THE JOURNAL OF INFECTIOUS DISEASES. VOL. 135. SUPPLBIENT • 1977 by the University of Chicago. All rights reserved.

~fARCH

1977

©

Evaluation of Clindamycin and Other Antibiotics in the Treatment of Anaerobic Bacterial Infections of the Lung R. Kapila, P. Sen,

J. Salaki, and

D. B. Louria

From the Departments of Preventive Medicine and Community Health and Medicine, New Jersey Medical School Newark, New Jersey

Anaerobic infections of the lung continue to be a major therapeutic problem, particularly for bibulous patients and those with obstructing neoplasms of the lung. For determination of the efficacy of clindamycin therapy for the treatment of anaerobic lung infections, this study addressed three questions. (1) Is clindamycin an effective therapeutic agent? (2) Is it more effective than other agents in the treatment of patients with severe or life-threatening infection? (3) Are the adverse effects of clindamycin therapy sufficient to avoid prescription of the drug for lung disease?

However, such situations are so infrequent that a presumptive diagnosis of anaerobic infection based on odor is justifiable. In the majority of patients with an anaerobic disease of the lung, blood cultures are negative and there is no pleural fluid. If no invasive procedure is utilized for the establishment of a firm bacteriologic diagnosis, and sputum cultures are helpful only in excluding the possibility of aerobic infection, then the only realistic approach to diagnosis and therapy is dependence upon the odor of expectorated sputum. However, in about one-half of patients with anaerobic infection, the sputum is not putrid [1 J. For such patients the diagnosis can be made with certainty only by invasive procedures (transtracheal aspiration or percutaneous lung aspiration), or by positive cultures from empyema fluid, abscess aspirate, or blood cultures. In most hospitals transtracheal aspiration is not done routinely for patients 'with pneumonia, and many bacteriology laboratories are not adroit in the techniques required for anaerobic cultures. Furthermore, the clinician must make therapeutic decisions before laboratory results are available. Consequently, in cases of pneumonia, lung abscess, and empyema, it is correct to take a putrid odor, when present, as an indicator of anaerobic infection. We studied 50 patients with pneumonia, lung abscess, or empyema. The criterion for selection of the patient was a fetid odor from the specimen. Subsequently, patients were excluded

Evaluation of Clindamycin Therapy

During the last five years, we have used clindamycin preferentially for the treatment of patients with pneumonia, lung abscess, or empyema, from whom expectorated sputum or fluid obtained from the pleural space had a putrid odor. It has been believed that, when a fecal odor is detectable from a specimen, the patient is most likely to have an anaerobic bacterial infection. Although in some instances the odor suggests a diagnosis of anaerobic infection, subsequent aerobic and anaerobic cultures have shown only the presence of Escherichia coli or Proteus mirabilis. Please address requests for reprints to Dr. D. B. Louria, Department of Preventive Medicine and Community Health, New Jersey Medical School, Newark, New Jersey 07103.

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Fifty patients who had pneumonia, lung abscess, or empyema, and whose specimens had a fetid odor, were presumed to be suffering from anaerobic lung infection and were treated with clindamycin either orally (33 patients) or parenterally (17). Forty-six patients showed marked improvement or recovered; two also underwent lung resection, and thoracotomy was performed in 10. There were three outright treatment failures, and superinfection occurred in one patient. A review of the literature suggests that clindamycin and penicillin (in substantial dosage) are equally effective in treatment of anaerobic lung infection. Transtracheal aspiration is not deemed necessary if the patient is expectorating fetid sputum.

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entire period of treatment or at least until marked improvement in clinical symptoms occurred, after which four patients were given the drug orally. One patient received 800 mg of clindamycin im every 8 hr. Results of parenteral treatment are summarized in table 1. Two of the 50 patients died. In one patient superinfection occurred, and one patient was considered a treatment failure. A failure rate of .-8% (four of 50) seemed reasonable, especially for individuals with serious illnesses who were already compromised by alcoholism or an underlying disease. Case reports of unsatisjactory responses to therapy with clindamycin. Case no. 1. A 28-yearold patient with alcoholism and a history of pulmonary tuberculosis and seizures developed bilateral necrotizing pneumonia. After taking 300 mg of clindamycin perorally every 6 hr for seven days, he did not show signs of improvement. Clindamycin was discontinued, cephalothin therapy was started, and the patient improved markedly. In the treatment of severe anaerobic disease of the lung, significant improvement may not be

Table 1. Results of parenteral treatment with c1indamycin of patients with lung infection presumably due to anaerobes.

Case, sex, age

1, M, 29 2,M,48 3,M,3t 4, M,47 5, M, 61 6,M,36 7, M, 19

8,M,55 9, M, 31 10, M, 25 11, M, 45 12,M,52 13,M,31

14, IS, 16, 17,

M, 37 M, 37* F, 22 M, 35

Location, type of lesion Left lower lobe, abscess Empyema, right Left lower lobe pneumonia with empyema Right lower lobe abscess Left lower lobe abscess Pneumonia, bilateral Left-sided abscess and empyema Right lower lobe pneumonia with empyema Right lower lobe abscess Empyema, left Right lower lobe pneumonia Left upper lobe abscess Right lower lobe abscess, empyema Right upper lobe abscess Right lower lobe abscess Right upper lobe abscess Right upper lobe abscess

Cultures from Durablood or tion empyema fluid of positive for therapy anaerobes [days]" No Yes Yes No No No Yes Yes No Yes No No No No No No No

NOTE. M = male; F = female. *Unless indicated, patients received 300 or 600 mg of clindamycin iv every 6 hr. tReceived 150 mg of clindamycin every 6 hr. :j: Received 800 mg of clindamycin every 8 hr.

3

14 21 19 10 18

7 14 7 10

14

7 14 14 12 19

28

Outcome of treatment Died Recovered, closed thoracotomy Recovered, open thoracotomy Recovered Recovered Improved Recovered, resection Recovered, closed thoracotomy Improved Recovered, closed thoracotomy Recovered Improved Recovered, lobectomy Recovered Recovered Recovered Improved

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from the study if potential pathogens were cultured in significant numbers from expectorated sputum. Thus, if the sputum had a putrid odor and subsequent aerobic cultures showed moderate to large numbers of E. coli, the patient was not included in the series. In most cases, sputum was not cultured anaerobically. Empyema fluid, bronchoscopic washings, material aspirated from cavities, and blood were studied by both aerobic and anaerobic techniques. Blood was cultured in brucella broth with 10% sucrose. The other specimens were streaked on sheep blood agar and cultivated in a GasPak® anaerobic jar (Baltimore Biological Laboratories, Baltimore, Md.). Thirty-three patients, aged 28-72 years, were given 150 or 300 mg of clindamycin orally every 6 hr. The duration of treatment ranged from 14 to 28 days. Thirty patients recovered or significantly improved, six underwent closed thoracotomy, and one died. In one patient superinfection occurred, and one case was considered to be a treatment failure. Sixteen patients were treated with 300 or 600 mg of clindamycin iv every 6 hr either for the

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taken within the first 24-36 hr, given the patient's continuing toxicity and hypoxia, and the moderate hypotension. Case no. 3. A 38-year-old man was admitted with bilateral infiltrates, a cavity, putrid sputum, and evidence of concomitant active tuberculosis. Improvement was noted after clindamycin was given orally; the sputum lost its odor, but the chest X ray remained unchanged, and the patient died unexpectedly three weeks after admission. Permission for autopsy was denied. Although there is no convincing evidence that this case represented a failure for clindamycin, it has been considered as such because of the persisting infiltrate. There was no specific evidence of progressive or even continuing anaerobic infection. Case no. 4. A 42-year-old woman with alcoholism was hospitalized for pneumonia, with abscess formation involving the left lower lobe (figure 1, right). Foul-smelling material was obtained at bronchoscopy, and culture showed Bacteroides species. After three weeks of therapy with 300 mg of clindamycin administered perorally every 6 hr, chest X ray showed that the abscess had markedly increased in size (figure 1, left). When a second bronchoscopic examination was performed, the aspirated material was not foul; on culture, an isolate of Peptostreptococcus and a heavy growth of Pseudomonas aeruginosa were present. Gentamicin was then added to the regimen, and the patient improved. This was the only case of lung superinfection we have observed in six years of treating patients exclusively with clindamycin. Factors in Comparison of Treatment Regimens

The 50 cases studied have indicated that clindamycin is an effective agent in the treatment bf anaerobic lung infections, particularly when lung abscess is present. These findings are in agreement with those of Bartlett and his colleagues [3, 4]. In one study, Bartlett and Gorbach compared clindamycin with another agent in the treatment of aspiration pneumonia and lung abscess [4]. In general, clindamycin and penicillin seemed to be equally effective, even when the cases involving Bacteroides tragilis were considered separately. However, there were

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manifest for seven to 10 days after institution of adequate therapy. Possibly, this patient would have recovered if treatment with clindamycin had been continued. However, the patient's lack of response to clindamycin for seven days and the prompt defervescence and clinical improvement with another agent prompted designation of this case as a treatment failure for clindamycin. Case no. 2. A 29-year-old patient with alcoholism was hospitalized with a seven-day history of chest pain, cough, and expectoration of putrid material. His respiratory rate was recorded as 48/min, blood pressure as 105/70 mm Hg, rectal temperature as 103 F, and heart rate as 130/min. Chest X ray showed a very large cavity in the right lung field. On the night of admission, 300 mg of clindamycin was administered perorally every 6 hr. However, the next morning, because of marked toxicity and hypoxia, the drug was administered iv in doses of 600 mg every 6 hr. One day later, the patient was not improved; blood gas studies showed continuing hypoxia, the blood pressure remained somewhat low, and toxicity persisted. Open thoracotomy was undertaken to drain or resect the cavity. A massive area of necrosis and hemorrhage was found. While we attempted drainage of the profusely bleeding lesion, the patient had intractable cardiac arrhythmias and died. It is unlikely that treatment of this patient with any antimicrobial agent would have been successful. Our house staff had become convinced that clindamycin would be predictably effective in any patient with putrid lung abscess, a notion buttressed by the successful treatment with oral clindamycin of another patient with a giant lung abscess [2]. In this instance the patient improved dramatically, and, eventually, the huge cavity closed without surgical drainage. However, for case no. 2 the change to iv administration of clindamycin should have been accompanied by more attention to adequate oxygenation and surgical drainage. The partial pressure of oxygen (pOJ in this patient continuously hovered around 50, despite the use of respiratory assistance apparatuses. A surgical consultation was not obtained until 40 hr after admission; surgery was not performed until 48 hr after admission. Drainage or excision should have been under-

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difficulties in the epidemiologic methodology of this series. The groups of patients were roughly comparable, but responses were analyzed by mean age rather than specific age. Also, there was no mention of cavity size or duration of illness before institution of therapy. Although the three variables that appear to be most important in the determination of outcome of treatment are age, cavity size, and duration of illness [5-8], there is no unanimity of opinion in this matter. Several investigators have reported that the outcome of treatment was less favorable when large cavities were present [69], whereas others have not found this to be the case [5, 10]. Abernathy has noted that the only variable related to outcome was age [5], but Weiss has reported a poor correlation of outcome with age [10]. (This disagreement may be related, in part, to the fact that in the former study the cut-off point was age 60, and in the latter study the cut-off point was age 50.) Bernhard et al. [8] and Andersen and McDonald [7] have observed that the prognosis was less favorable when the duration of illness was more than eight weeks, whereas Abernathy [5] and Weiss [10] have reported no such association. Andersen and McDon-

ald [7] found that lower-lobe abscess had the least favorable prognosis. In contrast, Weiss [10] reported that the worst prognosis was associated with lesions involving. the posterior segment of the right upper lobe. For a completely satisfactory comparison of two or more regimens, a comparison of the groups with the least favorable prognosis should be included; that is, patients should be included who have been ill for more than six to eight weeks, who have cavities >6 em, and who are older than 60 years. Ideally, the numbers obtained should be large enough for these three parameters to be studied by univariate and multivariate analysis. For example, in the study by Bartlett and Gorbach [4], in which both the penicillin and clindamycin groups consisted almost exclusively of patients under age 50 who had small cavities and illnesses of three weeks or less, perhaps other regimens would have succeeded. A group of older patients with larger cavities and longer duration of illness would test the regimens more strenuously. Nevertheless, this is clearly the best study to date. Other studies do not compare regimens in a satisfactory manner; most have classified both putrid

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Figure 1. Right, a putrid lung abscess in the lower left lobe of a 42-year-old patient with alcoholism. Left, after three weeks of therapy with c1indamycin, an increase in the size of abscess, presumably due to superinfection with Pseudomonas.

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and nonputrid abscesses under the rubrics "primary lung abscess" and "nonspecific lung abscess." Nevertheless, a review of the literature suggests that, among patients with putrid lung abscess, the regimens described below have succeeded. Other Therapeutic Regimens in the Treatment of Anaerobic Infections

chloramphenicol. The latter combination of drugs was also studied by Levine et al. [14]. Schweppe et al. [15] have administered penicillin in modest dosage with streptomycin. Although the efficacy of penicillin, like clindamycin, has been proven, the lower limit of the proper dose range of penicillin is not established. Also, the evidence does not show that a second drug added to the penicillin regimen provides better treatment results. Diagnosis of Anaerobic Infections with Transtracheal Aspiration

The general view is that sputum cultures are of "nonvalue" in the diagnosis of pneumonia [16]. Pierce and Sanford, in a discussion of gram-negative pneumonias, noted that the most useful diagnostic procedure was transtracheal aspiration of material for gram stain and culture [17]. Others have found that standard sputum culture is still a helpful diagnostic procedure [18]. A recent report did not show a profound increase in information resulting from the performance of transtracheal aspiration [19]. The main advantage of the procedure was the ability to distinguish pneumococcal pneumonia from pneumonia due to Haemophilus infiuenzae. When a patient is expectorating feculent sputum and an anaerobic infection is suspected, justification of transtracheal aspiration is difficult since the odor establishes the diagnosis. Only rarely is this type of infection due to gram-negative aerobes that are not susceptible to therapy for presumed anaerobic infection. In such cases, culture of the sputum is likely to show virtually pure growth of gram-negative aerobes, permitting adjustment of the antibiotic regimen. Because the sputum does not have a putrid odor in almost one-half of the cases of anaerobic disease, in such cases transtracheal aspiration may be more useful than sputum cultures and gram stains. However, the procedure is far from benign, as bleeding, mediastinal emphysema, localized abscess formation, aspiration, cardiac arrhythmia, and death have been reported [20, 21]. We believe that, in patients hospitalized with non-foul-smelling sputum and a mixed flora on gram stain of expectorated sputum, Streptococcus pneumoniae, H. infiuenzae, and anaerobes are the

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Penicillin in small dosages. Fox et al. [11] have reported that 28 of 32 patients treated daily with ~1.2 X 106 units of penicillin responded satisfactorily. Of 15 patients who were reported by Abernathy [5] and who received 1.2-3.6 X 106 units of penicillin, it was not clear how many did well, but some patients recovered after treatment with small amounts of penicillin. Weiss [10] administered modest amounts of penicillin (1.2-2.4 X 106 units) im or 750 mg of potassium penicillin G orally four times daily. Shoemaker et al. [12] also used small amounts of penicillin (300,000 units every 6 hr) with significant success. Because it is impossible to tell what proportion of these patients had putrid sputum, and what proportion of those with putrid sputum recovered without adjunctive surgery, the only conclusion that can be drawn is that a substantial number of patients with putrid lung abscess were treated successfully with small amounts of penicillin. Larger doses of penicillin. Bartlett et al. [3], Abernathy [5], and Jensen and Amdrup [12a] have reported on dosage regimens of 3-10 x 106 units of penicillin administered daily. Tetracycline. A report on only a small number of patients treated with tetracycline is available [10]. Chloramphenicol alone. Despite the general acceptance of chloramphenicol as a first-line drug for anaerobic lung infections, there are few reports of its use as a single agent. In one series, 12 of 14 patients were reported to have responded adequately after the antibiotic was administered intrabronchially [13]. The data on chloramphenicol are not adequate to make any specific statement. Penicillin with a second drug. Barnett and Herring [6J have investigated the use of penicillin in modest dosage with tetracycline as well as the use of penicillin in modest dosage with

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three most frequent causes of the pneumonia. Antibiotic regimens are available that are effective against these organisms without undue risk of superinfection. For patients with communityacquired pneumonia, transtracheal aspiration is generally not necessary. Another circumstance in which transtracheal aspiration might be used is illustrated by the following case. A 22-year-old drug abuser injected heroin, subsequently vomited, and brought up foul-smelling sputum. The chest roentgenogram (figure 2, right) showed a modest right mid-lung infiltrate. He was given 600 mg of clindamycin iv four times daily. Aerobic cultures of sputum showed a Proleus species. When the infiltrate increased, gentamicin was added to the treatment regimen (figure 2, left). Despite appropriate antibiotic therapy, fever and the infiltrate persisted. At the end of the second week of therapy, fever was present, and the lung infiltrate had not resolved. I t was decided to perform bronchoscopy to determine whether foreign bodies were present; transtracheal aspiration would also have been justified for definition of the bacteriology of the lower respiratory tract. We are concerned with an overuse of invasive procedures in the diagnosis of lung infection

when a clinician can approach the problem equally well by taking an adequate history, examining a gram stain of sputum, smelling the sputum, and using a reasonable therapeutic trial of antimicrobial agents, We believe that invasive procedures should be reserved for certain patients with life-threatening pneumonia and situations similar to that outlined above. References

J. G., Sutter, V. L., Finegold, S. M. Anaerobic pleuropulmonary disease: clinical observations and bacteriology in 100 cases. In A. Balows, R. M. neHaan, L. B. Guze, and V. R. Dowell [ed.]. Anaerobic bacteria. Charles C Thomas, Springfield, Ill., 1974, p.327. Sen, P., Tecson, F., Kapila, R., Louria, D. B. Clindamycin in the oral treatment of putative anaerobic pneumonias. Arch. Intern. Med. 134:73-77, 1974. Bartlett, J. G., Sutter, V. L., Finegold, 5. M. Treatment of anaerobic infections with lincomycin and clindamycin. N. Engl. J. Med. 287:1006-1010, 1972. Bartlett, J. G., Gorbach, S. L. Treatment of aspiration pneumonia and primary lung abscess: penicillin G vs. c1indamycin. J.A.M.A. 234:935-937, 1975. Abernathy, R. S. Antibiotic therapy of lung abscess: effectiveness of penicillin. Chest 53:592-598, 1968. Barnett, T. B., Herring, C. L. Lung abscess: initial and late results of medical therapy. Arch. Intern. Med. 127:217-227, 1971.

1. Bartlett,

2.

3.

4.

5. 6.

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Figure 2. Right, aspiration pneumonia in a 22-year-old patient with a history of drug abuse. Left, after one week of therapy with clindamycin, a marked increase in infiltrate.

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at.

14. Levine, M. M., Ashman, R., Heald, F. Anaerobic (putrid) lung abscess in adolescence. Am. J. Dis. Child. 130:77-81,1976. 15. Schweppe, H. I., Knowles, J. H., Kane, L. Lung abscess: an analysis of the Massachusetts General Hospital cases from 1943 through 1956. N. Engl. J. Med. 265:1039-1043, 1961. 16. Barrett-Connor, E. The non-value of sputum culture in the diagnosis of pneumococcal pneumonia. Am. Rev. Respir. Dis. 103:845-848, 1971. 17. Pierce, A. K., Sanford, J. P. Aerobic gram-negative bacillary pneumonias. Am. Rev. Respir. Dis. 110:647658,1974. 18. Tilton, R. C., Maderaza, E., Iannini, P., Quintiliani, R. The bacteriological examination .of the sputum. Ann. Clin. Lab. Sci. 4:60-63, 1974. 19. Davidson, M., Tempest, B., Palmer, D: L. Bacteriologic diagnosis of acute pneumonia. J.A.M.A. 235: 158-163,1976. 20. Yoshikawa, T. T., Chow, A. W., Montgomerie, J. Z. Paratracheal abscess: an unusual complication of transtracheal aspiration. Chest 65: 105-106, 1974. 21. Spencer, C. D., Beaty, H. N. Complications of transtracheal aspiration. N. Engl. J. Med. 286:304-306, 1972.

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7. Andersen, M. N., McDonald, K. E. Prognostic factors and results of treatment in pyogenic pulmonary abscess. J. Thorac, Cardiovasc. 5urg. 39:573-578, 1960. 8. Bernhard, W. F., Malcolm, J. A., Wylie, R. H. Lung abscess: a study of 148 cases due to aspiration. Chest 43:620-630, 1963. 9. Fifer, W. R., Husebye, K., Chedister, C., Miller, M. Primary lung abscess. Analysis of therapy and results in 55 cases. Arch. Intern. Med. 107:668-680, 1961. 10. Weiss, W. Delayed cavity closure in acute nonspecific primary lung abscess, Am. J. Med. Sci. 255:313-319, 1968. II. Fox, J. R., Hughes, F. A., Jr., Sutliff, W. D. Nonspecific lung abscess: experience with 55 consecutive cases. J. Thorac. Cardiovasc. Surg. 27:255-260, 1954. 12. Shoemaker, E. H., Yow, E. M., Byrd, W. C. Antibiotic therapy of primary pulmonary abscess. Arch. Intern. Med. 96:683-692, 1955. 12a. Jensen, H. E., Amdrup, E. Nonspecific abscess of the lung: 129 cases. I. Diagnosis and treatment. Acta. Chir. Scand. 127:487-494, 1964. 13. Stefanini, P., Ricci, C. The use of chloramphenicol in thoracic surgery and particularly in chronic bronchopulmonary suppuration. Postgrad. Med. J. 43 (Suppl.):73-78,1967.

Kapila et

Evaluation of clindamycin and other antibiotics in the treatment of anaerobic bacterial infections of the lung.

THE JOURNAL OF INFECTIOUS DISEASES. VOL. 135. SUPPLBIENT • 1977 by the University of Chicago. All rights reserved. ~fARCH 1977 © Evaluation of Cli...
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