THE JOURNAL OF IiIIFECTIOUS DISEASES. VOL.
iss. SUPPLDIE:\T
• :\IARCH 1977
© 1977 by the University of Chicago. All rights reserved.
Clindamycin and Carbenicillin in Treatment of Patients with Intraabdominal and Female Genital Tract Infections Robert M. Swenson and Bennett Lorber
From the Departments of Medicine, Microbiology, and Immunology, Temple University Health Sciences Center, Philadelphia, Pennsylvania
Anaerobic bacteria are involved in a wide variety of human infections [I, 2], particularly intraabdominal and pelvic infections, which often involve Bacteroides [ragilis [3, 4]. It has been found that as much as 70% of B. tragilis are resistant to penicillin [5, 6]. For this reason, chloramphenicol, clindamycin [7], and, more recently, carbenicillin [8] have been employed in the treatment of such infections. During the past several years, we have been reporting the use of clindamycin or carbenicillin in treatment of anaerobic infections. Results from the use of these two agents in the treatment of 173 patients with intraabdominal or pelvic infections are reported.
dicated by a specimen collected before or within 24 hr of the start of antimicrobial therapy. Patients with known allergic or toxic reactions to clindamycin, carbenicillin, other penicillins, or cephalosporins were excluded. Isolation and identification of bacteria. Specimens were usually collected by aspiration from a closed cavity with use of an 18-gauge needle and syringe. Exceptions included (1) endometrial cultures, which were obtained transcervically; (2) biopsy specimens; and (3) pus, which was aspirated from an open wound. All specimens collected by needle and syringe were immediately injected into an oxygen- and mediumfree tube for transportation to the laboratory. Biopsy specimens were placed in sterile tubes without media and taken immediately to the laboratory where specimens were passed into an anaerobic chamber in which all subsequent manipulations were done [9]. Anaerobic bacteria were identified by colonial morphology, reaction to gram stain, growth on selective media, biochemical reactions, and gas-liquid chromatography of fermentation products. The criteria for identification were those outlined by the Anaerobe Laboratory, Virginia Polytechnic Institute [10]. Facultative anaerobic bacteria were isolated and identified by means of standard techniques [11]. Antibiotic susceptibility tests. Anaerobic bacteria were tested by an agar dilution procedure with a Steers replicator [12] in an anaerobic chamber. Antibiotic susceptibilities for facultative anaerobes were performed by the disk method of Bauer et a1. [13]. Therapeutic regimen. Patients treated with
Materials and Methods
Patients. The 173 inpatients at Temple University Hospital from January 1970 through December 1975 who were included in the study had (1) received no antibiotic therapy in the previous seven days or had received antibiotic therapy for ~24 hr and (2) were infected only or predominantly with anaerobic bacteria, as inThis work was supported in part by grants from the Upjohn Company and Pfizer, Incorporated, Dr. Swenson was an Established Investigator of the American Heart Association when the studies were conducted. The authors arc grateful for the technical assistance of Valerie "argo, Myroslowa Korzeniewski, Sharon Brown, and Suzanne Mueller and for the secretarial help of Sharon Austin. Please address requests for reprints to Dr. Robert M. Swenson, Section of Infectious Disease, Temple University Medical Center, Philadelphia, Pennsylvania 19140.
540
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Clindamycin alone and with an aminoglycoside or carbenicillin alone and with an aminoglycoside were used in therapy for 173 patients with intraabdominal or genital tract infections. Excellent or good results were obtained in 115 of 131 patients treated with cIindamycin and 33 of 42 patients treated with carbenicillin. Few serious side effects were observed in patients who received either drug. The data indicate that clindamycin is an effective drug in these conditions and suggest that carbenicillin may be equally effective.
541
Clindamycin and Carbenicillin
Table 2. Types of infection and number of cases in which anaerobes were isolated from patients with various pelvic and/or intraabdominal infections treated with c1indamycin or carbenicillin.
Drug, infection Clindamycin Pelvic Endomyometritis Salpingitis, peritonitis Pelvic abscess Bartholin's abscess Vaginal cuff abscess Wound
9 18 14 11 10 5
6 15 9 10 8 2
4 9 6 4 4 2
Total Intraabdominal Peritonitis Visceral abscess Intraperitoneal abscess Retroperitoneal abscess Wound
67
50
29
28 14 3 8
24 7 10 3 6
12 6 7 2 3
Total Carbenicillin Pelvic and intraabdominal Peritonitis Visceral abscess Endomyometritis Salpingitis Wound infection
64
50
30
8 4 8 15 7
7 3 12 4
6 3 5 9 1
42
32
24
Total
Table 1. Therapeutic regimens for treatment of 173 patients with pelvic and/or intraabdominal infections. Type of infection*
Therapy Clindamycin, iv (300-450 mg every 6-8 hr) Clindamycin, po § (150-300 mg every 6-8 hr) Carbenicillin, iv (300-450 mgt kg every 24 hr) Aminoglycoside Surgical drainage Total no. of patients
Pelvic'[
Intraabdominal']
67 (2-33)
64 (2-41)
Pelvic and intraabdominal ]
AnMultiple aerobes No. of patients anaerobes only
11
6
sponse without change in or addition of antibiotics; and (4) poor - failure to respond, relapse that necessitated a change in drugs, or development of side effects that required discontinuation of the drug. Results
Clindamycin in the treatment of female genital tract infections. Table 2 lists the types of
13 (1-15)
17 (2-11)
59 (2-29) 52
56 (2-26) 50
42 (21) 36 (2-17) 34
67
64
42
*Number of patients with infection (duration of infection [days] ). tNumber of patients treated with clindamycin. :j:Number of patients treated with carbenicillin. § After initial therapy with iv clindamycin; po = peroral.
infection treated. Multiple strains of anaerobic bacteria were isolated in 50 (75%) of 67 cases. In 29 (43%) of 67 cases, only anaerobic bacteria were isolated. The bacteriology of these infections is presented in table 3. The anaerobic isolates that predominated were Bacteroides species, particularly Bacteroides melaninogenicus. As noted previously [4], Clostridium species were only rarely isolated. Gram-negative bacilli and Streptococcus species were the most frequently isolated facultative anaerobes.
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clindamycin initially received 300-450 mg iv every 6-8 hr. Since intraabdominal and pelvic infections frequently involve gram-negative enteric bacilli, most patients also received 7.5 mg of kanamycin/kg iv every 12 hr or 1-1.65 mg of gentamicin/kg iv every 8 hr. If no gram-negative, facultative, anaerobic bacteria were isolated, then use of the aminoglycoside was discontinued. All patients treated with carbenicillin received 300-450 mg/kg iv every 24 hr. Since these infections occasionally involve Klebsiella species. which are resistant to carbenicillin, most patients also were given kanamycin or gentamicin. If all facultative anaerobic bacteria isolated were susceptible to carbenicillin, therapy with the aminoglycoside was discontinued. A summary of the therapeutic regimens and their duration is presented in table 1. Evaluation of patients' responses. Results of therapy were evaluated according to the following criteria: (1) excellent - clinical resolution, marked improvement and negative cultures, or no further drainage from infection site within four days; (2) good - similar clinical and bacteriologic response within seven days; (3) fair - ultimate clinical and bacteriologic re-
842
Swenson and Lorber
Table 3. Bacteria isolated from patients with pelvic and/or intraabdominal infections treated with clindamycin or carbenicillin. Drug, type of infection, organism
Total Facultative anaerobes or aerobes Escherichia coli Streptococcus species Group A Streptococcus Group D Streptococcus Proteus species Klebsiella species Pseudomonas species Staphylococcus aureus Total Intraabdominal Anaerobes B. fragilis B. melaninogenicus Bacteroides species P. prevotii Peptococcus species P. anaerobius P. intermedius Peptostreptococcus species Fusobacterium species Eubacterium species Clostridium species Others Total Facultative anaerobes or aerobes E. coli Streptococcus species Proteus species Klebsiella species Pseudomonas species Others Total
23 9 16 18 4
10 15 7 5
7 4
2 6
126
21 18 7
2 6 4 I
3 53
71 30 15 13 8
14 5 3
15 8 7 9
198
36 27 6 6
2 6
83 continued
Drug, type of infection, organism Carbenicillin Pelvic and/or intraabdominal Anaerobic B. [ragilis B. melaninogenicus Bacteroides species Fusobacterium species Peptostreptococcus species Peptococcus species Clostridium species Others Total Facultative anaerobes and aerobes E. coli Streptococcus species Klebsiella-Enterobacter species Proteus species Pseudomonas species Total
No. of cases
31 8 11 12 11 8 6
14 101 14 12 8 7 1
42
Ninety-three of the 126 anaerobic isolates were susceptible to 2 p,g of clindamycinjml, and 23 isolates were susceptible to ~4 p,gjml. It was not possible to test 10 of the isolates. Responses to therapy with clindamycin are shown in table 4. Fair responses were observed in patients with pelvic peritonitis. In one patient, B. tragilis, Bacteroides melaninogenicus, and Peptococcus prevotii were isolated from peritoneal fluid, and B. [ragilis was isolated from three blood cultures. This patient was given clindamycin for 26 days, during which time she underwent three surgical drainage procedures. In the other patient, B. tragilis and Escherichia coli were isolated from both peritoneal fluid and two blood cultures; the patient was given 15 days of therapy with clindamycin and kanamycin. The poor response to therapy was observed in a patient with severe endomyometritis. When admitted, she was in shock with evidence of dissemiated intravascular coagulation. Clostridium perfringens and B. [ragilis were present in the initial blood cultures. She died 30 hr after admission. C lindamycin
dominal
in the treatment of intraabinfections. The types of infection
treated are listed in table 2. All cases of peritonitis were secondary to trauma, disease, or surgery of the gastrointestinal tract. Visceral abscesses included 10 hepatic abscesses and one splenic abscess. Wound infections followed trauma or sur-
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Clindamycin Pelvic Anaerobes Bacteroides melaninogenicus Bacteroides [ragilis Bacteroides species Peptococcus prevotii Peptococcus magnus Peptococcus species Peptostreptococcus anaerobius Peptostreptococcus intermedius Peptostreptococcus species Fusobacterium species Eubacterium species Clostridium species Others
No. of cases
Table 3 (continued).
Clindamycin and Carbenicillin
543
Table 4. Responses of 173 patients with pelvic and/or intraabdominal infections treated with clindamycin or carbenicillin. Response Drug, infection
Excellent
Good
Fair
Poor
3 7 6 8 7 3
5
18 14 11 10 5
Total Intraabdominal Peritonitis Visceral abscess Intraperitoneal abscess Retroperitoneal abscess Wound
67
34
30
2
28 11 14 3 8
11
6 6 1 6
10 2 7 1 1
5 1 1 1 1
2 1
Total Carbenicillin Pelvic and/or intraabdominal Peritonitis Visceral abscess Endomyometritis Salpingitis Wound infection
64
30
21
9
4
8
2 1
3
6
Total
9
9 8
3 3 2
8
b
15 7
13 4
2 2 1 1 2
42
25
8
4
gery of the gastroi n testinal tract. MultipIe anaerobic isolates were present in 50 cases (78%). In 30 cases (47%) only anaerobic bacteria were isolated. The bacteriology of these intraabdominal infections is presented in table 3. B. fragilis was the anaerobe most frequently isolated. Facultative anaerobes included gram-negative bacilli and streptococci, of which nine isolates were enterococci. Of 198 anaerobic isolates, 156 were susceptible to 2 /Lg of clindamycinjml, and 21 isolates were susceptible to ~4 /Lgjml. One isolate each of Clostridium ramosum and B. fragilis was resistant to 64 /Lg of clindamycinjml. Nineteen isolates could not be tested. The response to therapy in these cases is summarized in table 4. The response was considered good or excellent in 51 cases (80%). Five cases of diffuse peritonitis required prolonged drainage and multiple surgical procedures and were ultimately cured. Similar prolonged courses were seen in one case each of hepatic abscess, intraperitoneal
2
3
abscess, retroperitoneal abscess, and wound infection. One patient with diffuse peritonitis rapidly developed shock and disseminated intravascular coagulation; death occurred within 20 hr after therapy was started. Severe diarrhea developed in one patient with peritonitis, one with hepatic abscess, and one with retroperitoneal abscess, and use of clindamycin was discontinued. In two of these patients, pseudomembranous colitis was documented by sigmoidoscopy and biopsy. Carbenicillin in the treatment of intraabdominal and pelvic infections. The kinds of infection treated are listed in table 2. The cases of peritonitis were associated with trauma, disease, or surgery of the gastrointestinal tract. Of the visceral abscesses reported, three were hepatic abscesses and one was a pancreatic abscess. The wound infections occurred after trauma or operation on the gastrointestinal tract or the female geni tal tract. The bacteriology (table 3) is similar to that seen in the patients treated with clindamycin.
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Clindamycin Pelvic Endomyometritis Salpingitis, peritonitis Pelvic abscess Bartholin's abscess Vaginal cuff abscess Wound
No. of patients
S44
Discussion
The results of in vitro susceptibility tests on anaerobic isolates from 173 cases lend further support to previous observations that the majority of anaerobic bacteria, including B. [ragilis, are sus-
ceptible to clindamycin and carbenicillin. Our experience with 131 patients treated with clindamycin indicates that it is an effective agent in the treatment of anaerobic intraabdominal and pelvic infections. Serious side effects were minimal. The results in a smaller group of 42 patients treated with carbenicillin suggest that this antibiotic may be equally effective. Serious side effects were also minimal in this group. However, further prospective, randomized trials are required for comparison of the relative efficacy of these agents. References 1. Bornstein, D. L., Weinberg, A. N., Swartz, M. N., KUOl, L. J. Anaerobic infections-review of current experience. Medicine 43:207-232,1964. 2. Gorbach, S. L., Bartlett, j. G. Anaerobic infections. N. Engl. J. Med. 290: II 77-Il 84, 1237-1245, 12891294,1974. 3. Swenson, R. M., Lorber, B., Michaelson, T. C., Spaulding, E. H. The bacteriology of intra-abdominal infections. Arch. Surg. 109:398-399, 1974. 4. Swenson, R. M., Daly, M. J. Michaelson, T. C., Spaulding, E. H. Anaerobic bacteria in infections of the female genital tract. Obstet. Gynecol. 42:538, 1973. 5. Martin, W. j., Gardner, M., Washington, J. A. II. In vitro antimicrobial susceptibility of anaerobic bacteria isolated from clinical specimens. Antimicrob. Agents Chemother. 1:148-158, 1972. 6. Kislak, J. W. The susceptibility of Bacteroides fragilis to 24 antibiotics. J. Infect. Dis. 125:295-299,1972. 7. Swenson, R. M., Michaelson, T. C., Daly, M.]., Spaulding, E. H. Clindamycin in infections of the female genital tract. Obstet. GynecoI. 44:699-702, 1974. 8. Swenson, R. M., Lorber, B. Carbenicillin in the treatment of infections involving anaerobic bacteria. Antimicrob. Agents Chernother. 9:1025-1027.1976. 9. Spaulding, E. H., Vargo, V., Michaelson, T. C., Swenson, R. M. A comparison of two procedures for isolating anaerobic bacteria from clinical specimens. In A. Balows, R. M. DeHaan, L. B. Guze, and V. R. Dowell [ed.], Anaerobic bacteria. Charles C Thomas, Springfield, 111.,1974. p. 37-46. 10. Holdeman, L. V., Moore, W. E. C. [ed.]. Anaerobe laboratory manual. Ist ed. Virginia Polytechnic Institute and State University, Blacksburg, Va., 1972. 130 p. 11. Lennette, E. H., Spaulding, E. H., Truant, J. P. [ed.]. Manual of clinical microbiology. 2nd ed. American Society for Microbiology, Washington, D.C., 1974. 970 p. 12. Steers, E., Foltz, E. L., Graves, B. S. An inocula-replicating apparatus for routine testing of bacterial sus-
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Seventy-four of 101 anaerobic isolates were susceptible to 64 fJ-g of carbenicillin/rnl, and 13 isolates were susceptible to 256 fJ-g/ml. Two strains of B. tragilis were resistant to >256 fJ-g of carbenicillin/rnl. Twelve isolates could not be tested. The results of therapy are shown in table 4. Three patients with generalized peritonitis required prolonged surgical drainage and multiple surgical procedures. Similar prolonged courses of treatment were required in one patient with endomyometritis salpingitis and one patient with wound infection. Therapy with carbenicillin was discontinued in two patients because of gastrointestinal bleeding (although this could not be definitely ascribed to the drug); in one, therapy was discontinued because of severe hypokalemia. Tolerance and toxicity. Clindamycin was generally well tolerated by the majority of patients. Fourteen patients developed diarrhea, which was severe enough in three cases to warrant discontinuation of the antibiotic. Pseudomembranous colitis was documented by sigmoidoscopy and biopsy in two of these patients. Eight patients who received an aminoglycoside developed transient increases in serum levels of creatinine. Three developed unexplained rises in serum aspartate aminotransferase (SCOT), three developed a maculopapular rash, and another had transient thrombocytopenia. Carbenicillin was also well tolerated by most patients. Seven developed transient increases in SCOT. Four concomitantly received an aminoglycoside and showed transient increases in serum levels of creatinine. Carbenicillin was discontinued in two patients because of gastrointestinal bleeding, although bleeding could not be ascribed to the antibiotic in ei ther patient. Fially, unexplained hypokalemia occurred in one patient; this condition rapidly resolved when therapy with the antibiotic was stopped.
Swenson and Lorber
Clindamycin and Carbenicillin
ceptibility to antibiotics. Antibiot. Chemother. 9: 307-311, 1959. 13. Bauer, A. W., Kirby, W. M. M., Sherris, J. C., Turck,
545
M. Antibiotic susceptibility testing by a standardized single disk method. Am. J. Clin. Pathol. 45:493-496, 1966.
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Discussion Moderator: Philip Mead
cin should be used only for serious infections requiring hospitalization? If so, is there ever any indication for using the drug orally rather than parenterally? DR. SWENSON. This is an important consideration for the ambulatory patient with pelvic inflammatory disease who does not require hospitalization. What therapy would be prescribed for this patient? DR. MEAD. A gynecologist would probably want to treat such women as outpatients with what Dr. Finegold has referred to as secondline drugs-the tetracyclines or ampicillin by mouth. Even when these patients are hospitalized there is some reluctance to use drugs effective against Bacteroides [ragilis, such as clindamycin and chloramphenicol, because of the potential toxicity. The patient who has developed an abscess requires surgical treatment. I often wonder if more aggressive parenteral therapy for the initial infection might prevent some of these abscesses, which need to be drained surgically. DR. CHOW. There is no question that if abscess is present, and not simply an inflammatory mass with edema, then there is certainly a high incidence of B. fragilis. So, in addition to surgical drainage, antibiotic therapy effective against B. fragilis is important. However, we have found that B. fragilis has not been an important or common pathogen in other forms of pelvic infections such as acute salpingitis, C-section infections, and septic abortion. So, we treat these infections quite effectively with drugs such as ampicillin or analogues of tetracycline. In the initial management of salpingitis, one should consider the presence of Neisseria gonorrhoeae, and therapy should cover this organism. DR. FINEGOLD. For most drugs, parental therapy does not represent more aggressive therapy than oral therapy, providing that the patient can absorb the drug well and achieve adequate blood levels. If B. fragilis is present, clindamycin is effective therapy. If B. fragilis has not been confirmed and the patient is seriously ill, I use clindamycin or another agent such as chlorampheni-
546
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DR. P. MEAD. Drs. Bobitt and Ledger, I have not seen a significant number of enterococci in pelvic or abdominal infections. Does your experience suggest that the combination of clindamycin plus gentamicin is adequate, or is an additional drug necessary to cover this organism? DR. J. R. BOBITT. A study was done at the University of Michigan [1] in which antibiotic treatment did not cover the enterococcus, and some treatment failures were reported. In an evaluation of bacteremia in obstetric and gynecologic patients at the University of Southern California [2], the enterococcus was the second most common isolate. In our present series, the enterococcus was isolated from infection sites in three patients, although it was never recovered from the blood. For patients with serious pelvic infections, we believe therapy should cover this organism, although our study did not establish this. DR. R. M. SWENSON. We have not seen a single case of enterococcal bacteremia related to pelvic infections. Even in cultures from pelvic abscesses, enterococci were recovered on just two or three occasions. DR. A. W. CHOW. Our experience was similar. In our studies on septic abortion, sometimes we isolated fairly large numbers of enterococci from the endometrium, but we never had any cases of enterococcal bacteremia. Similarly, in our studies of C-section infections and acute salpingitis, we did not find enterococci to be an important pathogen. DR. S. M. FINEGOLD. I agree. I certainly don't believe the enterococcus is very important in that kind of situation. DR. S. L. GORBACH. In pelvic infections and intraabdominal sepsis, our incidence of recovery of enterococci is only 15%. Isolation from blood cultures in patients with these conditions is a rare occurrence. DR. F. J. TEDESCO. There is some evidence that there is a higher incidence of pseudomembranous colitis with the oral route of antibiotic administration. Does this suggest that clindamy-
Discussion
DR. CHOW. There is no question of the significance of N. gonorrhoeae in acute salpingitis. Our data are not that much at variance with those reported by Eshenbach et al. We are looking at a spectrum of the disease. Certainly, if culdocentesis is done early, there's a much higher incidence of isolation of gonococci from the upper pelvic tract. Early in the acute phase of the illness, gonococci can be found in the cul-de-sac along with a few other organisms; later on in the course of infection, gonococci disappear and are replaced by normal vaginal flora. In terms of proper sampling techniques in pelvic infections, blood cultures are the key in septic abortion since bacteremia is common. The role of cervical cultures would only be for the identification of gonococci. In other types of pelvic infections, bacteremia is uncommon, and it is necessary to sample the upper tract. The easiest way is by culdocentesis. DR. FINEGOLD. There are studies in which endometrial flora has been sampled from patients with and without endometritis. There was no significant difference in the bacteriology of the two groups, a finding suggesting that the normal geni tal tract flora was cultured in both situations. Dr. Chow, you presented a lot of data on endometrial cultures. I wonder if you conclude, at this point, that it might not be worth doing such cultures in the future? Also, why did you treat your patients with both penicillin and chloram phenicol? DR. CHOW. The purpose of showing results of endometrial culture is to indicate its limited usefulness. The combination of penicillin plus chloramphenicol was used because of its wide spectrum of activity and because it has been conventional therapy in our hospital. Previous studies by double-blind comparison in our institution show that this combination was not different from cephalothin plus kanamycin [3]. Our data on septic abortion presented earlier further attest to the clinical efficacy of this combination. DR. MEAD. Tissue removed at the time of laparotomy is an excellent source from which to recover potential pathogens. Some of this material can be snipped off, put into a gassed-out tube, and sent to the laboratory. Unfortunately, this is not often done. I would like to raise another issue; there is good evidence that wom-
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col until the results are available or the patient is distinctly better. When B. fragilis is not present, ampicillin or a similar drug is perfectly good therapy. DR. GORBACH. Dr. Bobitt, in your presentation the incidence of B. fragilis isolated from abscesses was high in the chloramphenicol group and zero in the clindamycin group. I gathered that these patients were taking antimicrobial agents when the abscess was cultured. One of the findings that we have noted is the difficulty of isolating B. fragilis from infected sites once clindamycin has been started. We are able to isolate it in patients treated with penicillin and even, as you showed, with chloramphenicol. Do you believe that some of the pathogens were masked by the prior use of antimicrobial agents? Obviously, this is required by the clinical setting, but, in terms of judging the data, is it a fair comparison? DR. BOBITT. Your question is a good one. There were fewer anaerobes recovered from abscesses when patients were treated preoperatively with clindamycin than when chloramphenicol was given. Obviously, further evaluation of this question is needed. DR. GORBACH. Dr. Chow, with regard to the problem of getting proper cultures from women with pelvic infections, what is a proper culture? It has been mentioned that culdocentesis may be negative; the infected site, which may be high in the pelvis or in the tubes and not draining into the cul-de-sac, may not even be sam pled. Also, there are women who respond rapidly to antimicrobial agents or to D and C, so that one never really gets an appropriate culture. I raise this point because of the perplexing question of N. gonorrhoeae. Your data are different from those reported by the group in Seattle, which noted a much higher isolation rate of gonococci. I am not sure whether the differences are related to sampling techniques or to the different clinical entities studied. We probably all agree that clindamycin plus an aminoglycoside is not adequate treatment for gonorrhea. Therefore, when the gonococcus is a potential pathogen, I'm attracted to the notion of using a third agent such as penicillin or ampicillin. The gonococcus is a significant problem, and maybe we have to define our patient population a bit more clearly.
547
Discussion
548
DR. REMINGTON. At the Stanford institutions we have not varied our use of clindamycin, as far as indications for iv usage. If a woman has severe pelvic inflammatory disease or infection following pelvic surgery, we routinely use clindamycin. If even 1% of patients with B. iragilis developed pelvic thrombophlebitis or septic pulmonary emboli and died or had to have the uterus removed because of this infection, I would be willing to use clindamycin or chloramphenicol, unless someone could show me there was a significant hazard with its use. However, it would be helpful to have some statistical data so that we know when to use these drugs. DR. MEAD. Basically, the problem is that it is very difficult to culture soft tissue infections such as pelvic peri toni tis and pelvic cellulitis. Large series of pelvic abscesses from studies in Atlanta and Houston showed that B. tragi lis was isolated from about 40% of patients cultured. In other pelvic infections not accompanied by abscess, B. iragilis was only isolated from 10%-15%. The isolation rate of B. [ragilis is >1 %, but I do not know how to determine whether or not a patient has B. [ragilis at the onset of her infection.
References
J., Kriewall, T. J., Sweet, R. L., Fekety, F. R., Jr. The use of parenteral clindamycin in the treatment of obstetric-gynecologic patients with severe infections. Obstet. Gynecol. 43 :490-497, 1974. 2. Ledger, W. J., Norman, M., Gee, C., Lewis, W. Bacteremia on an obstetric-gynecologic service. Am. J. Obstet. GynecoI. 121:205-212, 1975. 3. Ostergard, D. R. Comparison of two antibiotic regimens in the treatment of septic abortion. Obstet. Gynecol. 36:473-474, 1970. I. Ledger, W.
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en with septic abortion who are treated with D and C generally will respond without any antibiotic therapy. DR. J. S. REMINGTON. Dr. Chow's earlier comments are germane. When we utilize new antimicrobial agents or various combinations, we should do so without pious hopes and simply should try to improve upon what has been accomplished with the earlier agents. Some of the questions we might ask are: have we advanced? Are we seeing better treatment results than we did without any drug therapy or with previous regimens? DR. GORBACH. The crux of your question lies in the realm of B. tragi lis, because that is the one organism that separates the use of penicillin from chloramphenicol or clindamycin. In the studies reported by our group and Dr. Swenson's, B. [ragilis was a significant pathogen. These women were very ill, usually with a closed-space infection such as pelvic abscess. They had been treated previously with other drugs, so we were seeing a subset of the population with serious pelvic infections whose prior treatment had failed. B. [ragilis was isolated commonly from the bloodstream and from direct puncture of the abscess at the time of operation. Whether all patients should be treated at the outset with clindamycin or chloramphenicol, I find impossible to answer. My own view is that if a closed-space infection or abscess is suspected, that is, a mass is palpated, or if pelvic peritonitis is present or eminent, these patients should be selected for B. [ragilis treatment. In less serious infections such as salpingitis, I agree with the other panelists that the isolation of B. tragilis is relatively uncommon. These patients can be treated with a number of antimicrobial agents including ampicillin or tetracycline.
iss. SUPPLDIE:\T
• :\IARCH 1977
© 1977 by the University of Chicago. All rights reserved.
Clindamycin and Carbenicillin in Treatment of Patients with Intraabdominal and Female Genital Tract Infections Robert M. Swenson and Bennett Lorber
From the Departments of Medicine, Microbiology, and Immunology, Temple University Health Sciences Center, Philadelphia, Pennsylvania
Anaerobic bacteria are involved in a wide variety of human infections [I, 2], particularly intraabdominal and pelvic infections, which often involve Bacteroides [ragilis [3, 4]. It has been found that as much as 70% of B. tragilis are resistant to penicillin [5, 6]. For this reason, chloramphenicol, clindamycin [7], and, more recently, carbenicillin [8] have been employed in the treatment of such infections. During the past several years, we have been reporting the use of clindamycin or carbenicillin in treatment of anaerobic infections. Results from the use of these two agents in the treatment of 173 patients with intraabdominal or pelvic infections are reported.
dicated by a specimen collected before or within 24 hr of the start of antimicrobial therapy. Patients with known allergic or toxic reactions to clindamycin, carbenicillin, other penicillins, or cephalosporins were excluded. Isolation and identification of bacteria. Specimens were usually collected by aspiration from a closed cavity with use of an 18-gauge needle and syringe. Exceptions included (1) endometrial cultures, which were obtained transcervically; (2) biopsy specimens; and (3) pus, which was aspirated from an open wound. All specimens collected by needle and syringe were immediately injected into an oxygen- and mediumfree tube for transportation to the laboratory. Biopsy specimens were placed in sterile tubes without media and taken immediately to the laboratory where specimens were passed into an anaerobic chamber in which all subsequent manipulations were done [9]. Anaerobic bacteria were identified by colonial morphology, reaction to gram stain, growth on selective media, biochemical reactions, and gas-liquid chromatography of fermentation products. The criteria for identification were those outlined by the Anaerobe Laboratory, Virginia Polytechnic Institute [10]. Facultative anaerobic bacteria were isolated and identified by means of standard techniques [11]. Antibiotic susceptibility tests. Anaerobic bacteria were tested by an agar dilution procedure with a Steers replicator [12] in an anaerobic chamber. Antibiotic susceptibilities for facultative anaerobes were performed by the disk method of Bauer et a1. [13]. Therapeutic regimen. Patients treated with
Materials and Methods
Patients. The 173 inpatients at Temple University Hospital from January 1970 through December 1975 who were included in the study had (1) received no antibiotic therapy in the previous seven days or had received antibiotic therapy for ~24 hr and (2) were infected only or predominantly with anaerobic bacteria, as inThis work was supported in part by grants from the Upjohn Company and Pfizer, Incorporated, Dr. Swenson was an Established Investigator of the American Heart Association when the studies were conducted. The authors arc grateful for the technical assistance of Valerie "argo, Myroslowa Korzeniewski, Sharon Brown, and Suzanne Mueller and for the secretarial help of Sharon Austin. Please address requests for reprints to Dr. Robert M. Swenson, Section of Infectious Disease, Temple University Medical Center, Philadelphia, Pennsylvania 19140.
540
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Clindamycin alone and with an aminoglycoside or carbenicillin alone and with an aminoglycoside were used in therapy for 173 patients with intraabdominal or genital tract infections. Excellent or good results were obtained in 115 of 131 patients treated with cIindamycin and 33 of 42 patients treated with carbenicillin. Few serious side effects were observed in patients who received either drug. The data indicate that clindamycin is an effective drug in these conditions and suggest that carbenicillin may be equally effective.
541
Clindamycin and Carbenicillin
Table 2. Types of infection and number of cases in which anaerobes were isolated from patients with various pelvic and/or intraabdominal infections treated with c1indamycin or carbenicillin.
Drug, infection Clindamycin Pelvic Endomyometritis Salpingitis, peritonitis Pelvic abscess Bartholin's abscess Vaginal cuff abscess Wound
9 18 14 11 10 5
6 15 9 10 8 2
4 9 6 4 4 2
Total Intraabdominal Peritonitis Visceral abscess Intraperitoneal abscess Retroperitoneal abscess Wound
67
50
29
28 14 3 8
24 7 10 3 6
12 6 7 2 3
Total Carbenicillin Pelvic and intraabdominal Peritonitis Visceral abscess Endomyometritis Salpingitis Wound infection
64
50
30
8 4 8 15 7
7 3 12 4
6 3 5 9 1
42
32
24
Total
Table 1. Therapeutic regimens for treatment of 173 patients with pelvic and/or intraabdominal infections. Type of infection*
Therapy Clindamycin, iv (300-450 mg every 6-8 hr) Clindamycin, po § (150-300 mg every 6-8 hr) Carbenicillin, iv (300-450 mgt kg every 24 hr) Aminoglycoside Surgical drainage Total no. of patients
Pelvic'[
Intraabdominal']
67 (2-33)
64 (2-41)
Pelvic and intraabdominal ]
AnMultiple aerobes No. of patients anaerobes only
11
6
sponse without change in or addition of antibiotics; and (4) poor - failure to respond, relapse that necessitated a change in drugs, or development of side effects that required discontinuation of the drug. Results
Clindamycin in the treatment of female genital tract infections. Table 2 lists the types of
13 (1-15)
17 (2-11)
59 (2-29) 52
56 (2-26) 50
42 (21) 36 (2-17) 34
67
64
42
*Number of patients with infection (duration of infection [days] ). tNumber of patients treated with clindamycin. :j:Number of patients treated with carbenicillin. § After initial therapy with iv clindamycin; po = peroral.
infection treated. Multiple strains of anaerobic bacteria were isolated in 50 (75%) of 67 cases. In 29 (43%) of 67 cases, only anaerobic bacteria were isolated. The bacteriology of these infections is presented in table 3. The anaerobic isolates that predominated were Bacteroides species, particularly Bacteroides melaninogenicus. As noted previously [4], Clostridium species were only rarely isolated. Gram-negative bacilli and Streptococcus species were the most frequently isolated facultative anaerobes.
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clindamycin initially received 300-450 mg iv every 6-8 hr. Since intraabdominal and pelvic infections frequently involve gram-negative enteric bacilli, most patients also received 7.5 mg of kanamycin/kg iv every 12 hr or 1-1.65 mg of gentamicin/kg iv every 8 hr. If no gram-negative, facultative, anaerobic bacteria were isolated, then use of the aminoglycoside was discontinued. All patients treated with carbenicillin received 300-450 mg/kg iv every 24 hr. Since these infections occasionally involve Klebsiella species. which are resistant to carbenicillin, most patients also were given kanamycin or gentamicin. If all facultative anaerobic bacteria isolated were susceptible to carbenicillin, therapy with the aminoglycoside was discontinued. A summary of the therapeutic regimens and their duration is presented in table 1. Evaluation of patients' responses. Results of therapy were evaluated according to the following criteria: (1) excellent - clinical resolution, marked improvement and negative cultures, or no further drainage from infection site within four days; (2) good - similar clinical and bacteriologic response within seven days; (3) fair - ultimate clinical and bacteriologic re-
842
Swenson and Lorber
Table 3. Bacteria isolated from patients with pelvic and/or intraabdominal infections treated with clindamycin or carbenicillin. Drug, type of infection, organism
Total Facultative anaerobes or aerobes Escherichia coli Streptococcus species Group A Streptococcus Group D Streptococcus Proteus species Klebsiella species Pseudomonas species Staphylococcus aureus Total Intraabdominal Anaerobes B. fragilis B. melaninogenicus Bacteroides species P. prevotii Peptococcus species P. anaerobius P. intermedius Peptostreptococcus species Fusobacterium species Eubacterium species Clostridium species Others Total Facultative anaerobes or aerobes E. coli Streptococcus species Proteus species Klebsiella species Pseudomonas species Others Total
23 9 16 18 4
10 15 7 5
7 4
2 6
126
21 18 7
2 6 4 I
3 53
71 30 15 13 8
14 5 3
15 8 7 9
198
36 27 6 6
2 6
83 continued
Drug, type of infection, organism Carbenicillin Pelvic and/or intraabdominal Anaerobic B. [ragilis B. melaninogenicus Bacteroides species Fusobacterium species Peptostreptococcus species Peptococcus species Clostridium species Others Total Facultative anaerobes and aerobes E. coli Streptococcus species Klebsiella-Enterobacter species Proteus species Pseudomonas species Total
No. of cases
31 8 11 12 11 8 6
14 101 14 12 8 7 1
42
Ninety-three of the 126 anaerobic isolates were susceptible to 2 p,g of clindamycinjml, and 23 isolates were susceptible to ~4 p,gjml. It was not possible to test 10 of the isolates. Responses to therapy with clindamycin are shown in table 4. Fair responses were observed in patients with pelvic peritonitis. In one patient, B. tragilis, Bacteroides melaninogenicus, and Peptococcus prevotii were isolated from peritoneal fluid, and B. [ragilis was isolated from three blood cultures. This patient was given clindamycin for 26 days, during which time she underwent three surgical drainage procedures. In the other patient, B. tragilis and Escherichia coli were isolated from both peritoneal fluid and two blood cultures; the patient was given 15 days of therapy with clindamycin and kanamycin. The poor response to therapy was observed in a patient with severe endomyometritis. When admitted, she was in shock with evidence of dissemiated intravascular coagulation. Clostridium perfringens and B. [ragilis were present in the initial blood cultures. She died 30 hr after admission. C lindamycin
dominal
in the treatment of intraabinfections. The types of infection
treated are listed in table 2. All cases of peritonitis were secondary to trauma, disease, or surgery of the gastrointestinal tract. Visceral abscesses included 10 hepatic abscesses and one splenic abscess. Wound infections followed trauma or sur-
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Clindamycin Pelvic Anaerobes Bacteroides melaninogenicus Bacteroides [ragilis Bacteroides species Peptococcus prevotii Peptococcus magnus Peptococcus species Peptostreptococcus anaerobius Peptostreptococcus intermedius Peptostreptococcus species Fusobacterium species Eubacterium species Clostridium species Others
No. of cases
Table 3 (continued).
Clindamycin and Carbenicillin
543
Table 4. Responses of 173 patients with pelvic and/or intraabdominal infections treated with clindamycin or carbenicillin. Response Drug, infection
Excellent
Good
Fair
Poor
3 7 6 8 7 3
5
18 14 11 10 5
Total Intraabdominal Peritonitis Visceral abscess Intraperitoneal abscess Retroperitoneal abscess Wound
67
34
30
2
28 11 14 3 8
11
6 6 1 6
10 2 7 1 1
5 1 1 1 1
2 1
Total Carbenicillin Pelvic and/or intraabdominal Peritonitis Visceral abscess Endomyometritis Salpingitis Wound infection
64
30
21
9
4
8
2 1
3
6
Total
9
9 8
3 3 2
8
b
15 7
13 4
2 2 1 1 2
42
25
8
4
gery of the gastroi n testinal tract. MultipIe anaerobic isolates were present in 50 cases (78%). In 30 cases (47%) only anaerobic bacteria were isolated. The bacteriology of these intraabdominal infections is presented in table 3. B. fragilis was the anaerobe most frequently isolated. Facultative anaerobes included gram-negative bacilli and streptococci, of which nine isolates were enterococci. Of 198 anaerobic isolates, 156 were susceptible to 2 /Lg of clindamycinjml, and 21 isolates were susceptible to ~4 /Lgjml. One isolate each of Clostridium ramosum and B. fragilis was resistant to 64 /Lg of clindamycinjml. Nineteen isolates could not be tested. The response to therapy in these cases is summarized in table 4. The response was considered good or excellent in 51 cases (80%). Five cases of diffuse peritonitis required prolonged drainage and multiple surgical procedures and were ultimately cured. Similar prolonged courses were seen in one case each of hepatic abscess, intraperitoneal
2
3
abscess, retroperitoneal abscess, and wound infection. One patient with diffuse peritonitis rapidly developed shock and disseminated intravascular coagulation; death occurred within 20 hr after therapy was started. Severe diarrhea developed in one patient with peritonitis, one with hepatic abscess, and one with retroperitoneal abscess, and use of clindamycin was discontinued. In two of these patients, pseudomembranous colitis was documented by sigmoidoscopy and biopsy. Carbenicillin in the treatment of intraabdominal and pelvic infections. The kinds of infection treated are listed in table 2. The cases of peritonitis were associated with trauma, disease, or surgery of the gastrointestinal tract. Of the visceral abscesses reported, three were hepatic abscesses and one was a pancreatic abscess. The wound infections occurred after trauma or operation on the gastrointestinal tract or the female geni tal tract. The bacteriology (table 3) is similar to that seen in the patients treated with clindamycin.
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Clindamycin Pelvic Endomyometritis Salpingitis, peritonitis Pelvic abscess Bartholin's abscess Vaginal cuff abscess Wound
No. of patients
S44
Discussion
The results of in vitro susceptibility tests on anaerobic isolates from 173 cases lend further support to previous observations that the majority of anaerobic bacteria, including B. [ragilis, are sus-
ceptible to clindamycin and carbenicillin. Our experience with 131 patients treated with clindamycin indicates that it is an effective agent in the treatment of anaerobic intraabdominal and pelvic infections. Serious side effects were minimal. The results in a smaller group of 42 patients treated with carbenicillin suggest that this antibiotic may be equally effective. Serious side effects were also minimal in this group. However, further prospective, randomized trials are required for comparison of the relative efficacy of these agents. References 1. Bornstein, D. L., Weinberg, A. N., Swartz, M. N., KUOl, L. J. Anaerobic infections-review of current experience. Medicine 43:207-232,1964. 2. Gorbach, S. L., Bartlett, j. G. Anaerobic infections. N. Engl. J. Med. 290: II 77-Il 84, 1237-1245, 12891294,1974. 3. Swenson, R. M., Lorber, B., Michaelson, T. C., Spaulding, E. H. The bacteriology of intra-abdominal infections. Arch. Surg. 109:398-399, 1974. 4. Swenson, R. M., Daly, M. J. Michaelson, T. C., Spaulding, E. H. Anaerobic bacteria in infections of the female genital tract. Obstet. Gynecol. 42:538, 1973. 5. Martin, W. j., Gardner, M., Washington, J. A. II. In vitro antimicrobial susceptibility of anaerobic bacteria isolated from clinical specimens. Antimicrob. Agents Chemother. 1:148-158, 1972. 6. Kislak, J. W. The susceptibility of Bacteroides fragilis to 24 antibiotics. J. Infect. Dis. 125:295-299,1972. 7. Swenson, R. M., Michaelson, T. C., Daly, M.]., Spaulding, E. H. Clindamycin in infections of the female genital tract. Obstet. GynecoI. 44:699-702, 1974. 8. Swenson, R. M., Lorber, B. Carbenicillin in the treatment of infections involving anaerobic bacteria. Antimicrob. Agents Chernother. 9:1025-1027.1976. 9. Spaulding, E. H., Vargo, V., Michaelson, T. C., Swenson, R. M. A comparison of two procedures for isolating anaerobic bacteria from clinical specimens. In A. Balows, R. M. DeHaan, L. B. Guze, and V. R. Dowell [ed.], Anaerobic bacteria. Charles C Thomas, Springfield, 111.,1974. p. 37-46. 10. Holdeman, L. V., Moore, W. E. C. [ed.]. Anaerobe laboratory manual. Ist ed. Virginia Polytechnic Institute and State University, Blacksburg, Va., 1972. 130 p. 11. Lennette, E. H., Spaulding, E. H., Truant, J. P. [ed.]. Manual of clinical microbiology. 2nd ed. American Society for Microbiology, Washington, D.C., 1974. 970 p. 12. Steers, E., Foltz, E. L., Graves, B. S. An inocula-replicating apparatus for routine testing of bacterial sus-
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Seventy-four of 101 anaerobic isolates were susceptible to 64 fJ-g of carbenicillin/rnl, and 13 isolates were susceptible to 256 fJ-g/ml. Two strains of B. tragilis were resistant to >256 fJ-g of carbenicillin/rnl. Twelve isolates could not be tested. The results of therapy are shown in table 4. Three patients with generalized peritonitis required prolonged surgical drainage and multiple surgical procedures. Similar prolonged courses of treatment were required in one patient with endomyometritis salpingitis and one patient with wound infection. Therapy with carbenicillin was discontinued in two patients because of gastrointestinal bleeding (although this could not be definitely ascribed to the drug); in one, therapy was discontinued because of severe hypokalemia. Tolerance and toxicity. Clindamycin was generally well tolerated by the majority of patients. Fourteen patients developed diarrhea, which was severe enough in three cases to warrant discontinuation of the antibiotic. Pseudomembranous colitis was documented by sigmoidoscopy and biopsy in two of these patients. Eight patients who received an aminoglycoside developed transient increases in serum levels of creatinine. Three developed unexplained rises in serum aspartate aminotransferase (SCOT), three developed a maculopapular rash, and another had transient thrombocytopenia. Carbenicillin was also well tolerated by most patients. Seven developed transient increases in SCOT. Four concomitantly received an aminoglycoside and showed transient increases in serum levels of creatinine. Carbenicillin was discontinued in two patients because of gastrointestinal bleeding, although bleeding could not be ascribed to the antibiotic in ei ther patient. Fially, unexplained hypokalemia occurred in one patient; this condition rapidly resolved when therapy with the antibiotic was stopped.
Swenson and Lorber
Clindamycin and Carbenicillin
ceptibility to antibiotics. Antibiot. Chemother. 9: 307-311, 1959. 13. Bauer, A. W., Kirby, W. M. M., Sherris, J. C., Turck,
545
M. Antibiotic susceptibility testing by a standardized single disk method. Am. J. Clin. Pathol. 45:493-496, 1966.
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Discussion Moderator: Philip Mead
cin should be used only for serious infections requiring hospitalization? If so, is there ever any indication for using the drug orally rather than parenterally? DR. SWENSON. This is an important consideration for the ambulatory patient with pelvic inflammatory disease who does not require hospitalization. What therapy would be prescribed for this patient? DR. MEAD. A gynecologist would probably want to treat such women as outpatients with what Dr. Finegold has referred to as secondline drugs-the tetracyclines or ampicillin by mouth. Even when these patients are hospitalized there is some reluctance to use drugs effective against Bacteroides [ragilis, such as clindamycin and chloramphenicol, because of the potential toxicity. The patient who has developed an abscess requires surgical treatment. I often wonder if more aggressive parenteral therapy for the initial infection might prevent some of these abscesses, which need to be drained surgically. DR. CHOW. There is no question that if abscess is present, and not simply an inflammatory mass with edema, then there is certainly a high incidence of B. fragilis. So, in addition to surgical drainage, antibiotic therapy effective against B. fragilis is important. However, we have found that B. fragilis has not been an important or common pathogen in other forms of pelvic infections such as acute salpingitis, C-section infections, and septic abortion. So, we treat these infections quite effectively with drugs such as ampicillin or analogues of tetracycline. In the initial management of salpingitis, one should consider the presence of Neisseria gonorrhoeae, and therapy should cover this organism. DR. FINEGOLD. For most drugs, parental therapy does not represent more aggressive therapy than oral therapy, providing that the patient can absorb the drug well and achieve adequate blood levels. If B. fragilis is present, clindamycin is effective therapy. If B. fragilis has not been confirmed and the patient is seriously ill, I use clindamycin or another agent such as chlorampheni-
546
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DR. P. MEAD. Drs. Bobitt and Ledger, I have not seen a significant number of enterococci in pelvic or abdominal infections. Does your experience suggest that the combination of clindamycin plus gentamicin is adequate, or is an additional drug necessary to cover this organism? DR. J. R. BOBITT. A study was done at the University of Michigan [1] in which antibiotic treatment did not cover the enterococcus, and some treatment failures were reported. In an evaluation of bacteremia in obstetric and gynecologic patients at the University of Southern California [2], the enterococcus was the second most common isolate. In our present series, the enterococcus was isolated from infection sites in three patients, although it was never recovered from the blood. For patients with serious pelvic infections, we believe therapy should cover this organism, although our study did not establish this. DR. R. M. SWENSON. We have not seen a single case of enterococcal bacteremia related to pelvic infections. Even in cultures from pelvic abscesses, enterococci were recovered on just two or three occasions. DR. A. W. CHOW. Our experience was similar. In our studies on septic abortion, sometimes we isolated fairly large numbers of enterococci from the endometrium, but we never had any cases of enterococcal bacteremia. Similarly, in our studies of C-section infections and acute salpingitis, we did not find enterococci to be an important pathogen. DR. S. M. FINEGOLD. I agree. I certainly don't believe the enterococcus is very important in that kind of situation. DR. S. L. GORBACH. In pelvic infections and intraabdominal sepsis, our incidence of recovery of enterococci is only 15%. Isolation from blood cultures in patients with these conditions is a rare occurrence. DR. F. J. TEDESCO. There is some evidence that there is a higher incidence of pseudomembranous colitis with the oral route of antibiotic administration. Does this suggest that clindamy-
Discussion
DR. CHOW. There is no question of the significance of N. gonorrhoeae in acute salpingitis. Our data are not that much at variance with those reported by Eshenbach et al. We are looking at a spectrum of the disease. Certainly, if culdocentesis is done early, there's a much higher incidence of isolation of gonococci from the upper pelvic tract. Early in the acute phase of the illness, gonococci can be found in the cul-de-sac along with a few other organisms; later on in the course of infection, gonococci disappear and are replaced by normal vaginal flora. In terms of proper sampling techniques in pelvic infections, blood cultures are the key in septic abortion since bacteremia is common. The role of cervical cultures would only be for the identification of gonococci. In other types of pelvic infections, bacteremia is uncommon, and it is necessary to sample the upper tract. The easiest way is by culdocentesis. DR. FINEGOLD. There are studies in which endometrial flora has been sampled from patients with and without endometritis. There was no significant difference in the bacteriology of the two groups, a finding suggesting that the normal geni tal tract flora was cultured in both situations. Dr. Chow, you presented a lot of data on endometrial cultures. I wonder if you conclude, at this point, that it might not be worth doing such cultures in the future? Also, why did you treat your patients with both penicillin and chloram phenicol? DR. CHOW. The purpose of showing results of endometrial culture is to indicate its limited usefulness. The combination of penicillin plus chloramphenicol was used because of its wide spectrum of activity and because it has been conventional therapy in our hospital. Previous studies by double-blind comparison in our institution show that this combination was not different from cephalothin plus kanamycin [3]. Our data on septic abortion presented earlier further attest to the clinical efficacy of this combination. DR. MEAD. Tissue removed at the time of laparotomy is an excellent source from which to recover potential pathogens. Some of this material can be snipped off, put into a gassed-out tube, and sent to the laboratory. Unfortunately, this is not often done. I would like to raise another issue; there is good evidence that wom-
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col until the results are available or the patient is distinctly better. When B. fragilis is not present, ampicillin or a similar drug is perfectly good therapy. DR. GORBACH. Dr. Bobitt, in your presentation the incidence of B. fragilis isolated from abscesses was high in the chloramphenicol group and zero in the clindamycin group. I gathered that these patients were taking antimicrobial agents when the abscess was cultured. One of the findings that we have noted is the difficulty of isolating B. fragilis from infected sites once clindamycin has been started. We are able to isolate it in patients treated with penicillin and even, as you showed, with chloramphenicol. Do you believe that some of the pathogens were masked by the prior use of antimicrobial agents? Obviously, this is required by the clinical setting, but, in terms of judging the data, is it a fair comparison? DR. BOBITT. Your question is a good one. There were fewer anaerobes recovered from abscesses when patients were treated preoperatively with clindamycin than when chloramphenicol was given. Obviously, further evaluation of this question is needed. DR. GORBACH. Dr. Chow, with regard to the problem of getting proper cultures from women with pelvic infections, what is a proper culture? It has been mentioned that culdocentesis may be negative; the infected site, which may be high in the pelvis or in the tubes and not draining into the cul-de-sac, may not even be sam pled. Also, there are women who respond rapidly to antimicrobial agents or to D and C, so that one never really gets an appropriate culture. I raise this point because of the perplexing question of N. gonorrhoeae. Your data are different from those reported by the group in Seattle, which noted a much higher isolation rate of gonococci. I am not sure whether the differences are related to sampling techniques or to the different clinical entities studied. We probably all agree that clindamycin plus an aminoglycoside is not adequate treatment for gonorrhea. Therefore, when the gonococcus is a potential pathogen, I'm attracted to the notion of using a third agent such as penicillin or ampicillin. The gonococcus is a significant problem, and maybe we have to define our patient population a bit more clearly.
547
Discussion
548
DR. REMINGTON. At the Stanford institutions we have not varied our use of clindamycin, as far as indications for iv usage. If a woman has severe pelvic inflammatory disease or infection following pelvic surgery, we routinely use clindamycin. If even 1% of patients with B. iragilis developed pelvic thrombophlebitis or septic pulmonary emboli and died or had to have the uterus removed because of this infection, I would be willing to use clindamycin or chloramphenicol, unless someone could show me there was a significant hazard with its use. However, it would be helpful to have some statistical data so that we know when to use these drugs. DR. MEAD. Basically, the problem is that it is very difficult to culture soft tissue infections such as pelvic peri toni tis and pelvic cellulitis. Large series of pelvic abscesses from studies in Atlanta and Houston showed that B. tragi lis was isolated from about 40% of patients cultured. In other pelvic infections not accompanied by abscess, B. iragilis was only isolated from 10%-15%. The isolation rate of B. [ragilis is >1 %, but I do not know how to determine whether or not a patient has B. [ragilis at the onset of her infection.
References
J., Kriewall, T. J., Sweet, R. L., Fekety, F. R., Jr. The use of parenteral clindamycin in the treatment of obstetric-gynecologic patients with severe infections. Obstet. Gynecol. 43 :490-497, 1974. 2. Ledger, W. J., Norman, M., Gee, C., Lewis, W. Bacteremia on an obstetric-gynecologic service. Am. J. Obstet. GynecoI. 121:205-212, 1975. 3. Ostergard, D. R. Comparison of two antibiotic regimens in the treatment of septic abortion. Obstet. Gynecol. 36:473-474, 1970. I. Ledger, W.
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en with septic abortion who are treated with D and C generally will respond without any antibiotic therapy. DR. J. S. REMINGTON. Dr. Chow's earlier comments are germane. When we utilize new antimicrobial agents or various combinations, we should do so without pious hopes and simply should try to improve upon what has been accomplished with the earlier agents. Some of the questions we might ask are: have we advanced? Are we seeing better treatment results than we did without any drug therapy or with previous regimens? DR. GORBACH. The crux of your question lies in the realm of B. tragi lis, because that is the one organism that separates the use of penicillin from chloramphenicol or clindamycin. In the studies reported by our group and Dr. Swenson's, B. [ragilis was a significant pathogen. These women were very ill, usually with a closed-space infection such as pelvic abscess. They had been treated previously with other drugs, so we were seeing a subset of the population with serious pelvic infections whose prior treatment had failed. B. [ragilis was isolated commonly from the bloodstream and from direct puncture of the abscess at the time of operation. Whether all patients should be treated at the outset with clindamycin or chloramphenicol, I find impossible to answer. My own view is that if a closed-space infection or abscess is suspected, that is, a mass is palpated, or if pelvic peritonitis is present or eminent, these patients should be selected for B. [ragilis treatment. In less serious infections such as salpingitis, I agree with the other panelists that the isolation of B. tragilis is relatively uncommon. These patients can be treated with a number of antimicrobial agents including ampicillin or tetracycline.
