- Email: [email protected]
Questions from the audience
Questions from the audience The following highlights are excerpted from two informative and spirited question-and-answer sessions, moderated by F. Gary Cunningham, M.D., Symposium Chairman. Session 1 Q. Dr. Gall, could you reiterate the failure rates of the two prophylaxis regimens you used in your studythe triple-dose course of piperacillin versus the single dose? Dr. Gall. The multi-dose regimen was successful in approximately 94% of patients compared with 87% for the single-dose group. Although these figures were not significantly different, I originally expected that they would be. That's the nice ~hing about a randomized, blinded, prospective trial: your own bias is irrelevant. Moderator. Dr. Gall, what kind of infection rate could you have expected in your population if no perioperative prophylaxis had been administered? Dr. Gall. On the basis of previous placebo studies, we might have expected a postoperative incidence of infection in the range of 45% to 50%. Moderator. This is an important point because our background infection rate in high-risk patients at Parkland Hospital in Dallas is probably closer to 85% without perioperative prophylaxis. We should remember that most of these investigations are carried out in highrisk women from low socioeconomic groups in large urban hospitals. It is likely that single-dose prophylaxis would be much more effective for most of the private patients treated by the practitioners in our audience than for our patients in Chicago or Dallas. Dr. Gall. In 1979, we published results of a study conducted at Duke University in which cefazolin was compared with placebo for patients undergoing cesarean section. Socioeconomic status, defined as public patient versus private patient, was one of the factors we looked at. We found a difference: the worst case scenario was placebo in a public patient, which resulted in a 51% infection rate. The same placebo in private patients resulted in a 40% incidence of infection. We don't really know whether these differences can be attributed to better protoplasm, or fewer bacteria, or other factors, but it may indeed be true that the shortest course of a prophylactic antimicrobial-the single dose-may be quite adequate for most private patients. Q. Dr. Gall, could you comment on the significance, if any, of isolating mycoplasmas in so many of your patients who became infected? Dr. Gall. Among infected patients, there was a much higher, albeit statistically nonsignificant, incidence of mycoplasmal colonization. Other investigators also
have alluded to the possibility that the presence of mycoplasmas in the amniotic fluid might be a kind of marker for the development of clinical postoperative endometritis. Moderator. Dr. Gall, did you isolate any enterococci in your postoperative cultures? Dr. Gall. Yes, there were a few enterococci, but I only worry about them if they are isolated from the blood or from an immunocompromised patient. Moderator. I as-ree with you, but I am worried about what happens with enterococci in 10 years. For instance, the "sin" of antimicrobial misuse is catching up with us in that we are now seeing methicillin-resistant Staphylococcus aureus catheter-associated infection in intensive care units. We are paying dearly for such past practices by treating patients with expensive intravenous vancomycin. It would behoove all of us to keep abreast of the literature and clinical evaluations of various drug regimens lest we risk using therapies that are becoming ineffective. Session 2 Q. How do the third-generation cephalosporins penetrate into difficult-to-reach areas, or across biologic membranes, compared with penicillins? Moderator. First of all, we've got to understand that a drug may be present in an abscess, for instance, without exerting any biologic activity. These things are actually becoming more difficult to study because more prophylaxis and more vigorous treatment with better drugs are making pelvic abscesses much less common than they used to be. Most of our data on abscess penetration therefore come from the rat model of Gorbach et al. Q. I just find it surprising that a large cephalosporintype molecule would be able to penetrate at all. Dr. Hemsell. Penetration probably does not occur in undamaged meninges, for example. Inflamed meninges, on the other hand, apparently react differently. Dr. Gall. The concentration of bacteria and the concentration of enzymes that break down inactive metabolites are several logs higher in an abscess. Even if an antibiotic gets in, it is in a much more hostile environment. The pH is lower and the polymorphonuclear leukocytes are probably not functioning well. Moderator. In the final analysis, we have to look at whether these experimental results correspond in any way with clinical outcomes. Although we who are interested in research have to continue to get answers to questions about penetration, half-lives, serum levels, etc., the bottom line has to be, "does the drug work?" and "how long will it continue to be effective?" 511
512
Questions from the audience
Q. How should chorioamnionitis be managed?
Moderator. I think we can all agree that a woman with chorioamnionitis needs to be delivered. If she's not in labor already, labor should be induced. Moreover, we should treat these patients vigorously with some sort of intensive antimicrobial regimen during labor. I ani troubled, however, by those individuals who are recommending that delivery by the most expeditious route-cesarean section-be undertaken when chorioamnionitis is diagnosed. On the basis of my clinical experience, it seems that cesarean section in a laboring woman who has ruptured, leaking membranes, fever, and clinical chorioamnionitis can result in some pretty severe outcomes. The babies do not seem harmed by at least a trial of labor if appropriately monitored, and the mothers do better with vaginal deliveries. Dr. Gall. At our institution, patients diagnosed as having chorioamnionitis and who have a temperature of ""38° C are started on an antibiotic every 6 hours. We obtain a culture and induce labor or allow labor to proceed for 4 to 6 hours. If appropriate progress has not been made after a reasonable trial, the patient would probably be delivered of her infant by cesarean section. The antibiotic is continued for 72 hours post partum or for 24 hours after the patient becomes afebrile. Moderator. I'd like to emphasize the fact that patients with chorioamnionitis who are delivered of their infants by cesarean section need intensive therapy with something. A few years ago, we used penicillin plus an aminoglycoside with poor results: a third of those women ultimately required hysterectomy within the first 10 days post partum for parimetrial phlegmons, broad ligament abscesses, and things of that nature. It's best to use the kind of "big gun" regimen-such as clindamycin and gentamicin, a cephalosporin with chloramphenicol, or piperacillin alone-that would be appropriate for the worst kind of pelvic sepsis. When a surgical delivery has been performed, chorioamnionitis presents a serious threat to maternal health. In summary, we know that women with significant pelvic infections suffer some sort of breach of the ep-
August 1987 Am J Obstet Gynecol
ithelial defenses, either from surgical trauma or from infection with a primary invading organism (for example, Neisseria gonorrhoeae, Chlamydia trachomatis). We also know that these infections are polymicrobial. The overuse of certain drugs, such as cephalosporins, has resulted in the emergence of bacterial strains that are resistant to some currently used regimens. Dr. Galask described a particularly interesting and important mechanism of gram-negative resistance-induction of ~-lactamase production by exposure to cer~ain ~-lactam agents. It sounds theoretical, but we're already dealing with the clinical implications of this phenomenon in terms of increased resistance to cefoxitin. In his discussion of therapy for serious female pelvic infections, Dr. Hemsell emphasized that the standard for any regimen-whether it is clindamycin plus gentamicin, or piperacillin-is a 90% to 95% success rate. I prefer to use single-agent therapy whenever efficacy is equivalent. Enhancement or depression of polymorphonuclear leukocyte functions by antimicrobial agents, addressed by Dr. Ford, is a fascinating aspect of infection control. Moreover, he showed us how the higher overall costs of less effective prophylactic regimens underscore the importance and impact of using appropriate, effective surgical prophylaxis, particularly in high-risk patients. While it still may be a theoretical problem, I am nevertheless disturbed by the finding that many women who receive perioperative prophylaxis have enterococci in the lower genital tract for 2 to 5 days after operation. It makes me think that piperacillin, which is quite effective against enterococci, will become more and more attractive as a prophylactic agent in the future. In general, piperacillin is an ideal single agent for prevention and therapy of female pelvic infection. It has an excellent antibacterial spectrum, is clinically effective, and enjoys the safety of the penicillins. Its future value is not jeopardized by ~-lactamase induction but rather is enhanced by its somewhat unique activity against enterococci. Finally, its cost is reasonable and competitive. I'd like to thank the faculty for their outstanding presentations and the audience for providing such stimulating discussion.
have alluded to the possibility that the presence of mycoplasmas in the amniotic fluid might be a kind of marker for the development of clinical postoperative endometritis. Moderator. Dr. Gall, did you isolate any enterococci in your postoperative cultures? Dr. Gall. Yes, there were a few enterococci, but I only worry about them if they are isolated from the blood or from an immunocompromised patient. Moderator. I as-ree with you, but I am worried about what happens with enterococci in 10 years. For instance, the "sin" of antimicrobial misuse is catching up with us in that we are now seeing methicillin-resistant Staphylococcus aureus catheter-associated infection in intensive care units. We are paying dearly for such past practices by treating patients with expensive intravenous vancomycin. It would behoove all of us to keep abreast of the literature and clinical evaluations of various drug regimens lest we risk using therapies that are becoming ineffective. Session 2 Q. How do the third-generation cephalosporins penetrate into difficult-to-reach areas, or across biologic membranes, compared with penicillins? Moderator. First of all, we've got to understand that a drug may be present in an abscess, for instance, without exerting any biologic activity. These things are actually becoming more difficult to study because more prophylaxis and more vigorous treatment with better drugs are making pelvic abscesses much less common than they used to be. Most of our data on abscess penetration therefore come from the rat model of Gorbach et al. Q. I just find it surprising that a large cephalosporintype molecule would be able to penetrate at all. Dr. Hemsell. Penetration probably does not occur in undamaged meninges, for example. Inflamed meninges, on the other hand, apparently react differently. Dr. Gall. The concentration of bacteria and the concentration of enzymes that break down inactive metabolites are several logs higher in an abscess. Even if an antibiotic gets in, it is in a much more hostile environment. The pH is lower and the polymorphonuclear leukocytes are probably not functioning well. Moderator. In the final analysis, we have to look at whether these experimental results correspond in any way with clinical outcomes. Although we who are interested in research have to continue to get answers to questions about penetration, half-lives, serum levels, etc., the bottom line has to be, "does the drug work?" and "how long will it continue to be effective?" 511
512
Questions from the audience
Q. How should chorioamnionitis be managed?
Moderator. I think we can all agree that a woman with chorioamnionitis needs to be delivered. If she's not in labor already, labor should be induced. Moreover, we should treat these patients vigorously with some sort of intensive antimicrobial regimen during labor. I ani troubled, however, by those individuals who are recommending that delivery by the most expeditious route-cesarean section-be undertaken when chorioamnionitis is diagnosed. On the basis of my clinical experience, it seems that cesarean section in a laboring woman who has ruptured, leaking membranes, fever, and clinical chorioamnionitis can result in some pretty severe outcomes. The babies do not seem harmed by at least a trial of labor if appropriately monitored, and the mothers do better with vaginal deliveries. Dr. Gall. At our institution, patients diagnosed as having chorioamnionitis and who have a temperature of ""38° C are started on an antibiotic every 6 hours. We obtain a culture and induce labor or allow labor to proceed for 4 to 6 hours. If appropriate progress has not been made after a reasonable trial, the patient would probably be delivered of her infant by cesarean section. The antibiotic is continued for 72 hours post partum or for 24 hours after the patient becomes afebrile. Moderator. I'd like to emphasize the fact that patients with chorioamnionitis who are delivered of their infants by cesarean section need intensive therapy with something. A few years ago, we used penicillin plus an aminoglycoside with poor results: a third of those women ultimately required hysterectomy within the first 10 days post partum for parimetrial phlegmons, broad ligament abscesses, and things of that nature. It's best to use the kind of "big gun" regimen-such as clindamycin and gentamicin, a cephalosporin with chloramphenicol, or piperacillin alone-that would be appropriate for the worst kind of pelvic sepsis. When a surgical delivery has been performed, chorioamnionitis presents a serious threat to maternal health. In summary, we know that women with significant pelvic infections suffer some sort of breach of the ep-
August 1987 Am J Obstet Gynecol
ithelial defenses, either from surgical trauma or from infection with a primary invading organism (for example, Neisseria gonorrhoeae, Chlamydia trachomatis). We also know that these infections are polymicrobial. The overuse of certain drugs, such as cephalosporins, has resulted in the emergence of bacterial strains that are resistant to some currently used regimens. Dr. Galask described a particularly interesting and important mechanism of gram-negative resistance-induction of ~-lactamase production by exposure to cer~ain ~-lactam agents. It sounds theoretical, but we're already dealing with the clinical implications of this phenomenon in terms of increased resistance to cefoxitin. In his discussion of therapy for serious female pelvic infections, Dr. Hemsell emphasized that the standard for any regimen-whether it is clindamycin plus gentamicin, or piperacillin-is a 90% to 95% success rate. I prefer to use single-agent therapy whenever efficacy is equivalent. Enhancement or depression of polymorphonuclear leukocyte functions by antimicrobial agents, addressed by Dr. Ford, is a fascinating aspect of infection control. Moreover, he showed us how the higher overall costs of less effective prophylactic regimens underscore the importance and impact of using appropriate, effective surgical prophylaxis, particularly in high-risk patients. While it still may be a theoretical problem, I am nevertheless disturbed by the finding that many women who receive perioperative prophylaxis have enterococci in the lower genital tract for 2 to 5 days after operation. It makes me think that piperacillin, which is quite effective against enterococci, will become more and more attractive as a prophylactic agent in the future. In general, piperacillin is an ideal single agent for prevention and therapy of female pelvic infection. It has an excellent antibacterial spectrum, is clinically effective, and enjoys the safety of the penicillins. Its future value is not jeopardized by ~-lactamase induction but rather is enhanced by its somewhat unique activity against enterococci. Finally, its cost is reasonable and competitive. I'd like to thank the faculty for their outstanding presentations and the audience for providing such stimulating discussion.