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Ticarcillin/Clavulanate for Treatment of Postpartum Endometritis
s. Faro, H. A. Hammill, M. Maccato, and M. Martens
From the Section of Infectious Diseases, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas
Infection continues to be a significant cause of postoperative morbidity in patients who delivered by cesarean section. The incidence of postpartum endometritis ranges from 5 % to 85 %, depending on the population involved[1, 2]. Although this infection is usually mild to moderate in severity, at times it can be extremely serious and life-threatening. Patients who develop postpartum endometritis may require additional diagnostic tests, prolonged hospitalization, and additional operative procedures. Evolution to more complex infections such as suppurative myometritis or myometrial abscesses with necrosis makes hysterectomy necessary. Treatment of postpartum endometritis has centered on the assumption that this infection is primarily polymicrobial, involving aerobic, facultative, and obligate anaerobic bacteria. Therefore, the standard antimicrobial treatment has been the administration of a combination of antibiotics such as clindamycin plus gentamicin or metronidazole plus gentamicin and the addition of ampicillin if either combination is unsuccessful. However, with the development of the new {j-Iactam antibiotics, single-agent therapy has been utilized. The major concern has been that these agents are not sufficiently active against gram-negative facultative and obligate anaerobes. The development of {j-Iactamase inhibitors enables the physician to use these expanded-spectrum antibiotics for the treatment of postpartum endometritis.
Risk Factors for Postpartum Endometritis Patients who deliver by the vaginal route are at considerably less risk for the development of postpartum. endometri-
Reprints and correspondence: Dr. Sebastian Faro, Section of Infectious Diseases, Department of Obstetrics and Gynecology, Baylor College of Medicine, Smith Tower, 6550 Fannin, Suite 701, Houston, Texas 77030. Reviews of Infectious Diseases 1991;13(Suppl 9):S758-62 © 1991 by The University of Chicago. All rights reserved. 0162-0886/91/1304-0020$02.00
tis than are those who deliver by cesarean section (rv 1% vs. 5 %-85 %). Risk factors associated with the development of postpartum endometritis are listed in table 1. The leading factor is delivery by cesarean section [3]. Patients who labor for >6 hours with ruptured amniotic membranes and who deliver by cesarean section are at greater risk for the development of postpartum endometritis [4, 5]. Adolescents are at risk for developing postpartum endometritis, whether they undergo labor or not, if they deliver by cesarean section [6]. Patients who labor with intact membranes and subsequently deliver by cesarean section also are likely to develop postpartum endometritis, although the risk is considerably lower. An additional contributing factor is the placement of a transvaginal intrauterine device, e.g., a scalp electrode or an intrauterine pressure catheter, or repeated digital examinations. These devices or procedures can serve as conduits for the migration of bacteria upward into the uterine cavity.
Microbiology and Pathophysiology The etiology of postpartum endometritis may be either quite simple, involving only a single genus, or complex, involving a variety of organisms that may be gram-positive and gramnegative aerobic bacteria as well as anaerobic bacteria. Postpartum endometritis that develops within the first 24-36 hours after delivery tends to be unimicrobial, with the most commonly isolated organism being Streptococcus agalactiae [7-9]. Infections that develop beyond the first 48 hours tend to be polymicrobial, involving gram-positive bacteria as well as gram-negative aerobic, facultative, and obligate anaerobic bacteria. The bacteria involved originate from the patient's own lower genital tract and are introduced into the uterine cavity during labor. The endogenous microflora of the lower genital tract consists of commensal and potentially pathogenic bacteria (table 2). The dominant organism of the healthy vagina is the Lactobacillus, which maintains the equilibrium of the vaginal environment by producing and secreting lactic acid
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Postpartum endometritis continues to be the leading cause of morbidity following cesarean section. This infection is commonly polymicrobial, involving aerobic, facultative, and obligate anaerobic gram-negative bacteria as well as gram-positive bacteria. The major risk factor for the development of post-cesarean section endometritis is duration of labor with ruptured amniotic membranes of >6 hours. The most frequently utilized antibiotic regimen employed for treatment of postpartum endometritis is the combination' of clindamycin and gentamicin. The combination ticarcillin/clavulanate has a spectrum of activity resembling that of clindamycin and gentamicin. In the data reported, cure rates among patients treated with ticarcillin/clavulanate were similar to the rates for those treated with clindamycin plus gentamicin as well as those for cefoxitin.
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Table 1. Exogenous and endogenous factors associated with increased risk for development of postpartum endometritis. (1) (2) (3) (4) (5) (6) (7) (8) (9) (l0)
Cesarean section Ruptured membranes (~6 h) Prolonged labor Internal fetal monitoring Multiple vaginal examinations Morbid obesity Chronic diseases Anemia Malnutrition Lack of prenatal care
Table 2. Bacterial isolates from the endometrium of patients with postpartum endometritis.
Streptococcus agalactiae Enterococcus faecalis Staphylococcus aureus Staphylococcus epidermidis Enterobacter aerogenes Enterobacter agglomerans Enterobacter cloacae Klebsiella pneumoniae Morganella morganii Neisseria gonorrhoeae Proteus mirabilis Proteus vulgatus
Anaerobes Bacteroides bivius Bacteroides asacharolyticus Bacteroides disiens Bacteroides distasonis Bacteroides fragilis Bacteroides melaninogenicus Fusobacterium necrophorum Fusobacterium nucleatum Peptostreptococcus
[10]. The healthy vagina has a pH of 3.8-4.2. A decrease in the hydrogen ion concentration results in a decrease in the concentration of commensal bacteria, i.e., in lactobacilli, corynebacteria, and diphtheroids, and in an increase in the potentially pathogenic bacteria, i.e., gram-negative and grampositive facultative and obligate anaerobes [11, 12]. It is interesting that almost any of the endogenous bacteria of the vagina have the potential to cause infections such as chorioamnionitis and postpartum endometritis. Lactobacillus has been reported to cause not only chorioamnionitis but also bacteremia and postpartum endometritis [13]. This bacterium also caused bacteremia in two of the neonates born to two of these women. Gardnerella vaginalis has also been shown to cause chorioamnionitis and septic shock [14]. G. vaginalis and Chlamydia trachomatis are the two organisms isolated most frequently from adolescents with postpartum endometritis [6]. Postpartum endometritis most likely begins at some point during labor. When patients labor for a prolonged period with ruptured amniotic membranes, a route is established for bacteria to gain access to the upper genital tract. Studies in which samples from the uterine cavity obtained at the time of cesarean section have been cultured have demonstrated the presence of a variety of bacteria [2]. These bacteria reflect the flora of the lower genital tract. It has been theorized that dur-
ing a contraction, as the presenting fetal part is driven downward into the birth canal, a tight seal is established between the presenting part and the vaginal walls. When the uterine muscle relaxes, the presenting part is drawn upward, breaking the seal. The withdrawing fetal head or breech creates a suction, causing vaginal fluid to be pulled upward into the cavity. Thus, the bacteria from the vagina can enter the uterine cavity as well as the deciduous layer. The bacteria can attach to the chorionic membranes and myometrial tissue. After the initial contact is established, the bacteria may invade the myometrium. The fetus also is placed at risk because of the potential for swallowing during labor or delivery amniotic fluid colonized by bacteria. Ingestion of these bacteria can result in the development of pneumonia and bacteremia. The maternal patient who becomes colonized during labor is asymptomatic and, therefore, is not suspected of being infected. The principal method of preventing the development of postpartum endometritis is to administer prophylactic antibiotics. Numerous studies have shown that administration of antibiotics immediately after the clamping and severing of the umbilical cord prevents the development of postpartum endometritis. However, f\J15 %-25% of patients proceed to postpartum endometritis despite antibiotic prophylaxis. The prophylactic agents used most frequently are the cephalosporins cefazolin, cefoxitin, and cefotetan [15-20]. Although these agents have been shown to reduce the incidence of postpartum endometritis, they also can cause an increase in colonization by resistant bacteria, namely Enterococcus faecalis. Such colonization may be an important factor in those patients who develop postpartum endometritis and do not respond to initial therapy.
Patient Evaluation Patients who develop a fever following cesarean section should be evaluated for the presence of a soft tissue pelvic infection. A thorough chart review and physical examination should be followed by an assessment of the pelvis. The pelvic examination begins with an inspection of the external genitalia for lesions. A sterile speculum is then inserted into the vagina, and the lochia should be cleared from the vagina. The portio of the cervix should be cleansed with sterile gauze. Specimens for the isolation of Neisseria gonorrhoeae, C. trachomatis, Mycoplasma hominis, and Ureaplasma urealyticum should be obtained. A sterile dacron swab on a plastic shaft is preferable to a cotton swab, especially for the isolation of C. trachomatis. The specimens should be placed in appropriate transport media and brought to the laboratory immediately for processing. A ring forceps should be introduced into the uterine cavity to release any lochial plug or clot that may be preventing the uterus from draining spontaneously. Once the cavity has been drained, an endometrial specimen may be obtained. The specimen may be obtained by passing a sterile cotton-tipped ap-
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Treatment The treatment of patients with postpartum endometritis is begun empirically and is based on the assumption that this is a polymicrobial infection. Most cases of postpartum endometritis are polymicrobial, but a fair number are unimicrobial. Infections that become manifest within the first 24 hours of delivery tend to be unimicrobial and are likely to be caused by S. agalactiae. On average, this bacterium is noted 24 hours after delivery [9]. The infection can be quite serious, with the patient having an oral temperature exceeding 103°F, a rapid pulse, abdominal distention secondary to an adynamic ileus, and peritonitis. In contrast, the patient who develops infection ~48 hours following delivery is more likely to have a polymicrobial infection. It is assumed that polymicrobial infections are more common, and therefore antimicrobial therapy must provide coverage against grampositive and gram-negative aerobic, facultative, and obligate anaerobic organisms. The most commonly recommended regimen is clindamycin plus gentamicin; ampicillin is added if patients do not respond to this regimen [24]. Many studies have demonstrated that the newer penicillins and cephalosporins-the {3-lactam antibiotics-are as effective as the combinations clindamycin/gentamicin and metronidazole/gentamicin [25-31]. The newer {3-lactam agents, ticarcillin/clavulanate, and ampicillin/sulbactam have been
shown in vitro and in vivo to be as effective as the combinations listed earlier. It is interesting that in the studies cited and the data reported here ticarcillin/clavulanate was as effective as clindamycin/gentamicin in the treatment of patients who developed postpartum endometritis and had received prophylaxis with cefazolin at the time of cesarean section. Patients typically receive antibiotic prophylaxis immediately after the umbilical cord is clamped. Studies have shown no significant difference in outcome if antibiotic is administered before the abdominal incision is made or after the umbilical cord is clamped. The antibiotic administered for prophylaxis, either a single dose or three doses, appears to influence what bacteria colonize the lower genital tract. Several investigators have noted that when cephalosporins are used for prophylaxis, colonization by E. faecalis increases three- to sixfold. This selective colonization is an important factor in patients who develop postpartum endometritis following exposure to antibiotic prophylaxis and fail to respond to the initial therapeutic antimicrobial regimen. Comparison of ticarcillin/clavulanate with clindamycin/ gentamicin. The data presented here concern two groups of patients diagnosed as having postpartum endometritis and randomized to receive ticarcillin/clavulanate (3.1 g iv every 6 hours) or clindamycin (900 mg) and gentamicin (loading dose of2 mg/kg followed by maintenance dose of 1.5 mg/kg) every 8 hours. Serum trough and peak levels were measured to determine if therapeutic levels of gentamicin were achieved and to ensure the maintenance of nontoxic levels. The diagnosis of postpartum endometritis was made if the patient was found to have an oral temperature of ~101°F or a temperature of 100.4OF on two separate occasions at least 6 hours apart, tachycardia, a white blood cell count ~14,000/ mm', an increase in the percentage of immature polymorphonuclear leukocytes, and significant uterine tenderness. In addition to meeting all the criteria listed above, the patient may have a purulent and/or foul-smelling lochia and signs of peritonitis. Patients with S. agalactiae endometritis do not have a purulent or foul-smelling lochia. A total of 170 patients were enrolled in the study, and 18 patients were disqualified because of protocol violations. Seventy-five patients were enrolled in the ticarcillin/clavulanate arm and 77 in the clindamycin/gentamicin arm. The study populations of the two groups were well-matched. The composition ofeach group was rv52% white, 47% black, and 1% Asian. The average duration of ruptured amniotic membranes was 9.5 and 9.3 hours and that of labor was 16 hours and 14 hours for the ticarcillin/clavulanate group and the clindamycin/gentamicin group, respectively. Among the patients who received ticarcillin/clavulanate, 85 % were cured of their infection, and among those who received clindamycin/gentamicin, 81% were cured. Treatment failed in 11 patients who received ticarcillin/clavulanate; E. faecalis was isolated from five of these patients. The MIC 90 for these five isolates of E. faecalis was 32 j.tg/ml, placing
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plicator held with a ring forceps or a double-lumen catheter or the Pipelle endometrial suction curette (Unimar, Wilton, CT) [22, 23]. Studies comparing these sampling devices have shown essentially no difference between these instruments in their retrieval of bacteria, especially vaginal contaminants. The double catheter was utilized in this study to obtain a specimen from the inner uterine cavity. The catheter was introduced transcervically. Once the outermost catheter was transported to the uterine cavity, the second sheath was advanced 2 em beyond the end of the first cavity. The brush was then advanced beyond the most distal end to collect specimens and then inserted into an anaerobic transport vial. If C. trachomatis, M. hominis, or U. urealyticum is sought, the specimens must be placed in appropriate transport vials and processed in the laboratory as quickly as possible. Specimens for the isolation of Chlamydia are processed and utilized to inoculate McCoy cells [8], and those for isolation of Mycoplasma and Ureaplasma are inoculated onto A7 medium [8]. Aerobic and anaerobic blood culture bottles are inoculated with 5 mL of venous blood obtained from the volar aspect of the upper extremity with the use of aseptic technique. The blood culture bottles are examined daily for the presence of growth. If no growth is noted after 48 hours of incubation, aliquots are removed to inoculate A7 medium for the detection of Mycoplasma and Ureaplasma. A urine specimen is obtained by catheterization or when the Foley catheter is removed for the isolation and identification of uropathogens.
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epidermidis/Acinetobacter lwoffi, Peptostreptococcus/Bacteroides species, Peptostreptococcus/Mycoplasma, and Peptostreptococcus/S. epidermidis, respectively. Seven of the 29 patients with bacteremia did not respond to initial therapy. Sixteen patients received clindamycin/gentamicin, which failed to clear the bacteremia in four. In one patient the S. epidermidis isolate was resistant to both antibiotics; cefoxitin therapy was initiated and was successful. One patient with a P. acnes infection was cured with cefoxitin therapy. Three of 14 patients with bacteremia failed to respond to therapy with ticarcillin/clavulanate. Two patients were infected with Mycoplasma and responded to tetracycline therapy. One patient was infected with a B. fragilis strain that was resistant to ticarcillin/clavulanate. Other studies that compared ticarcillin/clavulanate with cefoxitin or clindamycin/gentamicin obtained similar results [32-36]. In comparisons ofticarcillin/clavulanate with cefoxitin, 93 % and 85 % of the patients were cured, respectively. In comparisons of ticarcillin/clavulanate with clindamycin/gentamicin, 88 % and 86 % of patients were cured, respectively. In the study reported by Apuzzio et al. the patients received neither antibiotic prophylaxis nor antibiotic in the 14 days preceding the delivery. E. faecalis was isolated from 10% of the patients [35]. In the study reported here, the patients all received cefazolin prophylaxis. E. faecalis was isolated from 52 % of the patients. A second organism of importance is Enterobacter cloacae, which was not reported by Apuzzio et al. but was isolated from Nll % of the patients who received prophylaxis. Thus, E.faecalis was isolated from 10% of patients who did not receive cephalosporin prophylaxis and from 52 % who received prophylaxis (P < .00001 by X2 test). E. cloacae was isolated from 10% of the patients
who received prophylaxis, whereas Apuzzio et al. did not isolate the organism (P < .0004 by Fisher's exact test).
Discussion The bacterial spectrum of activity of ticarcillin/clavulanate approaches that of the combination clindamycin/gentamicin. The spectrum of activity of ticarcillin/clavulanate against obligate anaerobes resembles that of clindamycin or of imipenem/cilastatin [37, 38]. Ticarcillinlclavulanate has a somewhat broader spectrum than the expanded-spectrum cephalosporins, i.e., cefoxitin and cefotetan. Cuchural et al. compared the in vitro activity of imipenem, ticarcillin/clavulanate, cefoxitin, piperacillin, moxalactam, cefotetan, ceftizoxime, cefotaxime, cefoperazone, ceftazidime, clindamycin, and tetracycline against 1,229 isolates of the B. fragilis group [37]. These investigators found that ticarcillin/clavulanate and imipenem were the most active of the compounds tested. The overall rate of resistance among these isolates for these antibiotics was 0.2 %, whereas the rate ranged from a low of 6.4 % for clindamycin to a high of 63 % for tetracycline. Bacteroides distasonis strains offered the most resistance. Fuchs et al. found that the combination ticarcillin/clavulanate had enhanced activity against Bacteroides species, certain members of the Enterobacteriaceae, Staphylococcus aureus,N. gonorrhoeae, and Haemophilus injluenzae [32]. However, the addition of clavulanic acid does not appear to enhance the activity of ticarcillin against Pseudomonas, Enterobacter cloacae, or
E. faecalis. Thus, patients who develop postpartum endometritis can be effectively treated with ticarcillin/clavulanate and need not be treated empirically initially with clindamycin/gentamicin, thereby reducing the potential for nephrotoxicity and ototoxicity and of diarrhea, which may signal the development of pseudomembranous colitis. Because most patients who deliver by cesarean section receive antibiotic prophylaxis, e.g., with a cephalosporin, colonization with E. faecalis is increased. Patients who develop endometritis and subsequently fail to respond to initial antibiotic therapy should be considered to be infected with E. faecalis. Patients treated with ticarcillinlclavulanate and infected with E.faecalis may not respond to therapy because the MIC90 is 32 p.g/ml, placing these organisms at an intermediate range of susceptibility to this combination. However, the addition of an aminoglycoside may result in synergistic activity against these bacteria.
References 1. Amstey MT, Sheldon OW,Blyth JF. Infectious morbidity after cesarean sections in a private institution. Am J Obstet Gynecol1980;136:205-10 2. Gilstrap LC III, Cunningham FG. The bacterial pathogenesis of infection following cesarean section. Obstet Gynecol 1979;53 :545-9 3. Polk BF, Krache M, Phillippe M, Munoz A, Hutchinson D, Miao L, Schoenbaum Sc. Randomized clinical trial of perioperative cefoxitin
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the organism at an intermediate susceptibility range at best. All five patients underwent complete resolution of their endometritis after receiving ampicillin. The remaining six patients responded to the addition of gentamicin to the ticarcillin/clavulanate regimen. Treatment failed in 14 patients who received clindamycin/gentamicin; E. faecalis was isolated from 10 of these patients. However, E. faecalis was present with one other bacterium in five of these patients and with three or more bacteria in the remaining five patients. All 10 patients were cured of the infection after ampicillin was added to the clindamycin/gentamicin regimen. Twenty-nine patients were bacteremic; 25 of these patients had a single bacterial genus isolated from their blood, and four had polymicrobial bacteremia. E. faecalis was not isolated from any of the bacteremic patients. The most common blood isolate was Mycoplasma, which was present in 11 patients. Staphylococcus epidermidis was isolated from the blood of six patients and Streptococcus mutans from one patient. Anaerobes were isolated from the blood of seven patients: Bacteroides bivius (four), Bacteroides fragilis (one), Bacteroides species (one), and Propionibacterium acnes (one). Four patients had polymicrobial bacteremia, one with S.
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in preventing maternal infectionafter primary cesarean section. Am J Obstet Gynecol 1982;142:983-7 ApuzzioJl, ReyeltC, Pelosi M, Sen P, Louria DB. Prophylacticantibiotics for cesarean section: a comparison of high- and low-risk patients for endometritis. Obstet Gynecol 1982;59:693-8 BenignoBB,FordLC, LawrenceWD, et al. A double-blind, controlled comparison ofpiperacillinand cefoxitin in thepreventionofpostoperativeinfection in patientsundergoing cesareansection. Surg Gynecol Obstet 1982;162:1-6 BerensonAB, Hammill HA, Martens MG, Pokorny SF, Faro S. Postcesarean section endometritis in adolescents: risk factors and bacteriology findings. Obstet Gynecol 1990;75:627-9 Faro S, Phillips LE, Martens MG. Perspectives on the bacteriology of postoperativeobstetricand gynecologicinfections. Am J Obstet Gynecol 1988;158:694-700 PhillipsLE, FaroS, MartensMG, BakerJL, GoodrichKH, Thrner RM, RiddleG. Posteesarean microbiologyof high-riskpatientstreated for endometritis. Curr Therap Res 1987;42:1157-65 Faro S. Group B beta-hemolytic streptococciand puerperal infections. Am J Obstet Gynecol 1981;139:686-9 Vontver LA, Eschenbach DA. The role of Gardnerella vaginalis in nonspecific vaginitis. Clin Obstet GynecolI981;24:439-60 Amsel R, Totten PA, Spiegel CA, Chen KC, Eschenbach D, Holmes KK. Nonspecific vaginitis.Diagnosticcriteria and microbial and epidemiological associations. Am J Med 1983;74:14-22 SpiegelCA, EschenbachDA, AmselR, HolmesKK. Curved anaerobic bacteriain bacterial(nonspecific) vaginosis and their response to antimicrobial therapy. J Infect Dis 1983;148:817-22 Cox SM, Phillips LE, Mercer U, Stager CE, WallerS, Faro S. Lactobacillemia of amnioticfluidorigin. ObstetGynecolI986;68:134-6 Lee W, Phillips LE, Carpenter RJ, Martens MG, Faro S. Gardnerella vaginalis chorioamnionitis: a report of two cases and a reviewof the pathogenic role of G. vaginalisin obstetrics. Diagn Microbiol Infect Dis 1987;8:107-11 DiPiro JT, Bowden TA, Hooks VH. Prophylactic parenteral cephalosporins in surgery. JAMA 1984;252:3277-9 FaroS. Antibiotic prophylaxis. In: GalaskRP,LarsenB, eds. New York: Springer-Verlag, 1985:243-50 Benigno BB, Evrard J, Faro S, Ford LC, LaCroix G, Lawrence WD, Ling FW, McNeeleySG, Nichols DH, SweetRL. A comparison of piperacillin, cephalothin, and cefoxitin in the prevention of postoperativeinfections in patientsundergoing vaginal hysterectomy. SurgGynecol Obstet 1986;163:421-7 Hemsell DL, Heard ML, Nobels BJ, Hemsell PG. Single-dosecefoxitin prophylaxis for premenopausal womenundergoingvaginal hysterectomy. Obstet Gynecol 1984;63:285-90 Gonik B. Single-Single- versus three-dose cefotaxime prophylaxis for cesarean section. Obstet GynecolI985:65:189-93 Stiver HG, ForwardKR, Tyrrell DL, Krip G, LivingstoneRA, Fugere P, Lemay M, Verschelden G, Hunter JD, Carson GD, et al, Comparativecervicalmicroflorashiftsafter cefoxitinor cefazolinprophylaxisagainst infection following cesarean section. Am J ObstetGynecol 1984;149:718-21 Faro S, Cox SM, Phillips LE, et al. Influenceof antibiotic prophylaxis on vaginal microflora. J Obstet Gynaecol(Bristol)1986;6(Suppll): 54-6 Martens MG, Faro S, Hammill HA, Riddle MS, Smith D. Transcervical uterine cultures with a new endometrialsuction curette. A comparisonof three sampling methodsin postpartum endometritis. Obstet Gynecol 1989;74:273-6
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23. Martens MG, Faro S, Hammill H, Phillips LE, Riddle GD. Comparison of two methodsof endometrialsampling devices. Cotton-tipped swaband double-lumencatheter with a brush. J Reprod Med 1989; 34:875-9 24. DiZerega G, Yonekura L, Roy S, Nakamura RM, Ledger WJ. A comparison of clindamycin-gentamicin and penicillin-gentamicin in the treatmentof post-eesarean sectionendomyometritis. Am J ObstetGynecol 1979;134:238-42 25. Poindexter AN, Ritter M, Faro S, Castellano MA, Centry LO, Ismail M, KnuppelRA, KreutnerAK, Lamb EI, LeFrock JL, et al. Results of non-comparativestudiesof cefotetanin the treatmentof obstetric and gynecologic infections. Am J Obstet GynecolI988;158:717-21 26. Faro S, Sanders CV, Aldridge KE. Use of single-agentantimicrobial therapy in the treatment of polymicrobial female pelvic infections. Obstet Gynecol 1982;60:232-6 27. Faro S, Phillips LE, BakerJL, Goodrich KH, Turner RM, RiddleGD. Comparative efficacy and safety of mezlocillin, cefoxitin, and clindamycinplus gentamicinin postpartumendometritis. ObstetGynecol 1987;69:760-6 28. Pastorek JG II, Faro S, AldridgeKE, Nicaud SK. Moxalactamversus clindamycin plus tobramycin for the treatmentof puerperalinfections. South Med J 1987;80:1116-9 29. Faro S, Pastorek JG, Aldridge KE, Martens M, Phillips LE, Nicaud S, Cunningham G. Piperacillinversus clindamycin plus gentamicin in the treatment of postpartumendometritis. Curr Therap Res 1987; 42:995-1002 30. HemsellDL, Cunningham FG, DePalmaRr, NoblesBJ, HeardM, Hemsell PG. Cefotaximesodiumtherapy for endomyometritis following cesarean section: dose-finding and comparative studies. Obstet Gynecol 1983;62:489-97 31. RoseneK, EschenbachDA, Tompkins LS, KennyGE, Watkins H. Polymicrobial early postpartumendometritiswith facultative and anaerobic bacteria, genital mycoplasmas and Chlamydia trachomatis: treatmentwithpiperacillin or cefoxitin. J InfectDis 1986;153:1028-37 32. Fuchs PC, Jones RN, Barry AL, Allen SD, AldridgeKE, Gerlach EH, SommersHM. Effectof clavulanic acid on the susceptibility of clinical anaerobic bacteria to ticarcillin: a multicenter study. Diagn Microbiol Infect Dis 1988;9:47-50 33. Gelfand MS, Lawson RD, Baucom W. Ticarcillin-clavulanate therapy for infections with ticarcillin-resistant microorganisms. South Med J 1989;82:433-7 34. Pastorek JG, Aldridge KE, CunninghamGL, Faro S. Comparison of ticarcillin plus clavulanic acid with cefoxitinin the treatment of female pelvic infections. Am J Med 1986;79:161-3 35. Apuzzio n, Ganesh V, Kaminski Z, Bergen B, Holland B, Lourla DB. Comparison of ticarcillinplus clavulanicacid with clindamycin and gentamicin in the treatment of posteesarean endomyometritis. Surg Gynecol Obstet 1988;166:413-7 36. FaroS, Martens M, HammillH, PhillipsLE, Smith D, RiddleG. TIcarcillin/clavulanicacid versusclindamycin and gentamicinin the treatment of post-cesareanendometritisfollowing antibioticprophylaxis. Obstet Gynecol 1989;73:808-12 37. Cuchural GJ Jr, TallyFP, JacobusNY, Aldridge K, Cleary T, Finegold SM, Hill G, Iannini P, O'Keefe JP, Pierson C, et al. Susceptibility ofthe Bacteroidesfragilis group in the United States: analysisby site of isolation. Antimicrob Agents Chemother 1988;32:717-22 38. TallyFP. Factors affecting the choiceof antibiotics in mixedinfections. J Antimicrob Chemother 1988;22:87-100
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Ticarcillin/Clavulanate for Treatment of Postpartum Endometritis
s. Faro, H. A. Hammill, M. Maccato, and M. Martens
From the Section of Infectious Diseases, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas
Infection continues to be a significant cause of postoperative morbidity in patients who delivered by cesarean section. The incidence of postpartum endometritis ranges from 5 % to 85 %, depending on the population involved[1, 2]. Although this infection is usually mild to moderate in severity, at times it can be extremely serious and life-threatening. Patients who develop postpartum endometritis may require additional diagnostic tests, prolonged hospitalization, and additional operative procedures. Evolution to more complex infections such as suppurative myometritis or myometrial abscesses with necrosis makes hysterectomy necessary. Treatment of postpartum endometritis has centered on the assumption that this infection is primarily polymicrobial, involving aerobic, facultative, and obligate anaerobic bacteria. Therefore, the standard antimicrobial treatment has been the administration of a combination of antibiotics such as clindamycin plus gentamicin or metronidazole plus gentamicin and the addition of ampicillin if either combination is unsuccessful. However, with the development of the new {j-Iactam antibiotics, single-agent therapy has been utilized. The major concern has been that these agents are not sufficiently active against gram-negative facultative and obligate anaerobes. The development of {j-Iactamase inhibitors enables the physician to use these expanded-spectrum antibiotics for the treatment of postpartum endometritis.
Risk Factors for Postpartum Endometritis Patients who deliver by the vaginal route are at considerably less risk for the development of postpartum. endometri-
Reprints and correspondence: Dr. Sebastian Faro, Section of Infectious Diseases, Department of Obstetrics and Gynecology, Baylor College of Medicine, Smith Tower, 6550 Fannin, Suite 701, Houston, Texas 77030. Reviews of Infectious Diseases 1991;13(Suppl 9):S758-62 © 1991 by The University of Chicago. All rights reserved. 0162-0886/91/1304-0020$02.00
tis than are those who deliver by cesarean section (rv 1% vs. 5 %-85 %). Risk factors associated with the development of postpartum endometritis are listed in table 1. The leading factor is delivery by cesarean section [3]. Patients who labor for >6 hours with ruptured amniotic membranes and who deliver by cesarean section are at greater risk for the development of postpartum endometritis [4, 5]. Adolescents are at risk for developing postpartum endometritis, whether they undergo labor or not, if they deliver by cesarean section [6]. Patients who labor with intact membranes and subsequently deliver by cesarean section also are likely to develop postpartum endometritis, although the risk is considerably lower. An additional contributing factor is the placement of a transvaginal intrauterine device, e.g., a scalp electrode or an intrauterine pressure catheter, or repeated digital examinations. These devices or procedures can serve as conduits for the migration of bacteria upward into the uterine cavity.
Microbiology and Pathophysiology The etiology of postpartum endometritis may be either quite simple, involving only a single genus, or complex, involving a variety of organisms that may be gram-positive and gramnegative aerobic bacteria as well as anaerobic bacteria. Postpartum endometritis that develops within the first 24-36 hours after delivery tends to be unimicrobial, with the most commonly isolated organism being Streptococcus agalactiae [7-9]. Infections that develop beyond the first 48 hours tend to be polymicrobial, involving gram-positive bacteria as well as gram-negative aerobic, facultative, and obligate anaerobic bacteria. The bacteria involved originate from the patient's own lower genital tract and are introduced into the uterine cavity during labor. The endogenous microflora of the lower genital tract consists of commensal and potentially pathogenic bacteria (table 2). The dominant organism of the healthy vagina is the Lactobacillus, which maintains the equilibrium of the vaginal environment by producing and secreting lactic acid
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Postpartum endometritis continues to be the leading cause of morbidity following cesarean section. This infection is commonly polymicrobial, involving aerobic, facultative, and obligate anaerobic gram-negative bacteria as well as gram-positive bacteria. The major risk factor for the development of post-cesarean section endometritis is duration of labor with ruptured amniotic membranes of >6 hours. The most frequently utilized antibiotic regimen employed for treatment of postpartum endometritis is the combination' of clindamycin and gentamicin. The combination ticarcillin/clavulanate has a spectrum of activity resembling that of clindamycin and gentamicin. In the data reported, cure rates among patients treated with ticarcillin/clavulanate were similar to the rates for those treated with clindamycin plus gentamicin as well as those for cefoxitin.
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Table 1. Exogenous and endogenous factors associated with increased risk for development of postpartum endometritis. (1) (2) (3) (4) (5) (6) (7) (8) (9) (l0)
Cesarean section Ruptured membranes (~6 h) Prolonged labor Internal fetal monitoring Multiple vaginal examinations Morbid obesity Chronic diseases Anemia Malnutrition Lack of prenatal care
Table 2. Bacterial isolates from the endometrium of patients with postpartum endometritis.
Streptococcus agalactiae Enterococcus faecalis Staphylococcus aureus Staphylococcus epidermidis Enterobacter aerogenes Enterobacter agglomerans Enterobacter cloacae Klebsiella pneumoniae Morganella morganii Neisseria gonorrhoeae Proteus mirabilis Proteus vulgatus
Anaerobes Bacteroides bivius Bacteroides asacharolyticus Bacteroides disiens Bacteroides distasonis Bacteroides fragilis Bacteroides melaninogenicus Fusobacterium necrophorum Fusobacterium nucleatum Peptostreptococcus
[10]. The healthy vagina has a pH of 3.8-4.2. A decrease in the hydrogen ion concentration results in a decrease in the concentration of commensal bacteria, i.e., in lactobacilli, corynebacteria, and diphtheroids, and in an increase in the potentially pathogenic bacteria, i.e., gram-negative and grampositive facultative and obligate anaerobes [11, 12]. It is interesting that almost any of the endogenous bacteria of the vagina have the potential to cause infections such as chorioamnionitis and postpartum endometritis. Lactobacillus has been reported to cause not only chorioamnionitis but also bacteremia and postpartum endometritis [13]. This bacterium also caused bacteremia in two of the neonates born to two of these women. Gardnerella vaginalis has also been shown to cause chorioamnionitis and septic shock [14]. G. vaginalis and Chlamydia trachomatis are the two organisms isolated most frequently from adolescents with postpartum endometritis [6]. Postpartum endometritis most likely begins at some point during labor. When patients labor for a prolonged period with ruptured amniotic membranes, a route is established for bacteria to gain access to the upper genital tract. Studies in which samples from the uterine cavity obtained at the time of cesarean section have been cultured have demonstrated the presence of a variety of bacteria [2]. These bacteria reflect the flora of the lower genital tract. It has been theorized that dur-
ing a contraction, as the presenting fetal part is driven downward into the birth canal, a tight seal is established between the presenting part and the vaginal walls. When the uterine muscle relaxes, the presenting part is drawn upward, breaking the seal. The withdrawing fetal head or breech creates a suction, causing vaginal fluid to be pulled upward into the cavity. Thus, the bacteria from the vagina can enter the uterine cavity as well as the deciduous layer. The bacteria can attach to the chorionic membranes and myometrial tissue. After the initial contact is established, the bacteria may invade the myometrium. The fetus also is placed at risk because of the potential for swallowing during labor or delivery amniotic fluid colonized by bacteria. Ingestion of these bacteria can result in the development of pneumonia and bacteremia. The maternal patient who becomes colonized during labor is asymptomatic and, therefore, is not suspected of being infected. The principal method of preventing the development of postpartum endometritis is to administer prophylactic antibiotics. Numerous studies have shown that administration of antibiotics immediately after the clamping and severing of the umbilical cord prevents the development of postpartum endometritis. However, f\J15 %-25% of patients proceed to postpartum endometritis despite antibiotic prophylaxis. The prophylactic agents used most frequently are the cephalosporins cefazolin, cefoxitin, and cefotetan [15-20]. Although these agents have been shown to reduce the incidence of postpartum endometritis, they also can cause an increase in colonization by resistant bacteria, namely Enterococcus faecalis. Such colonization may be an important factor in those patients who develop postpartum endometritis and do not respond to initial therapy.
Patient Evaluation Patients who develop a fever following cesarean section should be evaluated for the presence of a soft tissue pelvic infection. A thorough chart review and physical examination should be followed by an assessment of the pelvis. The pelvic examination begins with an inspection of the external genitalia for lesions. A sterile speculum is then inserted into the vagina, and the lochia should be cleared from the vagina. The portio of the cervix should be cleansed with sterile gauze. Specimens for the isolation of Neisseria gonorrhoeae, C. trachomatis, Mycoplasma hominis, and Ureaplasma urealyticum should be obtained. A sterile dacron swab on a plastic shaft is preferable to a cotton swab, especially for the isolation of C. trachomatis. The specimens should be placed in appropriate transport media and brought to the laboratory immediately for processing. A ring forceps should be introduced into the uterine cavity to release any lochial plug or clot that may be preventing the uterus from draining spontaneously. Once the cavity has been drained, an endometrial specimen may be obtained. The specimen may be obtained by passing a sterile cotton-tipped ap-
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Treatment The treatment of patients with postpartum endometritis is begun empirically and is based on the assumption that this is a polymicrobial infection. Most cases of postpartum endometritis are polymicrobial, but a fair number are unimicrobial. Infections that become manifest within the first 24 hours of delivery tend to be unimicrobial and are likely to be caused by S. agalactiae. On average, this bacterium is noted 24 hours after delivery [9]. The infection can be quite serious, with the patient having an oral temperature exceeding 103°F, a rapid pulse, abdominal distention secondary to an adynamic ileus, and peritonitis. In contrast, the patient who develops infection ~48 hours following delivery is more likely to have a polymicrobial infection. It is assumed that polymicrobial infections are more common, and therefore antimicrobial therapy must provide coverage against grampositive and gram-negative aerobic, facultative, and obligate anaerobic organisms. The most commonly recommended regimen is clindamycin plus gentamicin; ampicillin is added if patients do not respond to this regimen [24]. Many studies have demonstrated that the newer penicillins and cephalosporins-the {3-lactam antibiotics-are as effective as the combinations clindamycin/gentamicin and metronidazole/gentamicin [25-31]. The newer {3-lactam agents, ticarcillin/clavulanate, and ampicillin/sulbactam have been
shown in vitro and in vivo to be as effective as the combinations listed earlier. It is interesting that in the studies cited and the data reported here ticarcillin/clavulanate was as effective as clindamycin/gentamicin in the treatment of patients who developed postpartum endometritis and had received prophylaxis with cefazolin at the time of cesarean section. Patients typically receive antibiotic prophylaxis immediately after the umbilical cord is clamped. Studies have shown no significant difference in outcome if antibiotic is administered before the abdominal incision is made or after the umbilical cord is clamped. The antibiotic administered for prophylaxis, either a single dose or three doses, appears to influence what bacteria colonize the lower genital tract. Several investigators have noted that when cephalosporins are used for prophylaxis, colonization by E. faecalis increases three- to sixfold. This selective colonization is an important factor in patients who develop postpartum endometritis following exposure to antibiotic prophylaxis and fail to respond to the initial therapeutic antimicrobial regimen. Comparison of ticarcillin/clavulanate with clindamycin/ gentamicin. The data presented here concern two groups of patients diagnosed as having postpartum endometritis and randomized to receive ticarcillin/clavulanate (3.1 g iv every 6 hours) or clindamycin (900 mg) and gentamicin (loading dose of2 mg/kg followed by maintenance dose of 1.5 mg/kg) every 8 hours. Serum trough and peak levels were measured to determine if therapeutic levels of gentamicin were achieved and to ensure the maintenance of nontoxic levels. The diagnosis of postpartum endometritis was made if the patient was found to have an oral temperature of ~101°F or a temperature of 100.4OF on two separate occasions at least 6 hours apart, tachycardia, a white blood cell count ~14,000/ mm', an increase in the percentage of immature polymorphonuclear leukocytes, and significant uterine tenderness. In addition to meeting all the criteria listed above, the patient may have a purulent and/or foul-smelling lochia and signs of peritonitis. Patients with S. agalactiae endometritis do not have a purulent or foul-smelling lochia. A total of 170 patients were enrolled in the study, and 18 patients were disqualified because of protocol violations. Seventy-five patients were enrolled in the ticarcillin/clavulanate arm and 77 in the clindamycin/gentamicin arm. The study populations of the two groups were well-matched. The composition ofeach group was rv52% white, 47% black, and 1% Asian. The average duration of ruptured amniotic membranes was 9.5 and 9.3 hours and that of labor was 16 hours and 14 hours for the ticarcillin/clavulanate group and the clindamycin/gentamicin group, respectively. Among the patients who received ticarcillin/clavulanate, 85 % were cured of their infection, and among those who received clindamycin/gentamicin, 81% were cured. Treatment failed in 11 patients who received ticarcillin/clavulanate; E. faecalis was isolated from five of these patients. The MIC 90 for these five isolates of E. faecalis was 32 j.tg/ml, placing
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plicator held with a ring forceps or a double-lumen catheter or the Pipelle endometrial suction curette (Unimar, Wilton, CT) [22, 23]. Studies comparing these sampling devices have shown essentially no difference between these instruments in their retrieval of bacteria, especially vaginal contaminants. The double catheter was utilized in this study to obtain a specimen from the inner uterine cavity. The catheter was introduced transcervically. Once the outermost catheter was transported to the uterine cavity, the second sheath was advanced 2 em beyond the end of the first cavity. The brush was then advanced beyond the most distal end to collect specimens and then inserted into an anaerobic transport vial. If C. trachomatis, M. hominis, or U. urealyticum is sought, the specimens must be placed in appropriate transport vials and processed in the laboratory as quickly as possible. Specimens for the isolation of Chlamydia are processed and utilized to inoculate McCoy cells [8], and those for isolation of Mycoplasma and Ureaplasma are inoculated onto A7 medium [8]. Aerobic and anaerobic blood culture bottles are inoculated with 5 mL of venous blood obtained from the volar aspect of the upper extremity with the use of aseptic technique. The blood culture bottles are examined daily for the presence of growth. If no growth is noted after 48 hours of incubation, aliquots are removed to inoculate A7 medium for the detection of Mycoplasma and Ureaplasma. A urine specimen is obtained by catheterization or when the Foley catheter is removed for the isolation and identification of uropathogens.
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epidermidis/Acinetobacter lwoffi, Peptostreptococcus/Bacteroides species, Peptostreptococcus/Mycoplasma, and Peptostreptococcus/S. epidermidis, respectively. Seven of the 29 patients with bacteremia did not respond to initial therapy. Sixteen patients received clindamycin/gentamicin, which failed to clear the bacteremia in four. In one patient the S. epidermidis isolate was resistant to both antibiotics; cefoxitin therapy was initiated and was successful. One patient with a P. acnes infection was cured with cefoxitin therapy. Three of 14 patients with bacteremia failed to respond to therapy with ticarcillin/clavulanate. Two patients were infected with Mycoplasma and responded to tetracycline therapy. One patient was infected with a B. fragilis strain that was resistant to ticarcillin/clavulanate. Other studies that compared ticarcillin/clavulanate with cefoxitin or clindamycin/gentamicin obtained similar results [32-36]. In comparisons ofticarcillin/clavulanate with cefoxitin, 93 % and 85 % of the patients were cured, respectively. In comparisons of ticarcillin/clavulanate with clindamycin/gentamicin, 88 % and 86 % of patients were cured, respectively. In the study reported by Apuzzio et al. the patients received neither antibiotic prophylaxis nor antibiotic in the 14 days preceding the delivery. E. faecalis was isolated from 10% of the patients [35]. In the study reported here, the patients all received cefazolin prophylaxis. E. faecalis was isolated from 52 % of the patients. A second organism of importance is Enterobacter cloacae, which was not reported by Apuzzio et al. but was isolated from Nll % of the patients who received prophylaxis. Thus, E.faecalis was isolated from 10% of patients who did not receive cephalosporin prophylaxis and from 52 % who received prophylaxis (P < .00001 by X2 test). E. cloacae was isolated from 10% of the patients
who received prophylaxis, whereas Apuzzio et al. did not isolate the organism (P < .0004 by Fisher's exact test).
Discussion The bacterial spectrum of activity of ticarcillin/clavulanate approaches that of the combination clindamycin/gentamicin. The spectrum of activity of ticarcillin/clavulanate against obligate anaerobes resembles that of clindamycin or of imipenem/cilastatin [37, 38]. Ticarcillinlclavulanate has a somewhat broader spectrum than the expanded-spectrum cephalosporins, i.e., cefoxitin and cefotetan. Cuchural et al. compared the in vitro activity of imipenem, ticarcillin/clavulanate, cefoxitin, piperacillin, moxalactam, cefotetan, ceftizoxime, cefotaxime, cefoperazone, ceftazidime, clindamycin, and tetracycline against 1,229 isolates of the B. fragilis group [37]. These investigators found that ticarcillin/clavulanate and imipenem were the most active of the compounds tested. The overall rate of resistance among these isolates for these antibiotics was 0.2 %, whereas the rate ranged from a low of 6.4 % for clindamycin to a high of 63 % for tetracycline. Bacteroides distasonis strains offered the most resistance. Fuchs et al. found that the combination ticarcillin/clavulanate had enhanced activity against Bacteroides species, certain members of the Enterobacteriaceae, Staphylococcus aureus,N. gonorrhoeae, and Haemophilus injluenzae [32]. However, the addition of clavulanic acid does not appear to enhance the activity of ticarcillin against Pseudomonas, Enterobacter cloacae, or
E. faecalis. Thus, patients who develop postpartum endometritis can be effectively treated with ticarcillin/clavulanate and need not be treated empirically initially with clindamycin/gentamicin, thereby reducing the potential for nephrotoxicity and ototoxicity and of diarrhea, which may signal the development of pseudomembranous colitis. Because most patients who deliver by cesarean section receive antibiotic prophylaxis, e.g., with a cephalosporin, colonization with E. faecalis is increased. Patients who develop endometritis and subsequently fail to respond to initial antibiotic therapy should be considered to be infected with E. faecalis. Patients treated with ticarcillinlclavulanate and infected with E.faecalis may not respond to therapy because the MIC90 is 32 p.g/ml, placing these organisms at an intermediate range of susceptibility to this combination. However, the addition of an aminoglycoside may result in synergistic activity against these bacteria.
References 1. Amstey MT, Sheldon OW,Blyth JF. Infectious morbidity after cesarean sections in a private institution. Am J Obstet Gynecol1980;136:205-10 2. Gilstrap LC III, Cunningham FG. The bacterial pathogenesis of infection following cesarean section. Obstet Gynecol 1979;53 :545-9 3. Polk BF, Krache M, Phillippe M, Munoz A, Hutchinson D, Miao L, Schoenbaum Sc. Randomized clinical trial of perioperative cefoxitin
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the organism at an intermediate susceptibility range at best. All five patients underwent complete resolution of their endometritis after receiving ampicillin. The remaining six patients responded to the addition of gentamicin to the ticarcillin/clavulanate regimen. Treatment failed in 14 patients who received clindamycin/gentamicin; E. faecalis was isolated from 10 of these patients. However, E. faecalis was present with one other bacterium in five of these patients and with three or more bacteria in the remaining five patients. All 10 patients were cured of the infection after ampicillin was added to the clindamycin/gentamicin regimen. Twenty-nine patients were bacteremic; 25 of these patients had a single bacterial genus isolated from their blood, and four had polymicrobial bacteremia. E. faecalis was not isolated from any of the bacteremic patients. The most common blood isolate was Mycoplasma, which was present in 11 patients. Staphylococcus epidermidis was isolated from the blood of six patients and Streptococcus mutans from one patient. Anaerobes were isolated from the blood of seven patients: Bacteroides bivius (four), Bacteroides fragilis (one), Bacteroides species (one), and Propionibacterium acnes (one). Four patients had polymicrobial bacteremia, one with S.
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23. Martens MG, Faro S, Hammill H, Phillips LE, Riddle GD. Comparison of two methodsof endometrialsampling devices. Cotton-tipped swaband double-lumencatheter with a brush. J Reprod Med 1989; 34:875-9 24. DiZerega G, Yonekura L, Roy S, Nakamura RM, Ledger WJ. A comparison of clindamycin-gentamicin and penicillin-gentamicin in the treatmentof post-eesarean sectionendomyometritis. Am J ObstetGynecol 1979;134:238-42 25. Poindexter AN, Ritter M, Faro S, Castellano MA, Centry LO, Ismail M, KnuppelRA, KreutnerAK, Lamb EI, LeFrock JL, et al. Results of non-comparativestudiesof cefotetanin the treatmentof obstetric and gynecologic infections. Am J Obstet GynecolI988;158:717-21 26. Faro S, Sanders CV, Aldridge KE. Use of single-agentantimicrobial therapy in the treatment of polymicrobial female pelvic infections. Obstet Gynecol 1982;60:232-6 27. Faro S, Phillips LE, BakerJL, Goodrich KH, Turner RM, RiddleGD. Comparative efficacy and safety of mezlocillin, cefoxitin, and clindamycinplus gentamicinin postpartumendometritis. ObstetGynecol 1987;69:760-6 28. Pastorek JG II, Faro S, AldridgeKE, Nicaud SK. Moxalactamversus clindamycin plus tobramycin for the treatmentof puerperalinfections. South Med J 1987;80:1116-9 29. Faro S, Pastorek JG, Aldridge KE, Martens M, Phillips LE, Nicaud S, Cunningham G. Piperacillinversus clindamycin plus gentamicin in the treatment of postpartumendometritis. Curr Therap Res 1987; 42:995-1002 30. HemsellDL, Cunningham FG, DePalmaRr, NoblesBJ, HeardM, Hemsell PG. Cefotaximesodiumtherapy for endomyometritis following cesarean section: dose-finding and comparative studies. Obstet Gynecol 1983;62:489-97 31. RoseneK, EschenbachDA, Tompkins LS, KennyGE, Watkins H. Polymicrobial early postpartumendometritiswith facultative and anaerobic bacteria, genital mycoplasmas and Chlamydia trachomatis: treatmentwithpiperacillin or cefoxitin. J InfectDis 1986;153:1028-37 32. Fuchs PC, Jones RN, Barry AL, Allen SD, AldridgeKE, Gerlach EH, SommersHM. Effectof clavulanic acid on the susceptibility of clinical anaerobic bacteria to ticarcillin: a multicenter study. Diagn Microbiol Infect Dis 1988;9:47-50 33. Gelfand MS, Lawson RD, Baucom W. Ticarcillin-clavulanate therapy for infections with ticarcillin-resistant microorganisms. South Med J 1989;82:433-7 34. Pastorek JG, Aldridge KE, CunninghamGL, Faro S. Comparison of ticarcillin plus clavulanic acid with cefoxitinin the treatment of female pelvic infections. Am J Med 1986;79:161-3 35. Apuzzio n, Ganesh V, Kaminski Z, Bergen B, Holland B, Lourla DB. Comparison of ticarcillinplus clavulanicacid with clindamycin and gentamicin in the treatment of posteesarean endomyometritis. Surg Gynecol Obstet 1988;166:413-7 36. FaroS, Martens M, HammillH, PhillipsLE, Smith D, RiddleG. TIcarcillin/clavulanicacid versusclindamycin and gentamicinin the treatment of post-cesareanendometritisfollowing antibioticprophylaxis. Obstet Gynecol 1989;73:808-12 37. Cuchural GJ Jr, TallyFP, JacobusNY, Aldridge K, Cleary T, Finegold SM, Hill G, Iannini P, O'Keefe JP, Pierson C, et al. Susceptibility ofthe Bacteroidesfragilis group in the United States: analysisby site of isolation. Antimicrob Agents Chemother 1988;32:717-22 38. TallyFP. Factors affecting the choiceof antibiotics in mixedinfections. J Antimicrob Chemother 1988;22:87-100
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