Patient costs for prophylaxis and treatment of obstetric and gynecologic surgical infections

Patient costs for prophylaxis and treatment of obstetric and gynecologic surgical infections Gary E. Stein, PharmD East Lansing, Michigan The use of newer broad-spectrum antimicrobials for prophylaxis and treatment in obstetric and gynecologic surgery can reduce patient morbidity and hospital costs. For prophylaxis, a single dose of a cephalosporin with a long elimination half-life can be as effective as a more prolonged course. Single-dose prophylaxis reduces not only toxicity and cost to the patient but also the likelihood of colonization of the vagina by resistant organisms. Treatment regimens for postoperative pelvic infections should have broad-spectrum coverage against aerobic and anaerobic pathogens to ensure high cure rates and prevent subsequent abscess formation. With the introduction of newer cephalosporins and penicillin combinations that include a [3-lactamase inhibitor, it is now possible to treat these polymicrobial infections effectively with monotherapy. Compared with traditional antibiotic combinations, these drugs can reduce side effects and the costs of drug administration as well as the need for therapeutic monitoring. The use of oral antibiotics to complete a course of treatment can also help decrease the high costs of parenteral antibiotic therapy and hospitalization. (AM J OasTET GVNECOL 1991 ;164:1377-80.)

Key words: Costs, prophylaxis, obstetric and gynecologic surgical infections, quinolones

Infection after obstetric and gynecologic surgery continues to be an important source of patient morbidity despite improved surgical techniques and the use of prophylactic antibiotics. The cause of pelvic infections after common procedures such as vaginal hysterectomy or cesarean section has now been better defined and often involves both aerobic and anaerobic bacteria. I In addition to well-recognized pathogens such as 13hemolytic streptococci, Escherichia coli, Neisseria gonorrhoeae, Chlamydia trachomatis, and coagulase-negative staphylococci, anaerobic bacteria are commonly recovered in patients with postoperative endomyometritis or pelvic cellulitis. 2 The most common anaerobic organisms isolated include peptostreptococci, peptococci, Bacteroides bivius, B. disiens, B. fragilis, and Fusobacterium species. Because of the polymicrobial nature of these infections, it is important to use treatment regimens that have a broad spectrum of activity that includes aerobic and anaerobic bacteria.

Prophylaxis Antibiotics given before obstetric and gynecologic surgery can significantly decrease the number of operative site infections, reduce febrile morbidity, and From the Department of Medicine, Michigan State University School of Medicine. Reprint requests: Gary E. Stein, PharmD, Department of Medicine, Michigan State University, 13-220 Life Sciences Building, East Lansing, M148824. 610129322

shorten hospital stay.' The overall effectiveness of antibiotic prophylaxis is influenced by several factors, which include surgical technique, duration of the surgery, and the antibiotic chosen. It is vitally important that the antibiotic has not only good activity against potential pathogens but also attains high tissue levels at the time of bacterial contamination. Shapiro et al. 4 found that the salutary effect of prophylactic cefazolin diminished rapidly with increased duration of surgery. The ideal prophylactic antibiotic should be nontoxic, effective against most organisms encountered in the endogenous flora, long acting, and inexpensive. Although numerous antibiotics have been found to be effective prophylactic agents, cefazolin continues to be the recommended choice in gynecologic surgery." This cephalosporin has been studied extensively and has the advantage of a long half-life. A cost-benefit analysis of a three-dose regimen of cefazolin for prophylaxis found an average benefit of $492 in vaginal hysterectomy and a $102 savings in patients undergoing abdominal hysterectomy.6 Longer durations of prophylaxis or the use of more expensive cephalosporins were found to diminish these cost benefits. Zhanel et al,7 calculated that approximately $25,000 could be saved from their annual pharmacy budget if cefazolin was substituted for more expensive antimicrobials for prophylaxis in obstetric and gynecologic surgery. Because anaerobes such as B. fragilis are frequently recovered in postoperative pelvic infections, the need for prophylactic antibiotics with activity against these 1377

1378 Stein

organisms has been advocated by some investigators. Hamond et aLB demonstrated equal effectiveness of cephalothin and metronidazole in preventing infection after vaginal hysterectomy. This suggests that prophylactic agents need not be effective against all possible pathogens, but activity against either aerobic or anaerobic Aora would reduce postoperative infections. Other investigations have shown that antibiotics that are active against both aerobic and anaerobic organisms were more effective than agents with just an aerobic or an anaerobic spectrum. This has led to studies with broadspectrum antibiotics such as cefoxitin, piperacillin, and more recently cefotetan. These antibiotics are active against aerobic and anaerobic pathogens associated with pelvic infections and have been found to be effective prophylactic agents. In addition, Stiver et al. 9 observed a lower fever index and shorter hospital stays in patients in whom infections developed after cesarean section when they received prophylactic cefoxitin compared with cefazolin. Cefotetan has an advantage over these other antibiotics because of its extended half-life. A single, perioperative dose of cefotetan has been found to be as safe and effective as a three-dose regimen of cefoxitin for prophylaxis in cesarean section and hysterectomy. 10, II Antibiotic prophylaxis has become standard care for obstetric and gynecologic operations, but the most appropriate agent and duration of antibiotic administration have not been defined precisely. It appears that a single dose of an antibiotic with a long half-life can be as effective as prolonged courses of prophylaxis. A single, preoperative dose has the potential advantages of reduced cost and toxicity to the patient as well as reduced likelihood of increased colonization of the vagina by resistant organisms.

Treatment With the recognition that postoperative pelvic infections are frequently polymicrobial in nature , newer treatment strategies have recommended antibiotic regimens with activity against aerobic and anaerobic pathogens. 12 The rationale for these recommendations has been formulated from animal models such as the intraabdominal sepsis model of Weinstein et al. 13 These investigators found that untreated peritonitis resulted in a high mortality rate that was caused by gramnegative facultative bacteria such as E. coli. Abscesses observed in surviving animals appeared to be caused by microbial synergy between facultative and anaerobic bacteria. Only antibiotic regimens with both aerobic and anaerobic coverage were able to decrease mortality and the subsequent development of abscesses. 14 Although treatment of these polymicrobial infections has traditionally been with a combination of an aminoglycoside plus clindamycin, single broad-spectrum anti-

May 1991 Am J Obstet Gynecol

biotics are also effective. Monotherapy helps avoid side effects as well as the increased indirect costs of drug administration and therapeutic monitoring. Several newer antimicrobials have been suggested as alternatives to combination therapy. These include cephalosporins (cefoxitin and ceftizoxime), extendedspectrum penicillins (mezlocillin and piperacillin), monobactams (aztreonam), carba penems (imipenem) , and Auoroquinolones (oAoxacin and ciproAoxacin).15 These antibiotics are generally safe and effective alternatives to aminoglycosides, but several lack adequate anaerobic coverage and still require the addition of clindamycin or metronidazole in the treatment of mixed anaerobic-aerobic infections. In addition, some of these .drugs are not suitable for monotherapy because resistance or superinfection commonly develops during therapy. Numerous clinical trials have demonstrated the effectiveness of cefoxitin, and this antibiotic has generally been the preferred single agent for therapy of postoperative pelvic infections during the past decade. 16 Recently newer cephalosporins such as ceftizoxime and cefotetan have been found to be effective in the treatment of acute obstetric and gynecologic infections. 17 Because these antibiotics require fewer daily doses, they have become cost-effective alternatives to cefoxitin. Sochalski et al. 18 found that the total cost per day of cefotetan was approximately 40 % lower than cefoxitin in their hospital. One potential drawback to the use of these newer cephalosporins is their higher rates of resistance against clinically important anaerobic bacteria (Table 1).19 Of the newer broad-spectrum antimicrobials that have been introduced during the past few years, the single antibiotic combinations may prove to be the most useful for empiric treatment of polymicrobial infections. Combinations of older penicillins, such as ampicillin and ticarcillin with a 13-lactamase inhibitor, are active against a large number of facultative bacteria. In addition,- they are essentially always active against anaerobes and need not be tested for clinical purposes!O Clinical evaluations of ticarcillin-clavulanate and ampicillin-sulbactam have shown that they are as effective as cefoxitin, as well as combination therapy, in the treatment of pelvic infections. 2 1. 22 These single antibiotic combinations need to be administered more frequently than some of the newer cephalosporins, which ma kes them more costly to administer in the hospital. On the other hand , fewer treatment failures may occur with these drugs because of their expanded spectrum. 23 Imipenem-cilastatin is another single antibiotic combination that has been effective in the treatment of obstetric and gynecologic infections. 2• Unlike sulbactam and clavulanate, cilastatin does not inhibit bacterial 13lactamases but prevents renal enzymes from inactivating imipenem. Imipenem has the broadest coverage of

Prophylaxis and treatment of OB/GYN surgical infections

Volume 164 Number 5, Part 2

Table II. Patient costs for monotherapy of postoperative pelvic infections

Table I. Activity of antimicrobial agents against B, fragilis species % of species susceptible at the breakpoint Drug

Breakpoint ( /-Lg 1ml)

Imipenem Am picillin I sulbactam Metronidazole Clindamycin Cefoxitin Piperacillin Ceftizoxime Cefotetan

8 16 16 4 32 128 32 32

B. fragilis lB. fragilis sp group* 100 100 100 93 92 84 43 85

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100 100 100 81 75 85 45 56

From Finegold SM, Wexler HM. Antimicrob Agents Chemother 1988;32:611-6, by permission of American Society for Microbiology. *Includes B. fragilis species.

any single antibiotic, but because of its high cost it should be reserved for resistant cases (Table II). Because of the high cost of parenteral therapy and hospitalization, oral antibiotics should be considered to complete a course of therapy. The single antibiotic combination of amoxicillin-clavulanate is the oral equivalent of ampicillin-sulbactam and is useful in the treatment of polymicrobial infections. 25 Other antibiotic combinations, such as a ftuoroquinolone plus metronidazole, can also be effective oral therapy. The ftuoroquinolones are broad-spectrum antibiotics and attain high concentrations in reproductive tissues. 26 Oftoxacin may be especially useful in some patients because of its incr~ased activity against Chlamydia and Mycoplasma. 27·29 Conclusion

A large body of knowledge now exists concerning appropriate prophylaxis and treatment of obstetric and gynecologic infections. Effective prophylaxis can be accomplished with a single dose of a long-acting cephalosporin, such as cefazolin or cefotetan. Empiric treatment of postoperative pelvic infections requires an antimicrobial regimen with coverage against aerobic and anaerobic organisms. Monotherapy with a broadspectrum cephalosporin or a penicillin combination that includes a 13-lactamase inhibitor has been found to be as effective as combination chemotherapy. The conversion to oral antibiotics, when appropriate, will also help decrease treatment costs and hospital stay. REFERENCES I. Eschenbach DA. New concepts of obstetric and gynecologic infection. Arch Intern Med 1982;142:2039-44. 2. Chow AW, Marshall ]R, Guze LB. Anaerobic infections of the female genital tract: prospects and perspectives. Obstet Gynecol Surv 1975;30:477-94. 3. Hirsch HA. Prophylactic antibiotics in obstetrics and gynecology. Am] Med 1985;78(suppI6B):170-6.

Drug

Dose Ischedule

Cefotetan Ampicillin I sulbactam Ticarcillin-clavulanate Ceftizoxime Cefoxitin Imipenem

2 gm every 12 hr 3 gm every 6 hr 3.1 gm every 6 hr 2 gm every 8 hr 2 gm every 6 hr I gm every 8 hr

Cost per day*

$ $ $ $

62 84 84 93 $108 $144

*Average wholesale cost + administrative fee ($10).

4. Shapiro M, Munoz A, Tager lB, Schoenbaum SC, Polk BF. Risk factors for infection at the operative site after abdominal or vaginal hysterectomy. N Engl .l Med 1982;307:1661-6. 5. Antimicrobial prophylaxis in surgery. Med Lett 1989; 31:105-8. 6. Shapiro M, Schoenbaum SC, Tager IR, Munoz A, Polk BF. Benefit-cost analysis of antimicrobial prophylaxis in abdominal and vaginal hysterectomy. ]AMA 1983;249: 1290-4. 7. Zhanet GG, Gin AS, Przybylo A, Louie T], Otten NH. Effect of interventions on prescribing of antimicrobials for prophylaxis in obstetrics and gynecologic surgery. Am ] Hosp Pharm 1989;46:2493-6. 8. Hamond KA, Spence MR, Rosenshein NB, Dillon MB. Single-dose and multi dose prophylaxis in vaginal hysterectomy: a comparison of sodium cephalothin and metronidazole. AM .l OBSTET GYNECOI. 1980; 136:976-9. 9. Stiver HG, Forward KR, Livingstone RA, et al. Multicenter comparison of cefoxitin versus cefazolin for prevention of infectious morbidity after nonelective cesarean section. AM.l OBSTET GYNECOL 1983;145:158-63. 10. McGregor .lA, French .lI, Makowski E. Single-dose cefotetan versus multidose cefoxitin for prophylaxis in cesarean section in high-risk patients. AM .l OBSTET GYNECOL 1986; 154:955-60. 11. Orr .lW, Varner RE, Kilgore LC, Holloway RC, McDiarmid M. Cefotetan versus cefoxitin as prophylaxis in hysterectomy. AM .l OBSTET GYNECOL 1986; 154:960-3. 12. Ledger WJ. Current problems in antibiotic treatment in obstetrics and gynecology. Rev Infect Dis 1985;7(suppl 4):s679-88. 13. Weinstein WM, Onderdonk AB, Bartlett.lG, Gorbach SL. Experimental intraabdominal abscesses in rats: development of an experimental model. Infect Immunol 1974; 10: 1250-5. 14. Louie T.l, Onderdonk AB, Gorbach SL, Bartlett.lG. Therapy for experimental intraabdominal sepsis: comparison of four cephalosporins with clindamycin plus gentamicin. ] Infect Dis 1977; 135(suppl):sI8-24. 15. Dinsmoor M.l, Gibbs RS. The role of the newer antimicrobial agents in obstetrics and gynecology. Clin Obstet Gynecol 1988;31 :423-34. 16. Counts GW. Cefoxitin: its role in treatment and prophylaxis of obstetric and gynecologic infections. Rev Infect Dis 1988;10:76-91. 17. Hemsell DL, Wendel GD, Gall SA, et al. Multicenter comparison of cefotetan and cefoxitin in the treatment of acute obstetric and gynecologic infections. AM] OBSTET GYNECOL 1988;158:722-7. 18. Sochalski A, Sullman S, Andriole VT. Cost-effectiveness study of cefotetan versus cefoxitin and cefotetan versus combination antibiotic regimens. Am ] Surg 1988; 155 (suppI5A):96-101. 19. Finegold SM, Wexler HM. Therapeutic implications of bacteriologic findings in mixed aerobic-anaerobic infections. Antimicrob Agents Chemother 1988;32:611-6.

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20. Finegold SM. Susceptibility testing of anaerobic bacteria. ] Clin Microbiol 1988;26:1253-6. 21. Faro S, Martens M, Hammill H, Phillips LE, Smith D, Riddle G. Ticarcillin/clavulanic acid versus clindamycin in the treatment of post-cesarean endometritis following antibiotic prophylaxis. Obstet Gynecol 1989;73:808-12. 22. Crombleholme WR, Ohm-Smith M, Robbie MO, DeKay V, Sweet RL. Ampicillin/sulbactam versus metronidazolegentamicin in the treatment of soft tissue pelvic infections. AM] OSSTET GYNECOL 1987;156:507-12. 23. Senft HH, Stiglmayer R, Eibach HW, Koerner H. Sulbactam/ampicillin versus cefoxitin in the treatment of obstetric and gynecologic infections. Drugs 1986;31 (suppl 2):18-21. 24. Berkeley AS, Friedman K, Hirsch], Ledger WJ. Imipenem/cilastatin in the treatment of obstetric and gynecologic infections. Am] Med 1985;78(suppl 6A):79-84. 25. Ball P, Watson T, Mehtar S. Amoxicillin and clavulanic

Am J Obstet Gynecol

26.

27.

28. 29.

acid in intraabdominal and pelvic sepsis. ] Antimicrob Chemother 1981;7:411-44. Goormans E, Dalhoff A, Kazzaz B, Branolte]. Penetration of ciprofloxacin into gynecological tissue following oral and intravenous administration. Chemotherapy 1986; 32:7-17. Aznar], Caballero MC, Lozano MC, De Miguel C, Palomares ]C, Perea EJ. Activities of new quinolone derivatives against genital pathogens. Antimicrob Agents Chemother 1985 ;27: 76-8. Batteiger BE, Jones RB, White A. Efficacy and safety of ofloxacin in the treatment of nongonococcal sexually transmitted disease. Am] Med 1989;87(suppI6C):s75-7. Hayashi M, Imagawa N, Hayashi S, et al. Efficacy of ofloxacin against obstetric and gynecologic infections due to Chlamydia trachomatis. Rev Infect Dis 1989; 11 (suppl 5):sI281-2.

Effectiveness of ofloxacin in the treatment of Chlamydia trachoma tis and Neisseria gonorrhoeae cervical infection Sebastian Faro, MD, PhD, Mark G. Martens, MD, Maurizio Maccato, MD, Hunter A. Hammill, MD, Scott Roberts, MD, and Gerald Riddle, MS Houston, Texas Forty patients with cervical infection caused by Chlamydia trachomatis were treated with ofloxacin (20) or doxycycline (20). Ofloxacin was successful in eradicating C. trachomatis from all 20 (100%) patients. Doxycycline was effective in 18 of 20 (90%) patients. Three patients had a concomitant cervical gonococcal infection. All three were successfully treated: one with ofloxacin and two with doxycycline. Ofloxacin, 300 mg, taken twice daily for 7 days, is effective in eradicating endocervical C. trachomatis infection. (AM J OBSTET GYNECOL 1991 ;164:1380-3.)

Key words: Cervicitis, C. trachomatis, N. gonorrhoeae Antibiotic therapy for the treatment of cervIcItis caused by Neisseria gonorrhoeae is predicated on the suspicion that a penicillinase-producing strain may be present. In addition, N. gonorrhoeae is known to have both plasmid and chromosomal resistance, thus making penicillin, tetracycline, and cefoxitin less effective. I In a recent study of 6204 gonococcal isolates from 21 locations within the United States, 21 % were resistant to penicillin, tetracycline, cefoxitin, or spectinomycin. 2 Al-

From the Section of Infectious Diseases, Department of Obstetrics and Gynecology, Baylor College of Medicine. Reprint requests: Sebastian Faro, MD, PhD, Section of Infectious Diseases, Baylor College of Medicine, 6550 Fannin St., ST. 701, Houston, TX 77030. 610129323

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though all of the isolates tested were sensitive to ceftriaxone, there have been reports of decreasing sensitivity to ceftriaxone among isolates from Southeast Asia. 3 Thus the current recommendation by the Centers for Disease Control to treat all gonococcal cervicitis and urethritis with ceftriaxone continues to be appropriate! However, the current widespread use of ceftriaxone necessitates continued monitoring of isolates for resistance to ceftriaxone. Chlamydia trachomatis is considered the most common sexually transmitted organism. Like N. gonorrhoeae, it is responsible for pelvic inflammatory disease, ectopic pregnancy, and infertility, in addition to neonatal conjunctivitis and pneumonitis. C. trachomatis and N. gonorrhoeae may be found as coinfections in 30% to 60% of patients, and up to 15% of N. gonorrhoeae may be