165

ANAEROBIC LUNG INFECTIONS TREATED WITH DOXYCYCLINE* HARAGOPAL THADEPALLI, M.D. Chief, Division of Infectious Diseases

DAVID WEBB, M.D.

AND JONG T. HUANG Division of Infectious Diseases C.R. Drew Postgraduate School of Medicine Los Angeles, California

A LTHOUGH tetracycline was for many years the drug of choice for

A naerobic infections, there are no extensive clinical studies of tet-

racycline and the older tetracycline analogues against culture-documented anaerobic lung infections. Moreover, assumptions of efficacy have been contradicted by recent in vitro studies demonstrating that tetracycline resistance is increasing among a large variety of anaerobic bacteria.1 Even at 8 mcg./ml. only 46% of strains of Bacteroides fragilis are currently susceptible to tetracycline. At this level only 37% of peptococci, 72% of peptostreptococci, and 61% of clostridia other than Clostridium perfringens are sensitive.2 For these reasons tetracycline and its older analogues are not generally used to treat proved anaerobic lung infections at this time. The newer analogues of tetracycline, such as doxycycline and minocycline, have aroused interest, at least partly because of resistance to the original compound. Many studies have shown that doxycycline is more effective than tetracycline against anaerobic bacteria in vitro. 1-3 In our laboratory we tested 624 strains of anaerobic bacteria and found 74% to be susceptible to 5 mcg./ml of doxycycline (Table I). Seventy-four percent of all Bacteroides strains were susceptible at this level, including 73% of B. fragilis. Seventy percent of all anaerobic Gram-positive cocci tested were *Presented as part of A Symposium on the Tetracyclines: A Major Appraisal sponsored by the New York Academy of Medicine in cooperation with Science and Medicine Publishing Co., Inc. under a grant from Pfizer Laboratories, New York, N.Y., and held at the Academy October 15, 1977. Address for reprint requests: Haragopal Thadepalli, M.D., Division of Infectious Diseases, Martin Luther King, Jr., General Hospital, 12021 South Wilmington Avenue, Los Angeles, Calif. 90059.

Vol. 54, No. 2, February 1978

OTHERS H. THADEPALLI AND OTHERS

166

166H.

THADEPALLI

AND

TABLE I. SUSCEPTIBILITY OF ANAEROBIC BACTERIA TO DOXYCYCLINE

Organism

No. of strains tested

Bacteroides fragilis Bacteroides (all strains) Cocci Miscellaneous Total (all tested)

112 241 230 41 624

0.5

Percentage susceptible at MIC (mcg.Iml.) 4 2 1 1.5

5

29 36 27

34 38 32

40 44 44

50 51 49

63 63 60

73 74 70

33

36

45

51

64

74

TABLE II. CLINICAL DIAGNOSIS OF CASES TREATED

Aspiration pneumonia Lung abscess Empyema Total

12 10 8 30

TABLE III. CULTURE SOURCES

Transtracheal aspiration

Thoracentesis Blood cultures

22 patients with aspiration pneumonia and lung abscess Eight patients with empyema All

susceptible at this level.4 Doxycycline has also been demonstrated to give good levels in lung and bronchial tissue. In one study doxycycline levels* were 2.3 times higher in lung tissue than in serum.5 Further, clinical trials have shown doxycycline to be effective in aerobic infections of the respiratory tract. 6,7 For these reasons we have investigated the use of doxycycline in anaerobic infections of the lung.8'9 Among 30 adults treated in our series were 12 cases of aspiration pneumonia, 10 of lung abscess, and eight of empyema (Table II). Culture sources included transtracheal aspiration in 22 cases of lung abscess and aspiration pneumonia, thoracentesis in eight cases of empyema, and blood cultures in all patients (Table III). Seventeen of the patients had mixed aerobic and anaerobic infections, *Tissue penetration is essential to therapeutic efficacy; but specific antibiotic tissue levels have not been directly correlated with specific therapeutic benefits.

Bull. N.Y. Acad. Med.

167

ANAEROBIC LUNG INFECTIONS TABLE IV. BACTERIOLOGY-ANAEROBIC ORGANISMS ISOLATED

Peptostreptococci Peptococci Bacteroides fragilis Other Bacteroides sp. Eubacterium Bifidobacterium Clostridium

7 8

10 18 13 1 8 3

Actinomyces Total

68

TABLE V. MINIMAL INHIBITORY CONCENTRATION OF DOXYCYCLINE ON ANAEROBIC BACTERIA IN VITRO No. of strains

5 mcg.Iml.

Peptostreptococci Peptococci Bacteroides (all)

6 8 27

6 7 23

0 1 4

(B.fragilis)

(10)

( 9)

(1)

Clostridia Eubacteria Actinomycetes Fusobacteria Totals

8 13 3 2

67

6 12 3 2

59

2 1 0 0 8

and 13 had pure anaerobic infections. The bacteriology of the infections was complex; from one to seven species were isolated from each patient. Sixty-eight anaerobic bacteria were isolated from the 30 patients (Table IV). There were seven peptostreptococci, eight peptococci, 10 B. fragilis, 18 other Bacteroides sp., 13 eubacteria, one bifidobacteria, eight clostridia, and three actinomycetes. Minimal inhibitory concentrations were done on these isolates (Table V). Fifty-nine (87%) were susceptible to 5 mcg./ml. of doxycycline, while only eight strains were resistant at this level, namely, one Peptococcus, four Bacteroides (including one B. fragilis), two clostridia, and one Eubacterium. Thirty-one aerobic bacteria were isolated from the 17 patients with mixed aerobic-anaerobic infections (Table VI). These included two Staphylococcus aureus, three pneumococci, three alpha hemolytic streptococci, six gamma hemolytic streptococci (not Group D), one Enterococcus, and two micrococci. Among the bacilli were two Proteus, two Klebsiella, one Escherichia coli, one Citrobacter, and one Aerobacter. Two patients had associated pulmonary tuberculosis. Vol. 54, No. 2, February 1978

168

168

H. H. THADEPALLI THADEPALLI AND AND OTHERS

OTHERS~~~~~~~~~~~~~~~~~~~~~~~~~

TABLE VI. AEROBIC BACTERIA (TOTAL 31) Cocci Staphylococcus aureus Pneumococcus Alpha streptococcus Gamma streptococcus (not group D) Enterococcus Micrococcus Neisseria sp. Total

Bacilli Proteus Klebsiella Escherichia coli Citrobacter Aerobacter Bacillus sp. Mycobacterium tuberculosis Total

2 3 3 6 I 2 4

21 2 2 I 1 1 1 2 10

We treated all 30 patients with doxycycline alone; in no case was a second antibiotic administered concurrently, except for the patients with associated tuberculosis who also received INH and ethambutol. Dosage of doxycycline varied with the infection. Initially we treated all patients with a loading dose of 200 mg. intravenously, followed by a maintenance dose of 100 mg. every 12 hours. Because a delayed therapeutic response was initially observed in several of these patients, in particular those with empyema, we treated five patients with 100 mg. every eight hours and seven patients with 200 mg. every 12 hours.* All of these 12 patients given the higher dose responded promptly. It then became our policy to begin with the standard recommended dose and increase it if necessary, while monitoring for hepatic toxicity. Serum levels of doxycycline were studied in nine of the patients (Figure I). A dose of 100 mg. twice a day given intravenously provided peak blood levels of less than 4 mcg./ml. When the dose was increased to 100 mg. three times a day, a peak level of 7 mcg./ml. was reached.* When the dose was further increased to 200 mg. twice a day, the peak level was almost 15 mcg./ml.* At this level, at least in vitro, 97% of all anaerobic bacteria are inhibited by doxycycline.2'3 When 100 mg. of doxycycline is given orally, peak levels of less than 3 mcg./ml. are achieved. *Current maximum recommended dose: 200 mg. on the first day, followed by 100 to 200 mg.

daily.

Bull. N.Y. Acad. Med.

ANAEROBIC IUf.G INFECTIONS

-~

~

AAEOI

LUGIFCIN

Fig. 1. Serum levels of doxycycline obtained in nine patients *Current maximum recommended dose: 200 mg. the first day, followed by 100 to 200 mg.

169

daily.

TABLE VII. OVERALL CLINICAL RESULTS-30 PATIENTS Cured Failed

27* 3

*Recurrences 2. Overall, 27 of our 30 patients responded favorably (Table VII), but two later relapsed. Of the 27 patients who responded to doxycycline, 11 responded in the first week, 15 in the second week, and one in the third week. The average duration of intravenous therapy was 17.4 days. Oral therapy was then given for an average of 22.4 days. Three cases failed to respond, and these patients required treatment with alternative antibiotics. We observed no doxycycline toxicity among our patients, and serial liverfunction tests showed no hepatic toxicity. The following two brief case histories describe patients (included in our study) who were treated with doxycycline. A 25-year-old man was admitted with left-sided chest pain, cough, and fever of three days' duration, with recent production of purulent sputum.

Vol. 54, No. 2, February 1978

170)

170

H. H. THADEPALLI THADEPALLI AND AND OTHERS

OTHERS~

~

~ ~

ifi.p.

Fig. 2. Chest roentgenogram pretreatment (case No. 1)

He had no history of hemoptysis, respiratory disease, or previous hospitalization. The chest roentgenogram showed a left lower lobe infiltrate; blood, sputum, and urine cultures were negative (Figure 2). Treatment was started empirically with penicillin G. When the patient's temperature did not drop and his clinical status did not improve in 96 hours, we discontinued penicillin and began cefazolin in the belief that his Bull. N.Y. Acad. Med.

ANAEROBIC LUNG INFECTIONS

ANAEROBIC

TABLE VIII. CULTURE RESULTS

Streptococci Enterococci Bacteroidcsfrgii.iss.s. Jiragilis Eubacterium aerroJcwins Eubacterium contortuim Blood culture negative

v:-.-..::li.< - a,.... Xi Ssw:.: ..

S

sg, ......

1 I ? Of: ...:.. ......

....

a':

.::

w. .:. ....

..

:.

K1.1...... :.

3.......:. ,..::i ..:. ,......

s

. . : ..

Fig. 3. Chest roentgenogram pretreatment (case No. 2) Vol. 54, No. 2, February 1978

171

171

172

H. rHADEPALLI AND OrHERS

TABI E IX. CULTURE RESULTS Proteus morganii B(icteroid(s (clostridliiformis s.s. c(I)stridilformlis Blood culture negative

Fig. 4. Chest roentgenogram, posttreatment two weeks (case No. 2) Bull. N.Y. Acad. Med.

ANAEROBIC LUNG INFECTIONS

173

173

might be a Staphylococcus infection. His temperature decreased briefly and then rose again. Another roentgenogram showed no change in the left lower lobe infiltration, and a new pleural effusion with an air-fluid level was noted. Cefazolin was discontinued and doxycycline begun, 200 mg. twice a day, intravenously.* A pleural tap and biopsy revealed a pyopneumothorax with foulsmelling purulent fluid. Cultures yielded alpha-hemolytic Streptococcus, Enterococcus, B. fragilis, Eubacterium aerofaciens, and E. contortum (Table VIII). The pleural biopsy showed acute necrotizing fibrinous inflammation. A chest tube was inserted for drainage, and the doxycycline continued. The patient became afebrile on the fifth day and continued to recover uneventfully. On follow-up there was complete resolution of the empyema. The second case involves a 25-year-old man who was admitted with fever and chills. His history included abdominal trauma with laceration of the liver and left-sided pneumothorax three months prior to admission, followed by laparotomy and splenectomy. At operation he was found to have cirrhosis of the liver and congestive splenomegaly. Physical examination on this admission disclosed nothing remarkable. A chest roentgenogram was normal. Three weeks after admission the patient complained of pleuritic pain on the right side of his chest, where a pleural friction rub was heard. A chest roentgenogram at this time revealed a pleural effusion (Figure 3). Thoracentesis produced foul-smelling pus that on culture grew out P. morganii and B. clostriidiformis, subspecies clostriidiformis (Table IX). Blood cultures were negative. A chest tube was inserted for drainage. The patient was then treated with intravenous doxycycline, 200 mg. twice a day for 10 days and then 100 mg. twice a day for the next 14 days.* He became afebrile on the fifth day of therapy. The pleural effusion decreased in two weeks and cleared after four weeks of antibiotic therapy (Figure 4). Following intravenous medication he was given doxycycline capsules 100 mg. twice a day for 10 days. The patient was followed up in the clinic for several months without a recurrence of fever or empyema. We conclude that doxycycline is effective in the treatment of anaerobic infections of the lung, although at times a higher dosage than the currently *Current maximum recommended dose: 200 mg. the first day, followed by Vol. 54, No. 2, February 1978

100 to 200 mg. daily.

174

174

H. THADEPALLI AND OTHERS

H.

THADEPALLI

AND

OTHERS

recommended one may be needed for maximal therapeutic effect. Currently penicillin is considered by most authors to be the treatment of choice of anaerobic lung infections, and in retrospective studies it has been shown to be effective even when B. fragilis is present as part of a mixed

infection.'01 At another institution a controlled trial of oral and parenteral penicillin G against lung abscess in 36 patients1' showed that penicillin given both ways was effective, although treatment for two to eight weeks was required, with an average of 4.4 weeks. Although bacteriologic proof was not obtained in this series, anaerobic organisms are characteristically present in such infections. Both clindamycin and carbenicillin have also been shown to be effective in prospective studies of anaerobic pulmonary infections in which adequate anaerobic cultures were done.'2 In a more recent study done at our hospital8 we reviewed 39 patients with anaerobic infections of the lung. Twenty-one were treated by penicillin, six were treated by clindamycin, six were treated by carbenicillin, and six were treated by doxycycline. Therapeutic response was assessed after five days of antibiotic therapy. Using the five-day period for evaluation, only three of the 21 penicillin-treated patients responded. The failures included five who were infected with B. fragilis resistant to penicillin. Those who did not respond to penicillin within five days were then switched to clindamycin, carbenicillin, or doxycycline. All responded within five days of the change. Further, of the patients initially treated by clindamycin, carbenicillin, or doxycycline, all but one responded within five days. We conclude that the therapeutic effect of penicillin against anaerobic lung infections may be delayed compared to that of clindamycin, carbenicillin, and doxycycline. In view of these findings, we feel that prospective studies are warranted to reevaluate the efficacy of therapy with penicillin, as compared to other agents such as doxycycline in the treatment of anaerobic infections of the

lung. DIscUSSION DR. GEORGE A. PANKEY. I have just a brief comment about the dosage. We have been concerned about an absence of studies indicating the lack of hepatotoxicity with intravenous doxycycline. We have treated a number of patients with intravenous doxycycline who had cirrhosis and liver disease Bull. N.Y. Acad. Med.

ANAEROBIC LUNG INFECTIONS

175

without any adverse effect on the liver function. I know of no prospective studies with a 200 mg./day dose. DR. L.D. SABATH. It is well known that pregnant women are especially susceptible to tetracycline hepatotoxicity, and, of course, the histologic changes in the liver are very characteristic. But I am unaware of any correlation between preexisting liver disease such as alcoholic hepatitis and a special susceptibility to tetracycline toxicity. Dr. Pankey's comment suggests that even in spite of fairly severe liver disease, there is no evidence of hepatotoxicity. Perhaps preexisting liver disease may not increase the risk of hepatotoxicity at all. I am unaware of any hard data on this subject. I wonder if either Dr. Webb or Dr. Pankey has data on the role of anaerobes in bronchitis. DR. PANKEY. I do not know of many data based on a series of properly obtained cultures of anaerobes with good laboratory follow-up. To obtain a proper specimen in most of the patients with chronic bronchitis, one has to do transtracheal aspiration, and this is contraindicated in these patients. An additional point to keep in mind is that sputum does not have to be foul smelling for anaerobes to be present. Some of the patients with anaerobic infections do not have any foul-smelling secretions. DR. DAVID WEBB. A study in The Journal of Infectious Diseases last year reported that transtracheal aspirations were done on patients with chronic bronchitis, and instead of finding anaerobes the investigators found a low level of colonization with aerobic bacteria including Hemophilus influenzae. 1 3 DR. FRANK M. CALIA. We have had experience with patients with putrid lung abscess treated with low-dose penicillin-600,000 to 1.2 million units of procaine penicillin twice a day-with very acceptable results. However, we would not treat acutely ill patients that way. DR. HAROLD C. NEU. Since 35% of our patients walked into the hospital saying that they were allergic to penicillin, what would one use for their lung abscesses? DR. CALIA. We use either tetracycline or erythromycin. DR. PANKEY. We would use doxycycline. DR. NEU. I think that our consensus is that the tetracyclines are very effective. With regard to penicillin, there is really no consensus about whether one uses 1.2 million or 15 to 18 million units/day, and one makes a decision on perhaps how sick one thinks the patient is. In the penicillinallergic patient, the tetracyclines have appeared to remain extremely effecVol. 54, No. 2, February 1978

176

H. THADEPALLI AND OTHERS

tive drugs. The other consensus of this discussion is that one can give doxycycline without any evidence of hepatic or renal toxicity. A final thought: There is a technical question that we all have to be concerned with in this era of escalating costs, I refer to the fact that with intravenous doxycycline we use one or two setups a day. On the other hand, we give penicillin every four hours in our institution. So, aside from the cost of the drug we have the cost of the set plus the tubing in everything that we have to change. That means that automatically we now have six of those sets versus one or two sets, and suddenly this has assumed rather major financial aspects.

REFERENCES Bacterial Exacerbations of Chronic Bronchitis. In: Doxycycline. New York, Pfizer, 1974, pp. 29-42. 8. Rambhatla, K., Thadepalli, H., and Niden, A. H.: Treatment of anaerobic infections of the lung. Am. Rev. Respir. Dis. 115:54, 1977. 9. Thadepalli, H. and Huang, J. T.: Treatment of anaerobic lung infections with intravenous doxycycline. Curr. Ther. Res. 21:849, 1977. 10. Bartlett, J. G. and Gorbach, S. L.: Treatment of aspiration pneumonia and primary lung abscess: Penicillin G vs clindamycin. J.A.M.A. 234:935, 1975. 11. Weiss, W. Cherniack, N. S.: Acute nonspecific lung abscess: A controlled study comparing orally and parenterally administered penicillin G. Chest 66:349, 1974. 12. Thadepalli, H., Niden, A. H., and Huang, J. T.: Treatment of anaerobic pulmonary infections: Carbenicillin compared to clindamycin and gentamicin. Chest 69:743, 1976. 13. Jordan, G. W., Wong, G. A., and Hoeprich, P. 0.: Bacteriology of the lower respiratory tract as determined by fiberoptic bronchoscopy and transtrapp. 1-11. cheal aspiration. J. Infect. Dis. 134:428, 7. Chodosh, S. and Biagelman, W.: 1976. Doxycycline in the Treatment of Acute

1. Chow, A. W., Malkasian, K. L., Marshall, P. R., and Guze, L. B.: In Vitro Activity of Doxycycline Against Anaerobic Bacteria. In: Doxycycline. New York, Pfizer, 1974, pp. 9-11. 2. Sutter, V. L. and Finegold, S. M.: Susceptibility of anaerobic bacteria to 23 antimicrobial agents. Antimicrob. Agents Chemother. 10:736, 1976. 3. Roy, I., Bach, V., and Thadepalli, H.: The In Vitro Effect of Doxycycline against Anaerobic Bacterial Isolates from the Female Genital Tract. In: Doxycycline. Princeton, N.J., Excerpta Medica, 1977, pp. 12-20. 4. Thadepalli, H., Roy, I., and Bach, V.: Unpublished data, 1977. 5. Fabre, J., Milek, E., Kalfopoulos, P., and Merier, G.: The kinetics of tetracyclines in man. II. Schweiz. Med. Wochenschr. 101:625, 1971. 6. Chodosh, S. and Biagelman, W.: Doxycycline Compared with Amoxicillin in Acute Bacterial Exacerbations of Chronic Bronchitis: Preliminary Report of a Double-Blind Crossover Study. In: Doxycycline. New York, Pfizer, 1976,

Bull. N.Y. Acad. Med.

Anaerobic lung infections treated with doxycycline.

165 ANAEROBIC LUNG INFECTIONS TREATED WITH DOXYCYCLINE* HARAGOPAL THADEPALLI, M.D. Chief, Division of Infectious Diseases DAVID WEBB, M.D. AND JONG...
2MB Sizes 0 Downloads 0 Views