Effectiveness of mezlocillin in female genital tract infections

Transcription

1 Journal of Antimicrobial Chemotherapy (98) 9, Suppl. A, 9-8 Effectiveness of mezlocillin in female genital tract infections John R. Marshall, Anthony W. Chow* and Tania C. Sorrell** The Departments of Obstetrics and Gynecology, and Medicine, Harbor /UCLA Medical Center, Torrance, California, U.S.A. One hundred and twenty-six patients with female genital tract infections were treated with intravenous mezlocillin (g/day) in a prospective, multicentre, clinical trial. Clindamycin (- g/day) was added if patients failed to improve within 8 h of mezlocillin therapy. Cure was noted in 8-%, improvement in -8%, and failure in -9%. Using the same basic protocol, but with the addition of randomization and blinding, mezlocillin and ampicillin (8 g/day) were compared in 8 and postpartum patients, respectively. No significant differences between mezlocillin and ampicillin treated patients were demonstrable. Side-effects were minimal and insignificant. We conclude that mezlocillin is an effective drug for the treatment of female genital tract infections and that mezlocillin and ampicillin are equally effective in the treatment of postpartum genital tract infections. Introduction Infections of the female genital tract are a continuing and serious problem. Offending organisms may be either aerobes or anaerobes and commonly include members of the Peptococcus sp., Bacteroidaceae and Enterobacteriacae families as well as microaerophilic streptococci (Chow, Marshall & Guze, 9). To be maximally effective, an antibiotic should have an antibacterial spectrum which includes both aerobes and anaerobes. Mezlocillin, a new semisynthetic ureidopenicillin, has a spectrum of activity which encompasses most of the organisms involved in such infections (Bodey & Pan, 9; Sorrell, Marshall & Chow, 98). Preliminary trials in patients with septicaemia, biliary tract infections, peritonitis, urinary tract and gynaecologic infections have been conducted in Europe and have demonstrated a 9-% favourable response rate in patients with gynaecologic infections (Hullmann et al., 9). Because of its spectrum and reported effectiveness, mezlocillin appears to have promise in the treatment of gynaecologic infections. It might serve as a single drug replacement for both ampicillin and clindamycin, which are now the standard treatments for these infections in many medical centres. In order to further document the effectiveness of mezlocillin and to compare the effectiveness and safety of mezlocillin against ampicillin, the studies reported in this communication were undertaken. Downloaded from at Pennsylvania State University on September, Present address: Division of Infectious Disease, G. F. Strong Research Laboratories, Department of Medicine, Vancouver General Hospital, W. th Ave., Vancouver, B.C., Canada. ** Present address: Department of Medicine, University of Sydney and Infectious Disease Medicine Unit, Westmead Centre, Westmead, N.S.W., Australia. -/8/9A9- $./ 9 98 The British Society for Antimicrobial Chemotherapy

2 J. R. Marshall et al. We report data from two studies. First, data demonstrating general efficacy which were obtained from a multicentre, prospective, controlled trial conducted by Miles Pharmaceuticals, New Haven, CT, U.S.A.); and second, data comparing mezlocillin and ampicillin which were obtained in a prospective, randomized, double-blind, clinical trial using postpartum patients at the Harbor/UCLA Medical Center, Torrance, California. Materials and methods All patients were managed according to a common protocol concerning patient selection, data collection, study drug dosage and administration and post-therapy evaluation. In addition, postpartum patients treated at the Harbor/UCLA Medical Center were randomly assigned to mezlocillin or ampicillin. Patients receiving mezlocillin as a part of the Harbor comparative study have been included in the general efficacy study. General efficacy study Patient selection. Patients were hospitalized adult females with suspected or documented pelvic infection that required systemic antimicrobial therapy and for which a broad spectrum penicillin would be appropriate. Infections included vulvar abscess, Bartholin's abscess, vaginal abscess, vaginal cuff abscess, endometritis, septic abortion, acute salpingitis, para-ovarian abscess, or pelvic cellulitis. Patients must have signs and symptoms supportative of the clinical diagnosis. Previous unsuccessful antimicrobial treatment was allowable as long as the suspected pathogen was cultured from the infected site before initiation of mezlocillin therapy. Informed consent was obtained. Exclusion criteria were a history of allergy to any penicillin, pregnancy or severe renal impairment. Antibiotic protocol. The protocol for the administration of antibiotics is indicated in Figure. Mezlocillin (Miles Pharmaceuticals, New Haven, CT, U.S.A.) was reconstituted in sterile distilled water in unit doses of g, was dispensed into ml of % dextrose in water in the hospital pharmacy and supplied to the patient care area labelled only with the patient's name, hospital number and antibiotic protocol number. Unit doses were administered every h by infusion over min. Patients were examined daily for clinical response and side-effects. If a clinical response (reduction in fever and I Clinical response Continue Genital tract infection I Protocol drug Mezlocillin or ampicillin I 8 h Clinical response I No clinical response Add clindamycin 8 h No clinical response Downloaded from at Pennsylvania State University on September, Continue Add gentamicin Figure. Protocol for the prospective, randomized, double-blind clinical comparison of mezlocillin and ampicillin in postpartum patients.

3 Mezlocillin in female genital tract infections clinical signs) was evident at the first decision point, after 8 h of treatment (Figure ), intravenous antibiotic was continued until the patient had been afebrile and clinically well for a total of 8 h. No oral antibiotic was given subsequently. Patients who had not improved after 8 h of protocol antibiotic were given clindamycin, mg intravenously every h, in addition to the protocol antibiotic which was continued. Response within 8 h of the addition of clindamycin led to the cessation of all antibiotics after the patient had been afebrile and well for a further 8 h. If there were no response at this time, gentamicin, l-mg/kg every 8 h, was added to the regimen. Antibiotics were discontinued immediately when drug toxicity or allegy were suspected. The patients were discharged from the hospital when they had remained afebrile and clinically well for - h after cessation of protocol drug. Attempts were made to contact all patients within to days of discharge. Laboratory studies. Routine investigation included two sets of blood cultures (aerobic and anaerobic), an endocervical culture and a urinalysis and culture, complete blood count, renal and liver function studies, and other tests as indicated. All these tests were repeated every 8 h and after completion of therapy. Aerobic and anaerobic cultures and identification were performed as previously described (Sorrell et al., 98). Data analysis and statistical methods. The patients were considered for analysis if a definite non-gynaecologic cause of fever had been excluded and the patients had followed the protocol appropriately. Response data were analysed by Student's /-test (- tailed) or /-square analysis with Yeates correction. Data collection and analysis for the general efficacy study were performed by Miles Pharmaceuticals. Comparative study Patient selection, antibiotic protocol, laboratory studies and data analysis were the same as described above except that patients were postpartum and were randomly assigned to treatment with either mezlocillin or ampicillin. Ampicillin was prepared in g unit doses which were not distinguishable from the mezlocillin unit doses and which were administered using the same dosage schedule as described above. Data collection and analysis for the comparative study were performed by the authors. This portion of the study was reviewed and approved by the Institutional Review Board at the Harbor/UCLA Medical Center. General efficacy study Results One hundred and twenty-six patients received mezlocillin in these studies. Mean age was -8 ±-8 years. Pretreatment health status was deemed excellent to good in -% and fair to poor in 8-%. Prior antibiotic therapy for this infection had been given in % of patients. The infection was classified as acute in 9%, recurrent in -% and chronic in -8%. Surgery occurred before or during therapy in %. The ideal daily dose of mezlocillin was g, 8-% of patients received this dose, -% received more than g, -% received to g and -8% received less than g/day. Mean duration of therapy was + days, the maximum duration days. Overall clinical response is indicated in Table I. Cure was achieved in -%, partial Downloaded from at Pennsylvania State University on September,

4 J. R. Marshall et al. Table I. Overall clinical response to mezlocillin in female genital tract infections Patients Overall response No. % Cure Partial cure Failure Indetermine Total cure in 8-% and failure in -%. Response was judged to be indeterminate in -%. There were no deaths. The specific infection diagnosis and clinical response is shown in Table II. Cure rates of greater than 88-% were noted in patients with diagnoses of endometritis, salpingitis and septic abortion. Patients with para-ovarian abscesses had a lower resolution rate with % noting improvement and % noting failure. The relationship between the organisms cultured from the site of infection and the clinical responses is indicated in Table III for those organisms which were present in five or more specimens. Resolution of the clinical signs and symptoms occurred with 9% of isolates, improvement occurred in -% and failure in only -%. Only five of organisms. were associated with rates of resolution of less than 9% and only four, Staphylococcus aureus, Peptococcus sp., Streptococcus sp. and Staph. epidermidis, were associated with combined resolution/improvement rates of less than 9%. Pathogenic bacteria were eliminated from the site of infection in -% but persisted in -% (if, in a polymicrobial infection one organism persisted, the response was recorded as persistence). The relationship between specific infection diagnosis and bacteriological response is indicated in Table IV. Salpingitis was least effectively treated; bacteria from all other infections demonstrated at least a 8-% elimination rate. The relationship between the specific causative organism and the bacteriological response is indicated in Table V. Overall, 8-% of 8 isolates were eliminated, % were markedly reduced and -% were classified as persistent. Organisms associated with persistence rates of greater than % were Bacteroides fragilis, Clostridia sp., and Bad. melaninogenicus. Table II. Specific infection diagnosis vs clinical response in female genital tract infections treated with mezlocillin Cure Improvement Failure No. % No. % No. % Downloaded from at Pennsylvania State University on September, Endometritis Salpingitis Para-ovarian abscess Septic abortion Other Total

5 Mezlocillin in female genital tract infections Table III. Organism vs clinical response in female genital tract infections treated with mezlocillin Causative Cure Improvement Failure Total organisms No. % No. % No. % No. E. coli Klebsiella pneumoniae Neisseria gonorrhoeae Proteus mirabilis Staph. aureus Peplococcus sp. Bad. fragilis Lactobacillus sp. Bacteroides sp. Peptostreptococcus sp. Enterobacter sp. Fusobacterium sp. Streptococcus sp. Str. faecalis Staph. epidermidis Sir. viridans Clostridium sp. Klebsiella sp. Eubacterium sp. Bad. melaninogenicus Propionibactericium sp. Other Total Table IV. Specific infection diagnosis vs bacteriological response in female genital tract infections treated with mezlocillin Endometritis Salpingitis Para-ovarian abscess Septic abortion Other Elimination Marked reduction Persistent No. % No. % No. % 8- - Total Downloaded from at Pennsylvania State University on September, Mezlocillin vs ampicillin comparison Characteristics of the postpartum patients included in this prospective randomized, double-blind comparison are indicated in Table VI. There were no statistically significant differences between the mezlocillin and ampicillin groups in regard to age, mechanism of delivery, weight, gravidity or parity. The primary and associated infection diagnosis is indicated in Table VII. By far the most common diagnosis was endometritis with or without associated myometritis or perimetritis. The most common associated infection diagnosis was urinary tract

6 Table V. Organism vs bacteriological response in female genital tract infections treated with mezlocillin Marked Sub- Causative Eliminated reduction Persistent total Indeterminant Total organisms No. % No. % No. % No. No. No. E. coli Klebsiella pneumonae Neisseria gonorrhoeae Proteus mirabilis Slaph. aureus Peptococcus sp. Bad. fragilis Lactobacillus sp. Bacteroides sp. Peptostreptococcus sp. Enterobacter sp. Fusobaclerium sp. Streptococcus sp! Str. faecalis Staph. epidermidis Str. viridans Clostridium sp. Klebsiella sp. Eubacterium sp. Bad. melaninogenicus Propionibacteriwn sp. Other Total Downloaded from at Pennsylvania State University on September,

7 Mezlocillin in female genital tract infections Table VI. Characteristics of patients included in the randomized comparison of mezlocillin and ampicillin Statistical Mezlocillin Ampicillin significance Number Age (years) Delivery Vaginal Caesarean Weight, gravidity, parity Table VII. Infection diagnoses in the randomized comparison of mezlocillin and ampicillin Infection diagnosis, primary Endometritis Endometritis, myometritis parametritis Episiotomy infection Cervicitis Postpartum fever Infection diagnosis, associated Upper respiratory tract infection Urinary tract infection Abdominal wound infection Statistical Mezlocillin Ampicillin significance 9 infection. There were no significant differences between the mezlocillin or ampicillin groups in any of the infection diagnoses. Bacteraemia occurred in patients as shown in Table VIII. Incidence of bacteraemia did not differ significantly between the mezlocillin and the ampicillin groups. Likewise, the occurrence of bacteraemia was not a significant determinant of outcome in these young and otherwise healthy patients who all received antibiotics. Bacteraemic isolates for the combined mezlocillin/ampicillin groups are indicated in Table IX. 8% were anaerobes with members of the Peptococcus and Peptostreptococcus sp. being the most common. A comparison of the clinical efficacy of mezlocillin and ampicillin is indicated in Table X. No differences are statistically significant; mezlocillin and ampicillin appear to be equally effective. The addition of clindamycin therapy to those patients who did not respond to mezlocillin or ampicillin therapy alone resulted in prompt clinical improvement. No patient required gentamicin treatment. Again there were no deaths. There were no major side-effects. Six mezlocillin treated and four ampicillin treated patients developed phlebitis. One ampicillin treated patient developed a maculopapular rash and one mezlocillin treated patient developed diarrhoea; in both cases symptoms resolved when the antibiotic was stopped. I Downloaded from at Pennsylvania State University on September,

8 J. R. Marshall et al. Table VIII. Occurrence of bacteraemia by treatment group in the randomized comparison of mezlocillin and ampicillin Statistical Mezlocillin Ampicillin significance Bacteraemia 8 anaerobic aerobic polymicrobial Table IX. Bacteraemic isolates from patients in the randomized comparison of mezlocillin and ampicillin No. of isolates Aerobes a streptococcus non A, B, or D a streptococcus Group F Staphylococcus epidermidis Corynebaderium sp. Total Anaerobes Eubaderium sp. Eub. tenue Eub. lentum Pepiococcus sp. Pept. magnus Pept. prevotii Pept. saccharolyticus Unclassified Bacteroides sp. Bad. bivius Bad. coagulans* Unclassified Peptostreptococcus sp. Peptostr. micros Peptostr. anaerobius Bifidobacterium sp. Bif. bifidum Lactobacillus sp. Propionibacterium sp. Total Downloaded from at Pennsylvania State University on September, * Bact. coagulans isolated during treatment only. An elevation of serum alkaline phosphate was noted in one of the mezlocillin and two of the ampicillin treated patients. Three ampicillin treated patients demonstrated elevations of serum lactic acid dehydrogenase and/or serum glutamic-oxaloacetic transaminase. It is unclear whether these effects were antibiotic induced. No patients developed leukopaenia or hypocalaemia.

9 Mezlocillin in female genital tract infections Table X. Comparative clinical efficacy Mezlocillin Ampicillin Statistical significance Antibiotic doses Fever index (" h) Clinical recovery (days) Clindamycin Hospital stay (days) Delayed wound infection Re-admitted to hospital Discussion LI Data from the general clinical efficacy trial of mezlocillin indicate clinical resolution of the infection in 8-%. An additional -8% demonstrated improvement and only -9% demonstrated failure. These response rates compare favourably with those reported for pencillin plus kanamycin (-8%) (Ledger et al., 9; Gibbs, Jones & Wilder, 98), penicillin plus trobamycin (%) (Cunningham et al., 98), penicillin plus tetracyline (8%) (Cunningham et al., 98), ampicillin (89%) (Pond et al., 99), cefamandole (8-8%) (Cunningham et al., 99; Gibbs & Huff, 98), and metronidazole (8%) (Platt, Yonekura & Ledger, 99). Our study comparing mezlocillin and ampicillin indicates equal effectiveness in the treatment of postpartum pelvic genital tract infections. Side-effects also appeared with equal frequency. Bacteraemia was not associated with a diminished response rate to either mezlocillin or ampicillin nor with increased morbidity. Addition of clindamycin was followed by clinical resolution in all patients who failed to improve within 8 h of commencing mezlocillin or ampicillin therapy. Mezlocillin appears to be an effective antibiotic in the treatment of female genital tract infections. Mezlocillin and ampicillin appear equally effective. References Bodey, C. P. & Pan, T. (9). Mezlocillin in vitro studies of a new broad-spectrum penicillin. Antimicrobial Agents and Chemotherapy, -9. Chow, A. W., Marshall, J. R. & Guze, L. B. (9). Anaerobic infections of the female genital tract: Prospects and perspectives. Obstetrics and Gynecology Survey, -9. Cunningham, F. G., Hauth, J. C, Strong, J. D. & Kappus, S. S. (98). Infectious morbidity following Cesarean section. Comparison of two treatment regimens. Obstetrics and Gynecology, -. Cunningham, F. G., Gillstrap, L. C. Ill & Kappus, S. S. (99). Treatment of obstetric and gynecologic infections with cefamandole. American Journal of Obstetrics and Gynecology, -. Gibbs, R. S., Jones, P. M. & Wilder, C. J. (98). Antibiotic therapy of endometritis following Cesarean section. Treatment successes and failures. Obstetrics and Gynecology, -. Gibbs, R. S. & Huff, R. W. (98). Cefamandole therapy of endomyometritis following Cesarean section. American Journal of Obstetrics and Gynecology, -. Hullman, R., Metzger, K., Schacht, P., Tettenborn, D., Foerster, D. & Wegner, L. A. (9). Clinical studies on mezlocillin, a new broad-spectrum semisynthetic penicillin, presented at the Seventeenth Interscience Conference on Antimicrobial Agents and Chemotherapy, New York, October -, 9. (Abst. No. ). Downloaded from at Pennsylvania State University on September,

10 8 J. R. Marshall et al. Ledger, W. J., Kriewall, T. J., Sweet, R. L. & Fekety, F. R. (9). The use of parenteral clindamycin in the treatment of obstetric-gynecologic patients with severe infections. A comparison of a clindamycin-kanamycin combination with penicillin-kanamycin. Obstetrics and Gynecology, 9-. Platt, L. D., Yonekura, M. L. & Ledger, W. J. (99). The role of anaerobic bacteria in postpartum endomyometritis. American Journal of Obstetrics and Gynecology, 8-. Pond, D. G., Bernstein, P. E., Love, K. R., Morgan, J. R., Velland, II & Smith. J. A. (99). Comparison of ampicillin with clindamycin plus gentamycin in the treatment of postpartum uterine infection. Canadian Medical Association Journel, -. Sorrell, T. C, Marshall, J. R. & Chow, A. W. (98). Antimicrobial therapy of postpartum endomyometritis. I. Comparative susceptibility of mezlocillin and other antibiotics in genital anaerobic bacteria. American Journal of Obstetrics and Gynecology, -. Sorrell, T. C, Marshall, J. R., Yoshimori, R. & Chow, A. W. (98). Antimicrobial therapy of endometritis. II. Prospective, randomized trial of mezlocillin versus ampicillin. American Journal of Obstetrics and Gynecology, -. Downloaded from at Pennsylvania State University on September,