Ertapenem Once a Day Versus Piperacillin–Tazobactam Every 6 Hours for Treatment of Acute Pelvic Infections: a Prospective, Multicenter, Randomized, Double-Blind Study

Infect Dis Obstet Gynecol 2003;11:27–37

Ertapenem once a day versus piperacillin–tazobactam every 6 hours for treatment of acute pelvic infections: a prospective, multicenter, randomized, double-blind study

Subir Roy1, Iliana Higareda 2, Edith Angel-Muller 3, Mahmoud Ismail 4, Caren Hague 5, Ben Adeyi 5, Gail L. Woods 5 and Hedy Teppler 5, for the Protocol 023 Study Group

1Keck School of Medicine at USC, Los Angeles, CA 2Nuevo Hospital Civil, Guadalajara, Mexico 3Universidad Nacional de Colombia, Bogota, Colombia 4University of Chicago, Chicago, IL 5Merck Research Laboratories, West Point, PA

Objective: Tocompare ertapenemtherapy with piperacillin–tazobactam therapyfor the managementof acute pelvic infections. Methods: Ina multicenter,double-blind study, 412 women with acutepelvic infectionwere assigned to oneof two strata,namely obstetric/postpartuminfection or gynecologic/ postoperativeinfection, and were then randomizedto ertapenem, 1 goncea day,or piperacillin–tazobactam, 3.375 gevery6 hours,both administered intravenously. Results: Intotal,163 patientsin the ertapenemgroup and 153 patientsin the piperacillin–tazobactam groupwere clinically evaluable. The median durationof therapywas 4.0 daysin both treatmentgroups. The mostcommon singlepathogen was Escherichia coli .At the primaryefficacy endpoint2– 4 weeks posttherapy, 93.9% of patients who receivedertapenem and 91.5% of thosewho receivedpiperacillin– tazobactam werecured (95% confidenceinterval for the difference,adjusting for strata, -4% to8.8%), indicating that curerates for both treatmentgroups were equivalent. Cure rates for both treatmentgroups were also similar when comparedby stratumand severity of infection.The frequencyand severity of drug-relatedadverse events were generally similar in both groups. Conclusions: Inthis study,ertapenem was aseffective aspiperacillin– tazobactam forthe treatmentof acutepelvic infection,was generallywell tolerated,and had anoverall safetyprofile similar tothat of piperacillin–tazobactam.

Key words: E RTAPENEM; ACUTE PELVIC INFECTION; POSTPARTUM ENDOMYOMETRITIS ; GYNECOLOGIC INFECTION

Thesedata werepresented inpart atthe 41st Interscience Conference on Antimicrobial Agentsand Chemotherapy,Chicago, IL, December 2001.

Correspondenceto: Gail L.Woods,MD, Merck& Co., Inc., 10Sentry Parkway, BL 3-4, BlueBell, PA 19422,USA. E-mail: [email protected]

ã 2003 The Parthenon Publishing Group 27 Ertapenem for acute pelvic infection Roy et al.

Acutesoft tissue pelvic infectionsin women 3.375 gevery 6hoursfor thetreatment ofwomen includeseveral diagnoses thatmay becategorized with moderate to severe acute pelvic infection. as infectionsrelated todelivery andthose which occurafter gynecologicalsurgery. Risk factors foracute pelvic infectionare delivery by SUBJECTS AND METHODS Cesarean section, hysterectomyor septic incom- Patients plete abortion.Although these proceduresare oftenpreceded or followed(for Cesarean section) Females aged ³ 16years diagnosedwith acute byantimicrobial prophylaxis,the rate ofinfection pelvic infectionwere eligible forinclusion in the may beas highas 20% 1.Acutepelvic infections studyif theyrequired at least 3days ofparenteral are usually polymicrobial.The major causal antimicrobial therapyand if theinfection was pathogensare thosethat comprise thenormal causedby a pathogensusceptible tothe study vaginal flora, namely Streptococcus agalactiae , drugs.Criteria foracute pelvic infectionincluded Escherichia coli ,peptostreptococci, Prevotella spp., anoral temperature of> 38 °C(or equivalent), Bacteroides spp. and Gardnerellavaginalis . Anti- whiteblood cell (WBC) count> 10500/ ml or microbial regimens forthe treatment ofacute >10%immature granulocytes,and at least one pelvic infectionmust thereforeprovide coverage ofthe following: pelvic, abdominalor uterine against abroadspectrum of aerobicand anaerobic pain,cramping or tenderness, oranimaging study bacteria. Examples ofeffective regimens include suggesting pelvic abscess orinfection. Vaginal combinationtherapy with an aminoglycoside and delivery, Cesarean sectionor gynecological anagent such as metronidazoleor clindamycin surgery must have beenperformed between thatprovides anaerobiccoverage, ormonotherapy 24hours and 1 monthbefore enrollment. Patients withagents thatare dosedmultiple times aday, withseptic abortioncould represent nomore suchas cefoxitin,an extended-spectrum peni- than 15% of the total enrollment. cillin, or a b-lactam/b-lactamase inhibitorlike Patients withany of the following were piperacillin–tazobactam. excludedfrom the study: pregnancy or lactation, Ertapenem (Merck& Co., Inc.,formerly historyof serious allergy, hypersensitivity, or MK-0826,Whitehouse Station, NJ) is aonce-a- intoleranceof study therapy (patients witha dayparenteral b-lactam agentthat can be used historyof mild rash inresponse to b-lactams could as monotherapyfor the treatment ofseveral beenrolled), pelvic inflammatory disease, tubo- community-acquiredand mixed aerobicand ovarian abscess, postoperativeabdominal wall anaerobicinfections, including acute pelvic infec- infection,gynecological malignancy, anyrapidly tions, complicatedintra-abdominal, skin and progressive disease, immunocompromisingillness urinarytract infections, and community-acquired ortherapy, AIDS (patients withHIV infection pneumonia.This focused-spectrum carbapenem is couldbe enrolled if theymet theinclusion highlyactive in vitro against many Gram-positive criteria), theneed for concomitant antimicrobials andGram-negative aerobes andanaerobes thatin (otherthan vancomycin, which was permitted for general are associated withcommunity-acquired treatment ofresistant Gram-positive pathogensin infections,but has minimal activity against Pseudo- amixed infection,or antifungal agents), acute monasaeruginosa , Acinetobacter spp.and entero - hepaticfailure, theneed for peritoneal dialysis or cocci2,3.Thebacteria thatare usually susceptible hemodialysis, hypotension,a baseline pathogen toertapenem include S.agalactiae and many resistant toeither studydrug, treatment witha Enterobacteriaceae, otheraerobic streptococci, systemic antimicrobial agentfor ³ 24hourswithin andGram-positive andGram-negative anaerobes, 72hours prior to admission tothe study (unless whichare thepathogens most commonly failure ofthe prior regimen was documented), responsible for acute pelvic infections. aspartate oralanine aminotransferase >6times Theobjective of this studywas tocompare the theupper limit ofnormal(ULN), bilirubinor alka- efficacy, tolerability andsafety ofertapenem 1g line phosphatase> 3times ULN, absoluteneutro- oncea daywith those of piperacillin– tazobactam phil count £ 1000/ml, platelet concentration

28 INFECTIOUSDISEASES IN OBSTETRICS AND GYNECOLOGY Ertapenem for acute pelvic infection Roy et al.

< 75 000/ml, hematocrit< 20%,hemoglobin onthebasis ofprespecified criteria (patients who <6g/dl, or coagulation tests >1.5 ULN. were hemodynamicallyunstable were noteligible forenrollment in the study). The infection was consideredto be severe if thepatient was Study design and antimicrobial therapy bacteremic at baseline orhad fever >39 °C. All Thisprospective, double-blind(with sponsor otherinfections were consideredto beofmoderate blinding),randomized study was conductedfrom severity. Theclinical responses at theTOC visit November 1998to May 2000, at 47sites, ofwhich were categorizedas cure,presumptive cure(reso- 30sites (63.8%) were inthe USA.Intotal, 17 sites lutionof signs andsymptoms ofpelvic infection enrolled76.0% of the patients ( ³ 10patients/ site). confirmedby telephonecontact), failure (defined Writteninformed consent was obtainedfrom all as deathfrom acute pelvic infection,incomplete patients, andthe institutional review boardat resolutionor worseningof symptoms thatrequired eachparticipating site approvedthe protocol and additionalantimicrobial therapy,surgical inter- consentform. Eligible patientswere stratified as ventionfor pelvic infection> 24hours after entry follows.Stratum I consistedof patients with tothe study, or surgical site infectionthat required obstetricor postpartuminfection (including septic additionalantimicrobial therapy)or indeterminate abortion),and patients with gynecological or (data notavailable forevaluation ofefficacy). Tobe postoperativeinfection were includedin Stratum consideredan evaluable failure, patients hadto II. Randomizationin a 1:1ratio(ertapenem: have received at least 48hours of study anti- piperacillin–tazobactam) was performedusing an microbial therapy. allocationschedule that employed computer- generated random numbers. Microbiological assessments Ertapenem 1goncea dayand piperacillin– tazobactam3.375 gevery 6hourswere given Atenrollment, aspecimen foraerobicand anaero- as intravenous(IV) infusionsover aperiodof bicculture was collectedat surgery fromthe site of 30minutes. Theduration of treatment was deter- pelvic infectionor, for patients withendometritis, mined bythe investigator, andwas usually fromthe endometrium by using a protected 3–10 days. Forpatients with a creatinine clearance sampling device; highvaginal swabs were not of< 30ml/min/1.73 m 2,thedose of ertapenem acceptable.Subsequent pelvic cultureswere only was 500mg oncea day.The dose of piperacillin– obtainedif signs ofongoingor newpelvic infec- tazobactamwas adjustedto 2.25 gevery 6hours tionwere present. Bloodcultures were performed if thecreatinine clearance was inthe range if thepatient had chills and/ora temperature of 20–40 ml/ min/1.73 m 2,andto 2.25 gevery ³ 39°C.Allisolates were identifiedat thesite 8hoursif thecreatinine clearance was laboratory,and aerobic pathogens were tested <20ml/min/1.73 m 2.Toensure blinding, for in-vitro susceptibility toertapenem and patients inthe ertapenem groupalso received piperacillin–tazobactam following the guidelines subsequentmatching placebo infusions of 50ml of oftheNational Committee forClinical Laboratory normalsaline every 6hours.After at least 2days Standards4.Inaddition, study sites outsidethe USA ofhospital infusion therapy, study therapy could sent aduplicateclinical sample inan anaerobic becompletedin the hospital, at aclinicor at home. transporttube (Anaerobe Systems, MorganHill, CA)toacentrallaboratory (R. M.AldenResearch Laboratory,Santa Monica, CA) forculture and Clinical assessments susceptibility testing of anaerobes. Patients were evaluated at enrollmentand daily Themicrobiological outcomes were catego- thereafter while onparenteral studytherapy. The rizedas eradication,presumptive eradication(no clinical response was measured at thecompletion material available forculture in patients who were ofparenteral therapyand 2– 4 weeks posttherapy – clinically cured;repeat cultureswere required thetest ofcure (TOC) visit. Theseverity ofthe onlyin the context of clinical failure), persist- patient’s infectionwas assessed priorto unblinding ence, persistence acquiringresistance, presumed

INFECTIOUSDISEASES IN OBSTETRICS AND GYNECOLOGY 29 Ertapenem for acute pelvic infection Roy et al. persistence (culturenot performedin patients con- (definitely not,probably not, possibly, probably sidered tobe clinical failures) orindeterminate ordefinitely) were assessed bythe investigator. (microbiologicalresponse couldnot be deter- Thetolerability ofeach study drug at thelocal mined forany reason). Gram-positive pathogens infusionsite was evaluated daily bythe treated withvancomycin were consideredto have investigator. indeterminate microbiologicaloutcomes. Treat- ment withvancomycin did not affect clinical Statistical analyses assessability. Favorable microbiologicaloutcomes were eradication and presumptive eradication. Thestudy was designedto test forequivalence inefficacy of the ertapenem andpiperacillin– tazobactamclinically evaluable treatment groups. Populations for analysis Thesample size (a minimum of150 evaluable patientsper group) was calculatedusing Thetreated populationincluded all randomized Blackwelder’s formula 5 andfor the following patients whoreceived at least onedose of study values: alpha,0.025; beta, 0.20; expectedresponse therapy.The clinical modifiedintent-to-treat rate inthe comparator arm, 90%.Equivalence for (MITT)population consisted of treated patients this studywas determined bycalculation of the whomet theminimum disease definition.The 95%(two-sided) confidenceinterval (CI) for clinically evaluable (per protocol)population was a thedifference in response rates betweenthe two subset oftheclinical MITTpopulationfor whom treatment groups(ertapenem minus piperacillin– informationwas sufficientto determine outcome tazobactam).If the observed response rate inthe at theTOC visit, andif baseline pathogenswere comparatorgroup was >90%,for equivalence to present, at least oneofthese was susceptible toboth bedemonstrated, the CI ofthe difference had studyantimicrobials. Microbiologicallyevaluable tocontain zero and its lowerlimit couldnot be patients were thoseclinically evaluable patients less than -10%.CIs aboutthe difference were whohad a baseline pathogenidentified and a calculatedusing the normal approximation to the microbiological response assessed. binomial distribution,and were adjustedfor strata usingthe Cochran– Mantel– Haenzel approach 6. Efficacy variables Thetreatment ´ stratum interactionwas investi- gatedusing the Breslow– Day test ofhomogeneity Theprimary efficacyvariable inthis studywas ofoddsratios andthe Gail– Simon test, if needed. theclinical response assessment inthe clinically Anexploratory analysis usingKaplan– Meier evaluable populationat theTOC visit. Additional curves was also performedto examine time efficacyassessments were theclinical response rates todefervescence duringtherapy in clinically inthe supportive clinical MITTpopulationat the evaluable patients whowere cured.No formal tests TOCvisit andin the clinically evaluable popula- were performedbased on baseline demographics tionat completionof IVtherapy,and the propor- or disease characteristics (e.g. severity). tionof microbiologically evaluable patients with afavorable microbiologicalresponse at the TOC visit. RESULTS Patients Safety and tolerability assessment Thedistribution of the study patients is summa- Allpatients who received at least onedose of rizedin Figure 1. Intotal, 38 patients signed a thestudy therapy were evaluated forsafety and consentform but were notrandomized.The most tolerability. Patients were monitoreddaily for commonreasons whypatients were notrandom- adverse experiences duringparenteral therapy izedwere failure tomeet thecriteria fordiagnosis andfor 14 days thereafter. Theintensity (mild, ofacutepelvic infection(18 patients), withdrawal moderate orsevere) oftheadverse event andthe ofconsent (5 patients), andpresence ofa con- likelihoodof its beingrelated tothe study drug currentinfection that would have interferedwith

30 INFECTIOUSDISEASES IN OBSTETRICS AND GYNECOLOGY Ertapenem for acute pelvic infection Roy et al.

Randomized to therapy = 412

Treated with ertapenem = 216 Treated with piperacillin–tazobactam = 196

Clinical MITT population = 211 Clinical MITT population = 191

Microbiological MITT population = 161 Microbiological MITT population = 158

Clinical evaluable population = 163 Clinical evaluable population = 158

Microbiologically evaluable population = 128 Microbiologically evaluable population = 129

Figure 1 Profile of patient enrollment. MITT, modified intent to treat

evaluation ofthe response tostudy antimicrobial studytherapyin the treated andclinically evaluable therapy(four patients). Intotal, 412patients were patientswas comparablein the ertapenem randomized,216 patients inthe ertapenem group andpiperacillin– tazobactam treatment groups and196 patients in the piperacillin– tazobactam (Table 1). Themedian durationwas 4days ineach group,of whom 163 subjects (75.5%) and153 treatment groupof both populations. Six patients subjects(78.1%), respectively, were clinically received vancomycinfor resistant Gram-positive evaluable. Themost commonreasons whypatients pathogens;none of them met thecriteria for were notclinically evaluable were assessments inclusion in the clinically evaluable population. outsidethe protocol-defined follow-up period, andinadequate or inappropriate courses ofstudy Baseline microbiology therapy. Thebaseline demographicsof thepatients who Ofthe clinically evaluable patients, 128patients signeda consentform but were notrandomized (78.5%) inthe ertapenem groupand 129 patients appearedto becomparableto those of therandom- (84.3%) inthe piperacillin– tazobactam group had izedpopulation (data notshown). The baseline at least onepathogen isolated at baseline. Intotal, demographicsand disease characteristics ofthe 93microbiologically evaluable patients(72.7%) twotreatment groupsin the randomized and clini- whoreceived ertapenem and93 patients (72.1%) cally evaluable populationswere generally similar whoreceived piperacillin–tazobactam had poly- (Table 1). Themajority of patients inboth microbicinfections. The distribution of the populationswere instratum I(obstetric/ pathogensin each treatment groupof themicro- postpartuminfection), and the most common biologicallyevaluable populationand their diagnosis at entrywas endomyometritis (present susceptibility profiles were comparable.Anaerobes inapproximately 75% of patients inboth accountedfor 60.8% (257/ 423) ofthe isolates in populations).In approximately 25% of patients theertapenem groupand 58.6% (238/ 406) ofthe the infection was rated as severe. isolates inthe piperacillin– tazobactam group. The most commonsingle isolate ineach group was E. coli (41 (9.7%) and39 (9.6%) inthe ertapenem Therapy andpiperacillin– tazobactam groups, respectively). Thedosage of study drug was adjustedfor renal Mostisolates were susceptible tobothstudy drugs, insufficiencyin four patients (onein the ertapenem withthe exception of enterococci, which were groupand three inthe piperacillin– tazobactam oftenintermediate orresistant toertapenem. In group),all ofwhom were considerednot to be total,ten microbiologically evaluable patientsin clinically evaluable forreasons otherthan elevated theertapenem group(five withendometritis and creatinine clearance values. Theduration of five withseptic abortion)and six patients inthe

INFECTIOUSDISEASES IN OBSTETRICS AND GYNECOLOGY 31 Ertapenem for acute pelvic infection Roy et al.

Table 1 Baselinecharacteristics andtherapy ofrandomized and clinically evaluable patients with acutepelvic infection, by treatment group

Randomizeda Clinically evaluable

Ertapenem Pip–Taz Ertapenem Pip–Taz Characteristic (n = 216) (n = 196) (n = 163) (n = 153)

Ethnicity (percent) Caucasian 46 (21.3) 41 (20.9) 34 (20.9) 32 (20.9) Black 66 (30.6) 52 (26.5) 42 (25.8) 38 (24.8) Hispanic 73 (33.8) 69 (35.2) 57 (35.0) 55 (35.9) Mestizo 29 (13.4) 32 (16.3) 28 (17.2) 26 (17.0) Other ethnic group 2 (0.9) 2 (1.0) 2 (1.2) 2 (1.4)

Mean age (± SD) (years) 25.4 (± 7.5) 27.0 (± 8.9) 25.7 (± 7.6) 27.6 (± 9.2)

Stratumb (percent) Obstetric/postpartum infection 181 (83.8) 169 (86.2) 136 (83.4) 132 (86.3) Vaginal delivery 79 (36.6) 66 (33.7) 60 (36.8) 50 (32.7) Cesarean section 85 (39.4) 87 (44.4) 60 (36.8) 68 (44.4) Gynecological/postoperative infection 34 (15.7) 27 (13.8) 27 (16.6) 21 (13.7)

Severe infection (percent) 60 (27.8) 48 (24.5) 42 (25.8) 35 (22.9)

Antimicrobial prophylaxis given c (percent) 89 (41.2) 93 (47.4) 65 (39.9) 68 (44.4)

Diagnosis at entry (percent) Endomyometritis 164 (75.9) 148 (75.5) 120 (73.6) 115 (75.2) Septic abortion 22 (10.2) 23 (11.7) 20 (12.3) 19 (12.4) Pelvic cellulitis 7 (3.2) 10 (5.1) 6 (3.7) 9 (5.9) Pelvic abscess 8 (3.7) 7 (3.6) 4 (2.5) 5 (3.3) Parametritis 7 (3.2) 6 (3.1) 6 (3.7) 4 (2.6) Other 7 (3.2) 2 (1.0) 7 (4.3) 1 (0.7)

Median days on therapy (range) 4.0 (1–13) 4.0 (1–12) 4.0 (2–12) 4.0 (3–12) aTreated patients for days on therapy. For ertapenem, n = 214; for piperacillin–tazobactam, n = 192; bOne patient in the ertapenem group was not included in the stratification counts because no primary diagnosis information was provided and the patient received no therapy; cIncludes prophylaxis for surgical procedures and obstetric conditions; Pip–Taz, piperacillin–tazobactam; SD, standard deviation

piperacillin–tazobactam group (two with endo- spp.(the latter twoorganisms were recovered metritis, twowith septic abortionand two with from one patient). pelvic cellulitis) were bacteremic at baseline. In patientswho received ertapenem, causal patho- Efficacy gens were E. coli (n =6) andone each of thefollowing: Listeriamonocytogenes , Enterobacter Atthe primary efficacyendpoint, 93.9% of the cloacae, Klebsiellapneumoniae and Prevotellaloescheii . clinically evaluable patients inthe ertapenem Inthose who received piperacillin–tazobactam, groupand 91.5% of those in the piperacillin– causal pathogenswere E. coli (n =2) andone each tazobactamgroup were cured(95% CIforthe ofthe following: E. cloacae, Streptococcus pyogenes , difference,adjusting for strata, -4.0%to 8.8%), Peptostreptococcus asaccharolyticus , Streptococcus spp., indicatingequivalence betweenthe two treat- Arcanobacteriumbernardiae and Corynebacterium ments. Clinical success rates at theTOC assessment

32 INFECTIOUSDISEASES IN OBSTETRICS AND GYNECOLOGY Ertapenem for acute pelvic infection Roy et al.

Table 2 Cure rates in clinically evaluable patients, by stratum or subgroup

Ertapenem Piperacillin–tazobactam

Stratum/subgroup n/m % response (95% CI) n/m % response (95% CI)

At DCIV Stratum Obstetric/postpartum infection 130/137 94.9 (91.2, 98.6) 122/132 92.4 (87.9, 97.0) Gynecological/postoperative infection 25/26 96.2 (88.6, 100) 19/21 90.5 (77.6, 100) Overall 155/163 95.1 (91.8, 98.4) 141/153 92.2 (87.9, 96.4) At test of cure Stratum Obstetric/postpartum infection 129/137 94.2 (90.2, 98.1) 121/132 91.7 (86.9, 96.4) Gynecological/postoperative infection 24/26 92.3 (81.9, 100) 19/21 90.5 (77.6, 100) Severity Moderate infection 113/121 93.4 (87.4, 97.1) 110/118 93.2 (87.1, 97.0) Severe infection 40/42 95.2 (83.8, 99.4) 30/35 85.7 (69.7, 95.2) Diagnosis Endomyometritis 111/120 92.5 (86.2, 96.5) 104/115 90.4 (83.5, 95.1) Septic abortion 20/20 100 (83.2, 100) 19/19 100 (82.4, 100) Overall 153/163 93.9 (90.2, 97.6) 140/153 91.5 (87.1, 95.9) n/m, ratio of number of patients cured/number of patients with assessment; CI, confidence interval; DCIV, discontinuation of IV therapy

inthe supportive clinical MITTanalysis, which theTOC assessment), severity ofinfection and included97.6% of the randomized patients (211 primary diagnosis. Morethan 90% of the patients patientstreated withertapenem and191 patients ineach stratum orsubgroup of both treatment treated withpiperacillin– tazobactam), were groupshad a favorable clinical response, withone 85.9%in the ertapenem groupand 88.0% in the exception.In patients with severe infection,cure piperacillin–tazobactam group. This reflects the rates were 95.2%for those in the ertapenem group more conservative approachin the MITT out- and85.7% for those in the piperacillin– tazobactam come assessment, inwhich patients with in- group.Statistical analyses withinsubgroups, such adequateinformation or indeterminate outcomes as patients withsevere infection,were notspecified were consideredto be cases oftreatment failure. aprioriand therefore were notperformed. The Thedifference (95% CI) betweenthe response most commonreason whypatients were con- rates inthe two clinical MITTgroupsof -2.1% sidered tohave clinical failure attheTOC assess- (-9.2%to 5.0%) indicates thatthe two treatment ment was persistent, unresolvedor worsening groupswere similar, whichis consistentwith the infection(7/ 10or 70% of patients treated with results ofthe primary efficacyanalysis. Among ertapenem and7/ 13or53.8% of patients treated patientswith postpartum endomyometritis, cure withpiperacillin– tazobactam). Other reasons were rates were higherin those whohadvaginal delivery surgical intervention> 24hours after studyentry (ertapenem, 95.0%or 57/ 60; piperacillin– (1/10or 10%of patients in the ertapenem group tazobactam,96.0% or 48/ 50) thanin those who and4/ 13or 30.8% of those in the piperacillin– underwentCesarean section(ertapenem, 91.7%or tazobactamgroup), and surgical site infection 55/60; piperacillin–tazobactam, 86.8% or 59/68). requiringadditional antimicrobial therapy(2/ 10 Table2 showsthe cure rates forclinically or20% of patients in the ertapenem groupand evaluable patients inthe two treatment groupsby 2/13or 15.4% of patients inthe piperacillin– stratum (at completionof study therapy and at tazobactam group).

INFECTIOUSDISEASES IN OBSTETRICS AND GYNECOLOGY 33 Ertapenem for acute pelvic infection Roy et al.

Table 3 Eradication/presumederadication rates a at curedappeared to be similar forertapenem and test ofcure, by baseline pathogen isolated from the piperacillin–tazobactam (data notshown). Defer- site of the pelvic infection and/or from blood vescence was promptin each treatment group,as 90%of patients were afebrile, regardless ofstudy Proportion (%) eradicated by: therapy, by study day 2. Piperacillin– Theproportion of microbiologicallyevaluable Organism Ertapenem tazobactam patientswho at theTOC assessment hada favorable overall microbiologicalresponse (i.e. all base- Listeria monocytogenes 1/1 (100) NI line pathogenswere eradicatedor presumedto be Other aerobic GPB 4/5 (80.0) 2/2 (100) eradicated) was 93.7%in the ertapenem group Staphylococcus aureus 9/9 (100) 16/16 (100) and93.8% in the piperacillin– tazobactam group. Other staphylococci 17/17 (100) 15/16 (93.8) Bacterial eradication/presumederadication rates Streptococcus agalactiae 11/11 (100) 16/16 (100) Other streptococci 25/27 (92.6) 18/21 (85.7) at theTOC assessment, shownby the baseline Enterococci 23/23 (100) 30/31 (96.8) pathogenin Table 3, were generally similar inboth Other aerobic GPC 3/3 (100) NI treatment groups.Of the patients with an unfavor- Escherichia coli 37/41 (90.2) 36/39 (92.3) able microbiologicalresponse, persistence was Other Enterobacteriaceae 20/22 (90.9) 20/20 (100) documentedfor only one pathogen ( E. coli). For Nonfermentative GNB 3/4 (75.0) 4/4 (100) all otherpathogens, persistence was presumed Other aerobic GNB NI 2/2 (100) based on the clinical outcome. Neisseria spp. 1/1 (100) 1/1 (100) Clostridium spp. 11/11 (100) 10/10 (100) Other anaerobic GPB 7/7 (100) 11/13 (84.6) Safety and local tolerability Peptostreptococcus spp. 81/83 (97.6) 76/82 (92.7) Other anaerobic GPC NI 1/1 (100) Intotal, 214patients in the ertapenem groupand Bacteroides fragilis group 30/30 (100) 29/32 (90.6) 192patients inthe piperacillin– tazobactam group Bacteroides fragilis 15/15 (100) 19/20 (95.0) received at least onedose of study parenteral b c Other members of 15/15 (100) 10/12 (83.3) therapyand were evaluated foradverse experi- B. fragilis group ences. Duringparenteral therapyand for 14 days Fusobacterium spp. 15/15 (100) 9/11 (81.8) thereafter, oneor more drug-relatedadverse Porphyromonas spp. 26/26 (100) 22/23 (95.7) experiences were reportedfor 48 patients (22.4%) Prevotella spp. 54/54 (100) 46/50 (92.0) Other anaerobic GNB 30/30 (100) 14/14 (100) inthe ertapenem groupand 43 patients (22.4%) in Anaerobic GNC 3/3 (100) 2/2 (100) thepiperacillin– tazobactam group. The most commondrug-related adverse events were NI, no isolates; GPB, Gram-positive bacilli; GPC, Gram-positive mild gastrointestinal symptoms. Eightpatients cocci; GNB, Gram-negative bacilli; GNC, Gram-negative cocci. (3.7%) whowere treated withertapenem and aRepeat endometrial cultures were not collected from patients who were cured; bB. thetaiotaomicron (4/4), B. vulgatus (4/4), fourpatients (2.1%) whowere treated with B. distasonis (3/3), B. uniformis (2/2); cB. thetaiotaomicron (5/6), piperacillin–tazobactam had diarrhea. Vomiting B. vulgatus (1/2), B. distasonis (4/4) occurredin five patients(2.3%) inthe ertapenem groupand four patients (2.1%) inthe piperacillin– Thetime toresolution of baseline clinical tazobactamgroup, and six patients (2.8%) who signs andsymptoms was similar ineach treatment received ertapenem andthree patients(1.6%) group.Patient signs andsymptoms, assessed daily, whoreceived piperacillin–tazobactam experi- hadresolved in134 of 158patients (84.8%) inthe encednausea. Five patients (2.3%) whoreceived ertapenem groupand in 124 of 147 patients ertapenem andfive patients(2.6%) whoreceived (84.4%) inthe piperacillin– tazobactam group at piperacillin–tazobactam had headache. completionof study therapy, and in 141 of 154 Onepatient in the ertapenem groupdis- patients (91.6%) and132 of 146patients (90.4%), continuedstudy therapy due to elevation ofthe respectively, attheTOC assessment. Inaddition, serum creatinine levels andrenal insufficiencyon theKaplan– Meier curves fortime todefervescence studyday 3. Theinvestigator consideredthis tobe inthe clinically evaluable patientswho were aserious adverse event thatwas probablyrelated

34 INFECTIOUSDISEASES IN OBSTETRICS AND GYNECOLOGY Ertapenem for acute pelvic infection Roy et al. tostudy therapy; concomitant medications includingthose with severe infection,and was includedibuprofen. Antimicrobial therapy was equivalent totreatment withpiperacillin– changedfrom ertapenem toampicillin plus tazobactamgiven every 6hours.In addition, the clindamycin,both of whichwere discontinuedon time todefervescence andresolution of othersigns studyday 5 because thecreatinine concentration andsymptoms was similar forboth agents. continuedto rise. Onstudyday 6, anephrologist Approximately94% of clinically evaluable patients was consulted.It was this consultant’s opinionthat treated withertapenem were cured,compared thepatient had acute interstitial nephritisor an with92% of those who were treated with acuterenal insult, most probablycaused by piperacillin–tazobactam. These curerates are ibuprofenuse. Theserum creatinine concentra- similar toor higherthan those reported in previous tionhad returned to normal by studyday 10. Study studies ofpatientswith acute pelvic infection 7–11, therapywas discontinuedin three additional andthey are withinthe rangeof theexpectedcure patientsin the ertapenem group,due to an over- rate (i.e. approximately90%) when evaluating a doseof studydrug resulting froma pharmacydis- newanti-infective drugfor treatment ofacute pensingerror. No adverse effects associated with pelvic infection 12.Aspredicted, the success rates theoverdose were reported.None of the patients inpatients withseptic abortionwere excellent inthe piperacillin– tazobactam group had study (100%) in both treatment groups. therapydiscontinued because ofa drug-related Ertapenem is highlyactive in vitro against adverse experience. many Gram-positive andGram-negative aerobic, Drug-relatedlaboratory adverse experiences facultative andanaerobic bacteria thatare generally duringparenteral therapyand for 14 days there- associated withinfections acquired in the commu- after were reportedin 26 patients (13.2%) inthe nity2,3.Inthis study,aerobic streptococci, Entero- ertapenem groupand 29 patients (15.7%) in bacteriaceae, peptostreptococciand anaerobic thepiperacillin– tazobactam group. The most Gram-negative anaerobes, over 99%of which commondrug-related adverse laboratoryevents were susceptible toertapenem andpiperacillin– were thrombocytosis(19/ 190or 10.0%of patients tazobactam,accounted for approximately 80% inthe ertapenem groupand 20/ 178or 11.2%of ofall isolates frommicrobiologically evaluable patientsin the piperacillin– tazobactam group) and patients inboth treatment groups.Other investiga- elevation ofliver enzymes as follows:alkaline torshave also foundthat these same isolates are phosphatase,eight patients (4.6%) inthe erta- responsible formost acutepelvic infections 7–11. penem groupand four patients (2.4%) inthe In vitro,ertapenem has limited activity against piperacillin–tazobactam group; alanine amino- P.aeruginosa andenterococci. P.aeruginosa is rarely transferase, six patients (3.3%) andthree patients recovered frompatients with acute pelvic (1.8%), respectively; aspartate aminotransferase, infection.In this study,there were noisolates in six patients(3.2%) andtwo patients (1.1%), either treatment group.However, Enterococcus is respectively. occasionallyencountered in cultures from such Intotal, 26patients (12.2%) inthe ertapenem patients. Inthis study,23 patients whowere treated groupand 24 patients (12.5%) inthe piperacillin– withertapenem hada polymicrobialinfection tazobactamgroup experienced reactions of thatincluded Enterococcus ,andall ofthem hada moderate tosevere intensity at thelocal infusion favorable clinical andmicrobiological outcome at site duringparenteral therapy.The most common theTOC assessment. Thissuggests thatin poly- symptomin both treatment groupswas pain, microbial acutepelvic infections,additional followed by tenderness and induration. specific anti-enterococcaltherapy is notrequired. Similarly, many physiciansconsider enterococci tobe part of the normal vaginal florarather DISCUSSION thanpathogens, unless theyare recovered inthe Inthis multicenter clinical trial, ertapenem presence of a prosthesis 13. therapy,1 goncea day,was highlyeffective for Foracute pelvic infections,once-a-day dosing treatment ofwomenwith acute pelvic infection, withan antimicrobial agentsuch as ertapenem

INFECTIOUSDISEASES IN OBSTETRICS AND GYNECOLOGY 35 Ertapenem for acute pelvic infection Roy et al. offersseveral potentialadvantages over other PA;DeanCoonrod, Phoenix, AZ; Lawrence commontreatment regimens thatrequire Devoe, Augusta,GA; PatrickDuff, Gainsville, FL; multiple daily doses and/ora combinationof StanleyGall, Louisville, KY;Larry Gilstrap, antimicrobial agents. Suchadvantages may include Houston,TX; Alice Goepfert,Birmingham, AL; facilitationof outpatient therapy (either intra- PhillipGreig, Greenville, SC;MarkHarrison, venouslyor byintramuscular injection),decreased Berrien Center, MI;David Hemsell, Dallas, TX; treatment costs 14 anda potentialreduction in Peter Heyl, Norfolk,VA; MahmoudIsmail, themedication error rate inhospitalized patients 15. Chicago,IL; AbnerKorn, San Francisco, CA; Theoverall safety profileand tolerability of William Ledger, New York,NY; Maurizio ertapenem inthis studywere similar tothose Maccato,Houston, TX; Everett Magann,Jackson, ofpiperacillin– tazobactam. Mild gastrointestinal MS;MarkMartens, Minneapolis,MN; James symptoms were themost frequentlyreported McGregor,Denver, CO;S.GeneMcNeeley, drug-relatedclinical adverse events forboth Detroit, MI;LynnaeMillar, Honolulu,HA; Susan agents. Themost commondrug-related laboratory Mou,Rochester, NY;EdwardNewton, adverse events forboth drugs were thrombo- Greenville, NC;William O’Brien, Tampa, FL; cytosis andmild tomoderate elevation ofliver R.Lamar Parker, Winston-Salem, NC; Subir enzymes, bothof which were transient andwith- Roy,Los Angeles, CA;ThomasStovall, Memphis, out clinical consequence. TN;RichardSweet, Pittsburgh,PA; Kristi Van Insummary, ertapenem 1goncea daywas Nostrand,Oklahoma City, OK;AmadeoAldini, highlyeffective bothclinically andmicro- BuenosAires, Argentina;Pedro Lipszye, Buenos biologicallyin the treatment ofwomen with Aires, Argentina;Osvaldo Malafaia, Curitiba moderate tosevere acutepelvic infection.Erta- Parana’, Brazil; KaySander, San Jose, Costa Rica; penem therapywas as effective as therapywith EdithAngel-Muller, Bogota, Colombia; Vincente piperacillin–tazobactam, and had a comparable Carmona, Bogota,Colombia; AntonioCiudad, overall safety and tolerability profile. Lima, Peru;Juan Trelles, Lima, Peru;Denis Jacob, Paris, France; Prof.Philippe Judlin, Nancy, France; Eric deJonge, Pretoria, SouthAfrica; ACKNOWLEDGEMENTS ThembeniMisibi, Johannesburg,South Africa; This study was supported by Merck & Co., Inc. Bareno Lindeque,Pretoria, SouthAfrica; Members ofthe Protocol 023 Study Group AlexanderDavidov, Moscow,Russia; Galina includethe following: Joseph Apuzzio, Newark, Saveliea, Moscow,Russia; EnriqueGarcia-Lara, NJ; David Baker, StonyBrook, NY; GuyBenrubi, MexicoCity, Mexico;Iliana Higareda, Jacksonville, FL; AshwinChatwani, Philadelphia, Guadalajara, Jalisco, Mexico.

REFERENCES 1. FaroS. Antibiotic usagein pelvic infections: an DocumentM2-A6. Wayne,PA: National overview. J Reprod Med 1988;33(Suppl.6):566– 70 Committeefor Clinical LaboratoryStandards, 2. Livermore DM,Carter MW,BagelS, et al. In-vitro 1997 activities ofertapenem (MK-0826) against recent 5. BlackwelderWC. ‘Proving thenull hypothesis’ in clinical bacteria collected in Europeand Australia. clinical trials. Control Clin Trials 1982;3:345–53 Antimicrob Agents Chemother 2001;45:1860–67 6. CochranWG. Somemethods for strengthening 3. FuchsPC, Barry AL, BrownSD. In-vitro activities thecommon Chi-square tests. Biometrics 1954;10: ofertapenem(MK-0826) against clinical bacterial 417–51 isolatesfrom 11 NorthAmerican medicalcenters. 7. CrombleholmeWR, Ohm-SmithM, Robbie Antimicrob Agents Chemother 2001;45:1915–18 MO, et al.Ampicillin/sulbactamversus 4. NationalCommittee for Clinical Laboratory metronidazole–gentamicin in thetreatment of Standards. PerformanceStandard forAntimicrobial Disk softtissue pelvic infections. Am JObstet Gynecol Susceptibility Tests:Approved Standard . NCCLS 1987;156:507–12

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8. HemsellDL, WendelGD, GallSA, et al. Multi- 12. HemsellDL, SolomkinJS, SweetR, et al. center comparisonof cefotetan and cefoxitin in Evaluationof new anti-infective drugsfor thetreatment of acute obstetric andgynecologic thetreatment of acute pelvic infectionsin infections. Am J Obstet Gynecol 1988;158:722–7 hospitalizedwomen. ClinInfect Dis 1992;15 9. Apuzzio JJ,Stankiewicz R,GaneshV, et al. (Suppl. 1):S43–52 Comparisonof parenteral ciprofloxacin with 13. GallS. Therapeutic dilemmasin thetreatment clindamycin–gentamicin in the treatment of ofpelvic infections. J Reprod Med 5(Suppl.): pelvic infection. Am J Med 1989;87(Suppl.5A): 1091–4 S148–51 14. ForanRM, Brett JL, WulfPH. Evaluatingthe 10. SweetRL, RoyS, Faro S, et al.Piperacillin and costimpact of intravenous antibiotic dosing tazobactamversus clindamycin and gentamicin in frequencies. DICP 1991;25:546–52 thetreatment of hospitalized women with pelvic 15. NettlemanMD, BockMJ. Theepidemiology infection. Obstet Gynecol 1994;83:280–6 ofmissed medication doses in hospitalized 11. RoyS, KoltunW, ChatwaniA, et al.Treatmentof patients. ClinPerform Qual Health Care 1996;4: acute gynecologicinfections with trovafloxacin. 148–53 Am J Surg 1998;176(Suppl. 6A):S67–73

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