitis involving Proteus mirabilis and P. aeruginosa. Although both isolates were susceptible to gentamicin, there was no clinical improvement, and an amputation was performed on day 5 of treatment.
S84
emia, 36 had intraabdominal abscesses or generalized peritonitis, and seven had severe extremity wounds associated with vascular insufficiency. In addition, there were 30 cases of hospital-acquired pneumonia, and the mortality rate for this condition has been reported to be as high as 30% [11J. Analysis of the response to treatment with clindamycin and gentamicin showed that cure was achieved in 92 (90%) of the 102 cases. Even in the 10 therapeutic failures, virtually all pathogens were susceptible to clindamycin or gentamicin. However, the antibiotics were not effective for these patients because of the fulminant course of their illnesses, four of which were associated with bacteremia. The monitoring of patients for side effects showed a hypersensitive skin rash in one patient, although both antibiotics were continued in this individual without additional ill effects. Seven patients had increasing serum creatinine levels which may have been due to gentamicin, but this effect proved difficult to evaluate in view of the serious associated conditions. None of the patients had debilitating diarrhea or documented pseudomembranous colitis. It is our view that the regimen of clindamycin and gentamicin in combination is useful for patients in whom there is a likelihood that a mixed flora is present. Furthermore, selection of the appropriate patients to receive this regimen can usually be made clinically, based on a careful assessment of the disease process. References 1. Gorbach, S. L., Bartlett, J. G. Anaerobic infections. N. Eng!. ]. Med. 290:1177-1184, 1237-1245, 12891294,1974. 2. Holdeman, L. V., Moore, W. E. C. [cd.]. Anaerobe laboratory manual. 3rd ed. Virginia Polytechnic Institute and State University, Blacksburg, Va., 1975. 132 p. 3. Lennette, E. H., Spaulding, E. H., Truant, J. B. [ed.]. Manual of clinical microbiology. 2nd ed. American Society for Microbiology, Washington, D.C., 1974, p. 189-221,250-269. 4. Thadepalli, H., Gorbach, S. L., Broido, P. W., Norsen, j., Nyhus, L. M. Abdominal trauma, anaerobes, and antibiotics. Surg. Gynecol. Obstct. 137:270-276, 1973. 5. Bartlett, J. G., Finegold, S. M. Anaerobic infections of the lung and pleural space. Am. Rev. Respir. Dis. IlO:56-77,1974.
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infected sites seems to be rapidly reduced by the presence of clindamycin [9], the actual incidence of anaerobe-associated infections may be somewhat higher. Gentamicin is active against the vast majority of aerobic gram-negative bacilli, whereas clindamycin is effective against most anaerobic bacteria, including B. [ragilis. Analysis of the types of bacteria recovered from 83 patients with available culture data (exudate and/or blood cultures) showed that 18 had aerobic gram-negative bacilli that might be resistant to commonly used antibiotics other than gentamicin. These organisms included P. aeruginosa, indole-positive Proteus, and S. marcescens. The most frequently encountered anaerobe, B. fragilis, was recovered from exudate in 29 patients and from blood cultures in II patients; all of these strains were sensitive to clindamycin. Another possible advantage of clindamycin is its activity against S. aureus. This organism was isolated in seven patients with hospital-acquired aspiration pneumonia and in seven with soft tissue infections. Analysis of 1,050 strains of S. aureus over the past four years at our hospital showed that 1,022 strains (97%) were susceptible to clindamycin, with no apparent shift towards resistance in the more recent years (authors' unpublished observations). (Gentamicin also shows good activity against S. aureus, but there are few clinical studies to document its efficacy in serious staphylococcal infections.) In vitro tests of the organisms isolated from our patients showed that most were susceptible to either clindamycin or gentamicin. One exception was a blood culture isolate of C. paraputrificum that was resistant to clindamycin at a level of 25 fLg/ml. Signs of sepsis and bacteremia cleared in this patient during treatment with clindamycin and gentamicin, before susceptibility data were reported. Spontaneous clearing of clostridial bacteremia has been reported [1OJ. The only other resistant organism was Streptococcus [aecalis, which was recovered in 14 cases. In each instance this organism was part of a complex flora of exudate and was never encountered in blood cultures. The role of S. faecalis as a pathogen in this setting is ill-defined. All patients entered into the study were seriously ill. Twenty-nine had documented bacter-
Bartlett, Miao, and Gorbach
Empiric Treatment jor Sepsis
6. Louie, T. j., Bartlett, ]. G., Tally, F. P., Gorbach, S. L. Aerobic and anaerobic bacteria in diabetic foot ulcers. Ann. Intern. Med. 85:461-463, 1976. 7. MacLennan, J. D. The histotoxic clostridial infections of man. Bacteriol. Rev. 26:177-276,1962. 8. Altemeier, W. A. The cause of the putrid odor of perforated appendicitis with peritonitis. Ann. Surg. 107: 634-636, 1938. 9. Gorbach, S. L., Thadepalli, H. Clindamycin in pure
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and mixed anaerobic infections. Arch. Intern. Med. 134:87-92, 1974. 10. Gorbach, 5. L., Thadepalli, H. Isolation of Clostridium in human infections: evaluation of 114 cases. J. Infect. Dis. 131 (SuppI.):S81-S85, 1975. 11. O'Keefe, J. P., Bartlett, J. G., Tally, F. P., Gorbach, S. L. An heuristic approach to hospital-acquired pneumonia [abstract]. Clin. Res. 23:589A, 1975.
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Discussion Moderator: Robert Condon
don't perform proctoscopy routinely, so we can't make statements about pseudomembranous colitis. We've had very little trouble with clindamycin and therefore we like it. But on our service, if the house staff and other physicians decide to use penicillin instead, we do not disparage that choice. DR. J. G. BARTLETT. Dr. Louria, regarding the comparison study we did with penicillin and clindamycin, you mentioned that the risk factors had not been taken into account. I would agree with the risk factors you mentioned: age, chronicity of the lesion, and the size of the cavity. Although we may not have reported individual case data, we did report statistical means for each of those variables, and the two groups of antibiotic-treated patients proved to be comparable. I am not surprised that there are anecdotal experiences with lung abscess which do not respond to penicillin, but those cases appear to be relatively uncommon. Since the clinical experience with penicillin G is so extensive and the response is so good, I still think that penicillin has to be regarded as the drug of choice. DR. FINEGOLD. There are instances in which penicillin G fails. In the Western Journal of Medicine, there is a discussion of a patient with lung abscess who failed to respond despite two extended courses of penicillin G in a dosage of 10-12 X 106 units per day. Subsequently, he responded to clindamycin therapy. We are currently treating another patient with a lung abscess who also failed to respond to penicillin G but subsequently responded to chloramphenicol. Dr. Louria, I don't share your dim view of transtracheal aspiration (TTA). It is a safe procedure in the hands of those who have used it enough to be adept, provided that high-risk patients, such as those with bleeding tendencies or those having difficulty oxygenating, are excluded. DR. LaURIA. In the best of hands, there are patients who are going to die or be hurt by TTA. I am concerned about physicians who read the literature where it is suggested that TTA is the way to diagnose gram-negative pneu-
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DR. S. M. FINEGOLD. Dr. Louria, in regard to lung abscess, you commented that there were several factors that influenced prognosis, the most consistent being the size of the abscess. You seemed to imply that large abscesses often require surgical drainage. I would like to suggest that abscesses of great size often respond well to medical therapy. In fact, I believe that in most cases surgery is contraindicated since it carries the risk of the patient drowning from material spreading from the abscess cavity during positioning on the operating table. DR. D. B. LaURIA. With regard to cavity size, my point was that a fair number of studies utilized cavity size as a determinant as to whether they would likely heal on medical therapy, and this variable must be considered. We agree that the majority of patients do not require surgery. And, of course, if we're going to compare antibiotics, cavity size is just one variable to consider in terms of antimicrobial response. We have to look at duration of disease and rate of cavity closure as well. In certain cases, drainage is perhaps more efficacious than not using this technique, but I really think that's a nuance. DR. S. M. FINEGOLD. Dr. Louria, you mentioned the studies of Bartlett and Gorbach which indicate that penicillin works effectively in anaerobic pneumonia, whether or not Bacteroides fragilis is present. You pointed out that others have also had considerable experience using penicillin alone for lung abscess. My feeling is that penicillin is ordinarily the preferred drug in anaerobic pulmonary infection of any type including lung abscess, with the exception of patients with hospital-acquired aspiration pneumonia, in which case it is necessary to cover other organisms as well. Is your choice of therapy clindamycin? DR. LaURIA. As to choice, we prefer clindamycin, but I think you will concur that one really can't be dogmatic on the basis of current evidence. We feel comfortable with clindamycin and haven't had any significant toxicity. We've seen relatively little diarrhea. 'Ve do discontinue the drug as soon as any diarrhea occurs. We
Discussion
procedure for selected clinical settings such as necrotizing pneumonia, hospital-acquired pneumonia, and pulmonary infection in the compromised host. Another consideration is the patient who has an abnormality on chest X ray, and we're not certain if it represents bacterial infection. Our experience suggest that a negative result with TTA virtually excludes the possibility of bacterial infection. DR. S. L. GORBACH. To address a different subject, I would like to solicit comments concerning chloramphenicol therapy for B. fmgilis infection. We have been using clindamycin for so long in anaerobic infections that I can no longer compare it with chloramphenicol in terms of efficacy. Perhaps, the others here who have had experience with chloramphenicol might comment or provide actual data on the comparative use of these drugs. DR. R. J. FASS. Several studies have shown some cases of serious B. fragilis infections that failed to respond to chloramphenicol. One of our patients had persistently positive blood cultures of B. fragilis despite 6 g of chloramphenicol per day. This occurs less commonly with clindamycin. DR. M. E. LEVISON. Some patients with organisms ostensibly sensitive in vitro fail to respond to chloramphenicol and others to clindamycin. There does not seem to be adequate evidence to say which is the preferable agent. There are circumstances such as infections of the central nervous system in which chloramphenicol is the preferable drug. DR. CHOW. Much of our experience with chloramphenicol has been from a retrospective study of bacteriodes bacteremia. The results with clindamycin and chloramphenicol were comparable, but the numbers were small. DR. BARTLETT. \Ve have had several patients who failed to respond to chloramphenicol even though they were infected by organisms susceptible to that agent. In most cases, the pathogen was B. fmgilis, and these patients subsequently responded to clindamycin. We have also had failures with clindamycin, but the organisms have usually been resistant to the drug. DR. G. T. KEUSCH. I wonder if the panelists would agree that we can bury the issue of highdosage penicillin, in combination with an
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monia. Unfortunately, some will interpret this to mean every pneumonia. Certainly, I can't approve of doing TTA on a patient who is bringing up putrid sputum. I know what the diagnosis is. DR. R. 1\1. SWENSON. OU! approach to TTA is based on some studies we did a few years ago on patients with alcoholism. About 15% of alcoholics have significant numbers of gramnegative facultative anaerobes as part of their normal oropharyngeal flora. At least in theory, there is about a 15% chance of gram-negative rods being present in the expectorated sputum from patients with alcoholism. About 90% of the patients who develop anaerobic pulmonary infections outside of the hospital are not critically ill. We get blood cultures and a coughed specimen of sputum and begin penicillin therapy. The following day, if we find that the patients have gram-negative rods in the coughed sputum, we then do TTA to differentiate between oropharyngeal colonization and true gram-negative pneumonia. We think that TTA is desirable because the hazards of several weeks of gentamicin or kanamycin therapy probably outweigh the risks associated with TTA. DR. A. W. CHOW. The indications for doing TTA are not so much for diagnosis of anaerobic pulmonary infection, but rather for diagnosis of aerobic, gram-negative bacillary pneumonia. We have agreed that putrid sputum indicates the presence of anaerobes, but certainly it does not rule out coexisting aerobes, particularly gram-negative rods. Anaerobes can be treated with penicillin, regardless of whether the organisms are cultured. The problem is with aerobic gram-negative rods in patients with necrotizing bacillary pneumonia, a serious disease requiring potentially toxic antibiotic therapy. In that situation, as well as in hospital-acquired aspiration pneumonia and in patients who fail to respond to conventional therapy, TTA is very helpful. In addition, I think that TTA may be helpful sometimes in recovering tubercle bacilli. DR. BARTLETT. TTA is a good technique to identify the flora of the lower respiratory tract in a patient who has an ill-defined pneumonia. The suggestion that any patient who comes into the hospital with pneumonia should have TTA is not a reflection of our view. We reserve this
587
588
and the usual clinical context is that drainage occurs after a rather prolonged period of antibiotic therapy, usually administered in the hope that the abscess will heal without the necessity for surgical intervention. Do you administer antibiotics to all patients who are having surgical drainage of an abscess, and do you continue that treatment once drainage is established? What criteria do you use for either continuing or stopping antibiotic therapy? DR. R. L. NICHOLS. Surgical drainage alone is better than antibiotics alone, but drainage alone, even with good initial response, can lead to septicemia in some patients. I prefer drainage plus antibiotics for deep abscesses, assuming that some small loculations may persist. The routine use of potent antimicrobial agents for superficial wound abscess seems superfluous to me, because you can adequately drain, irrigate, and clean up any superficial wound. We know there are septicemic episodes during the period of drainage, but then there is no further contamination.
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aminoglycoside for treatment of intraabdominal sepsis, or is there still a question? DR. FASS. For colon-related intraabdominal sepsis, I would not recommend this combination. For some infections, such as biliary tract sepsis, these drugs might be useful, and I generally treat such patients with ampicillin and an aminoglycoside. DR. SWENSON. In the case of diffuse peritonitis, B. fragilis is common. In that circumstance I would be uncomfortable using just penicillin and an aminoglycoside. Even large doses of carbenicillinmight not be sufficient in this situation since about 10% of B. fragilis are resistant to this drug. My impression is that the primary modality of therapy for localized abscesses is surgical drainage, and it might be difficult to show much difference among a variety of regimens in this setting. DR. R. CONDON. Dr. Nichols, in your presentation you indicated that the treatment of an abscess was both drainage and the administration of antibiotics. Conventional wisdom says that drainage is sufficient treatment for an abscess,
Discussion
