Efficacy of ertapenem in the treatment of serious infections caused by Enterobacteriaceae: analysis of pooled clinical trial data

Richard M. Gesser, Kathleen McCarroll, Hedy Teppler and Gail L. Woods*

Merck Research Laboratories, West Point, PA 19486-0004, USA

Received 3 December 2002; returned 1 January 2003; revised 13 January 2003; accepted 3 March 2003


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective: The efficacy of ertapenem, 1 g once a day, for treatment of adults with serious infections caused by Enterobacteriaceae was compared with ceftriaxone 1 g once a day [complicated urinary tract infection (CUTI) and community-acquired pneumonia (CAP)] or piperacillin–tazobactam, 3.375 g every 6 h (complicated intra-abdominal, complicated skin/skin structure and acute pelvic infections).

Patients and methods: This combined analysis included the subgroup of all 1167 treated patients infected with Enterobacteriaceae from seven randomized double-blind studies.

Results: Escherichia coli was the most common pathogen, accounting for 65.3% of all Enterobacteriaceae. Among evaluable patients with deep tissue (intra-abdominal, skin and pelvic) infections, the combined clinical cure rates were 84.8% (223 of 263) for ertapenem and 82.9% (194 of 234) for piperacillin–tazobactam [95% confidence interval (CI) for the difference, adjusting for infection, –4.9% to 8.9%]. Cure rates by infection for ertapenem and piperacillin–tazobactam, respectively, were: intra-abdominal, 85.1% (143 of 168) and 79.9% (119 of 149); pelvic, 86.8% (46 of 53) and 94% (47 of 50); skin/skin structure, 81% (34 of 42) and 80% (28 of 35). Among patients with CUTI, microbiological cure rates were 90.5% (220 of 243) for ertapenem and 92% (196 of 213) for ceftriaxone (95% CI for the difference, –7.1% to 4.1%). In patients with CAP, clinical cure rates were 95% (19 of 20) for ertapenem and 88.9% (16 of 18) for ceftriaxone.

Conclusion: Ertapenem therapy was as effective as either piperacillin–tazobactam or ceftriaxone for serious infections caused by Enterobacteriaceae.

Keywords: ertapenem, Enterobacteriaceae, Escherichia coli, intra-abdominal infection, skin infection


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Enterobacteriaceae, especially Escherichia coli, Klebsiella spp. and Proteus spp., are important pathogens in serious community-acquired infections that require parenteral antimicrobial treatment. These pathogens are the most common cause of urinary tract infection (UTI), both simple cystitis and complicated UTI (CUTI), and are a frequent component, often with anaerobes, of many serious, deep tissue infections, including complicated intra-abdominal infections, acute pelvic infections, and complicated skin/skin structure infections.16 K. pneumoniae, and occasionally other Enterobacteriaceae, may be significant pathogens in community-acquired pneumonia (CAP) in certain populations, including the elderly, persons residing in long-term care facilities and persons who abuse alcohol.7,8

Ertapenem (formerly MK-0826; Merck & Co., Inc.) is a parenteral carbapenem that was licensed for once daily use in November 2001 in the USA and in April 2002 in Europe. Compared with imipenem and meropenem, ertapenem has a more focused spectrum of activity in that it is highly active in vitro against many Gram-positive and-negative aerobes and anaerobes that, in general, are associated with community-acquired infections, but has limited activity against Pseudomonas aeruginosa, Acinetobacter spp. and enterococci, which are more commonly associated with hospital-acquired infections.911 In seven independent clinical trials, ertapenem 1 g once a day was shown to be highly effective for treatment of CUTI, intra-abdominal, acute pelvic and skin/skin structure infections, and CAP, and equivalent to either piperacillin–tazobactam or ceftriaxone.1218 Because of the importance of Enterobacteriaceae as pathogens in these commonly encountered infectious processes, the present analysis was carried out to assess the efficacy of ertapenem in the large subgroup of patients from these seven trials who had one or more enteric Gram-negative pathogen, and to compare the efficacy of ertapenem 1 g once a day with that of ceftriaxone 1 g once a day (CUTI and CAP) or piperacillin–tazobactam 3.375 g every 6 h (intra-abdominal, skin/skin structure and acute pelvic infections).


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Study design

Seven prospective, double-blind (with sponsor blinding), multicentre studies were conducted worldwide (primarily in the USA, Europe and Latin America) from April 1998 to May 2000, in accordance with guidelines published by the Infectious Disease Society of America (IDSA).19 Written informed consent was obtained from all patients, and the institutional review board at each site approved the protocol and consent form. Eligible patients were randomized to ertapenem or comparator using an allocation schedule that employed computer-generated random numbers. Randomization, 1:1 (ertapenem:comparator) in five studies and 2:1 (ertapenem:ceftriaxone) in one CUTI and one CAP study, was stratified as follows: CUTI, acute pyelonephritis versus other CUTI without acute pyelonephritis; intra-abdominal, complicated appendicitis without generalized peritonitis versus all other diagnoses and APACHE II score <=15 versus APACHE II score >15; pelvic, obstetric/postpartum infection (including septic abortion) versus gynaecological/postoperative infection; skin/skin structure, presence of an underlying complicating condition (most often diabetes mellitus) versus all other diagnoses; CAP, Pneumonia Severity Index (PSI) <=3 versus PSI >3 and age <=65 years versus age >65 years.

Patients

Inclusion and exclusion criteria, as well as the design for each study, described in detail elsewhere, were in accord with IDSA guidelines.1219 In general, adult patients >=18 years of age (>=16 years for PI), diagnosed with CUTI, complicated intra-abdominal, acute pelvic or complicated skin/skin structure infection, or CAP based on standard clinical and radiographical criteria where pertinent were eligible for the study if they required parenteral antimicrobial therapy and if the causal pathogens were susceptible to both study drugs. Patients with conditions or situations that confounded the clinical assessment were excluded. If the infection was polymicrobial and included one or more resistant organism, the patient could remain in the study at the discretion of the investigator if at least one organism was susceptible to both study drugs.

Antimicrobial therapy

Ertapenem 1 g once a day, ceftriaxone 1 g once a day or piperacillin–tazobactam 3.375 g every 6 h was given as an intravenous infusion over 30 min. Some CUTI and CAP patients received ertapenem or ceftriaxone by intramuscular injection. To ensure blinding, for trials with ceftriaxone as the comparator, patients received one infusion of study drug and one infusion of colour-matched placebo each day; and when piperacillin–tazobactam was the comparator, patients in the ertapenem group also received subsequent placebo infusions of normal saline every 6 h. In the CUTI and CAP studies, patients could be switched to oral ciprofloxacin or coamoxiclav, respectively, after at least 3 days of parenteral therapy provided they met pre-specified improvement criteria.14,1618 Concomitant antibacterial agents in addition to study therapy were not allowed, except vancomycin for treatment of resistant Gram-positive pathogens in a polymicrobial intra-abdominal or pelvic infection. Duration of treatment was determined by the investigator; suggested ranges were 10–14 days for CUTI and CAP (parenteral plus optional oral), 5–14 days for intra-abdominal infection, 3–10 days for acute pelvic infection and 7–14 days for skin/skin structure infection.

Clinical and microbiological assessments

Clinical assessments were made daily while on study therapy and at pre-specified intervals post-therapy, as previously defined.1218 The test of cure (TOC) assessment occurred after completion of all study therapy (parenteral plus optional oral, if allowed), as follows: CUTI, 5–9 days; intra-abdominal infection, 4–6 weeks; acute pelvic infection, 2–4 weeks; skin/skin structure infection, 10–21 days; CAP, 7–14 days. Cultures were collected at baseline from the site of infection and from blood. All isolates were identified and aerobic pathogens were tested at the site laboratory for susceptibility to study drugs following NCCLS guidelines.20,21 Susceptibility and resistance were based on NCCLS breakpoints; isolates were not routinely tested for production of extended-spectrum ß-lactamases. Potential microbiological outcomes were eradication, presumed eradication (no material available for culture in patients clinically cured), persistence, persistence acquiring resistance, presumed persistence (culture not performed in patients considered clinical failures) or indeterminate (microbiological response cannot be determined for any reason). For intra-abdominal, pelvic and skin/skin structure infections and CAP, persistence was defined as recovery at the time of clinical failure of the same species identified at baseline; for CUTI, a pathogen was considered persistent if a urine culture performed any time after two full days of study therapy grew >=104 cfu/mL of an original uropathogen. Resistance was assumed to have developed in a persistent pathogen if the susceptibility result for the study drug had changed from susceptible at baseline to resistant and the results for all other agents were essentially unchanged. Molecular typing to confirm that the baseline and post-baseline isolates were identical was not performed.

Populations for analysis

This combined analysis is based on the large subgroup of 1167 patients from all seven studies whose baseline cultures grew one or more Enterobacteriaceae. The clinical modified intention-to-treat (MITT) population included patients who met the disease definition and received at least one dose of study therapy. The microbiological MITT population was the subset of the clinical MITT population who had one or more pathogens identified in a baseline culture, regardless of susceptibility to study drugs, and had a microbiological response assessed. For the purpose of this analysis, the microbiological MITT population included only those patients with Enterobacteriaceae identified at baseline. The evaluable population comprised MITT patients who had microbiological and clinical outcome assessments in the TOC window, at least one Enterobacteriaceae that was susceptible to both study antimicrobials and who had not received confounding, effective concomitant therapy.

Statistical analyses

Each of the seven comparative studies was designed to test for the non-inferiority of ertapenem versus comparator antimicrobial agents. In this combined analysis of patients with Enterobacteriaceae from all seven studies, the primary efficacy variables were the clinical response assessment in evaluable patients at the TOC visit for intra-abdominal, skin/skin structure and pelvic infections and CAP, and the microbiological response assessment for CUTI. Non-inferiority was defined as follows: the 95% (two-sided) confidence interval (CI) for the difference in response rates between the two treatment groups (ertapenem minus comparator) contains 0, and the lower limit of the CI is not less than –10% for a response rate in the comparator group of >=90%. Supportive efficacy analyses were performed for the MITT population, in which, conservatively, patients lost to follow-up or missing follow-up assessments were assumed to have had an unfavourable outcome. CIs stratified by infection were calculated for the combined proportions and for the difference between treatment groups. The stratified methods were based on Cochran–Mantel–Haenszel weights, which are proportional to the sample sizes. CIs for response rates for individual infections were calculated using exact methods based on the binomial distribution. Bacterial eradication rates at the TOC visit were also assessed for Enterobacteriaceae for which there were >=10 isolates in at least one treatment group; CIs were calculated if there were >=10 isolates in both treatment groups.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients

The distribution of patients is shown in Table Go. Of the 3255 patients treated in the seven studies, 1167 (35.9%) had Enterobacteriaceae identified as a baseline pathogen. In this subgroup of patients with Enterobacteriaceae, 991 (84.9%) were evaluable for the primary analysis. Baseline demographic and disease characteristics of these evaluable patients in the ertapenem and comparator treatment groups were generally similar for all infections (data not shown).


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Table 1.  Numbers of treated patients in IAI, PI, SSSI, CUTI and CAP studies
 
Therapy

The median (range) duration of ertapenem and comparator therapy, respectively, for evaluable patients was 7 (5–16) days and 7 (4–18) days for intra-abdominal infection, 5 (3–12) days and 4 (4–12) days for acute pelvic infection, 9 (5–15) days and 9 (4–17) days for skin/skin structure infection, 13 (4–22) days and 13 (1–17) days for CUTI, and 14 (3–15) days and 13.5 (1–17) days for CAP. Of evaluable patients with CUTI, 236 (97.1%) in the ertapenem group and 203 (95.3%) in the ceftriaxone group were switched to oral therapy; in the CAP studies, 17 (85%) patients in the ertapenem group and 13 (72.2%) in the ceftriaxone group were switched to oral therapy.

Baseline microbiology

Enterobacteriaceae isolated from the treated patients and their susceptibility profiles are shown in Table Go. E. coli, the most commonly isolated pathogen, accounted for 65.3% of all isolates. In vitro, ertapenem was more active than ceftriaxone or piperacillin–tazobactam; of the Enterobacteriaceae tested, 99% (1405 of 1419) were susceptible to ertapenem, 95.8% (657 of 686) were susceptible to ceftriaxone and 94.5% (715 of 757) were susceptible to piperacillin–tazobactam. Among evaluable patients, the majority of intra-abdominal (88.3%), acute pelvic (76.7%) and skin/skin structure (79.2%) infections were polymicrobial, whereas polymicrobial infection was less common in those with CAP (36.8%) and was rare in those with CUTI (3.1%). Anaerobes were isolated with Enterobacteriaceae from 236 (74.4%) of 317 patients with intra-abdominal infection, 54 (52.4%) of 103 patients with acute pelvic infection and 25 (32.5%) of 77 patients with skin/skin structure infection. Ten (3.2%) patients with intra-abdominal infection, 11 (10.7%) with acute pelvic infection, three (3.9%) with skin/skin structure infection, 51 (11.2%) with CUTI and two (5.3%) with CAP had Gram-negative enteric bacteraemia at baseline; all isolates were susceptible to study therapy. E. coli accounted for 75.3% of the Enterobacteriaceae isolated from blood.


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Table 2.  Enterobacteriaceae isolated from treated patients with complicated IAI, PI, SSSI, CUTI and CAP and their susceptibility profiles
 
Efficacy

Cure rates by type of infection are shown in Table Go. Among all evaluable patients with CUTI, microbiological cure rates were 90.5% (220 of 243 patients) for those who received ertapenem and 92% (196 of 213 patients) for those who received ceftriaxone (95% CI for the difference, –7.1% to 4.1%), indicating that ertapenem was as effective as (not inferior to) ceftriaxone. Clinical cure rates in all evaluable patients with deep tissue (intra-abdominal, pelvic or skin/skin structure) infections were 84.8% (223 of 263 patients) (95% CI 80.5–89.2%) for those treated with ertapenem and 82.8% (194 of 234 patients) (95% CI 78–87.6%) for those treated with piperacillin–tazobactam (95% CI for the difference, adjusted for type of infection, –4.9% to 8.9%), indicating that ertapenem was as effective as piperacillin–tazobactam. In the supportive MITT analysis, success rates were similar to those in the evaluable patient analyses (Table Go).


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Table 3.  Primary response ratesa by type of infection in patients with Enterobacteriaceae
 
Cure rates also were examined by stratum and/or severity for each of the infections studied, and were generally similar in the treatment groups. Among patients with CUTI, microbiological cure rates for those with acute pyelonephritis were 91.1% (112 of 123) for ertapenem and 93.3% (97 of 104) for ceftriaxone. Cure rates for those with other CUTI were comparable (data not shown). As anticipated, among those with intra-abdominal infection, cure rates were higher in both treatment groups in patients with appendicitis [86.8% (92 of 106) for the ertapenem group; 88.2% (82 of 93) for the piperacillin–tazobactam group] than in patients with infection involving the colon [73.1% (19 of 26) for the ertapenem group; 66.7% (18 of 27) for the piperacillin–tazobactam group]. Similarly, cure rates were lower in patients with than without generalized peritonitis [ertapenem, 81.6% (40 of 49) versus 86.6% (103 of 119); piperacillin–tazobactam, 74.4% (29 of 39) versus 81.8% (90 of 110)], but comparable between treatment groups.

Among all evaluable patients with intra-abdominal, pelvic or skin/skin structure infection or CAP, clinical cure rates for those with monomicrobial versus polymicrobial Enterobacteriaceae infections were 92% (46 of 50) versus 84.1% (196 of 233) for ertapenem, 77.5% (31 of 40) versus 84% (163 of 194) for piperacillin–tazobactam and 90.9% (10 of 11) versus 85.7% (six of seven) for ceftriaxone. Overall cure rates (microbiological for CUTI; clinical for intra-abdominal, pelvic and skin/skin structure infections and CAP) among patients with Gram-negative enteric bacteraemia at baseline were 90.7% (39 of 43; 95% CI 77.9–97.4%) for those treated with ertapenem and 82.4% (28 of 34; 95% CI 65.5–93.2%) for those treated with a comparator agent. For E. coli bacteraemia, cure rates were 94.1% (32 of 34; 95% CI 80.3–99.3%) for patients who received ertapenem and 83.3% (20 of 24; 95% CI 62.6–95.3%) for patients who received ceftriaxone or piperacillin–tazobactam. No patient in any treatment group had persistent bacteraemia; failure was based on unsuccessful treatment of the primary infection.

In the 991 evaluable patients with Enterobacteriaceae, the eradication rate for all pathogens was 88.8% for those treated with ertapenem (467 of 526) and 88.6% for those treated with a comparator (412 of 465). The primary outcome and eradication rates for each organism or organism group were generally similar in both treatment groups (Table Go). Eradication rates (documented and presumed eradication) for all Enterobacteriaceae were 90% (533 of 592) in the ertapenem group and 89.7% (480 of 535) in the comparator groups. For most patients who failed treatment, except those with CUTI, repeat cultures were not obtained, and the microbiological response was presumed persistence. In the 991 evaluable patients, persistence of one or more Enterobacteriaceae was documented in 29 patients with CUTI (18 in the ertapenem group, 11 in the ceftriaxone group), 16 patients with intra-abdominal infection [five in the ertapenem group, 11 (13 isolates) in the piperacillin–tazobactam group], four patients with pelvic infection (three in the ertapenem group, one in the piperacillin–tazobactam group) and one patient with CAP (ceftriaxone group). The most common persistent pathogen was E. coli, identified in 39 (78%) patients. Although these organisms were isolated from patients some time after initiating therapy, none of these pathogens from patients treated with ertapenem had developed resistance to ertapenem. In contrast, seven pathogens (five E. coli, two K. pneumoniae), all from patients with CUTI who were switched from ertapenem to oral ciprofloxacin, had developed resistance to ciprofloxacin. All persistent pathogens in the piperacillin–tazobactam group also remained susceptible to piperacillin–tazobactam. In the ceftriaxone group, however, two persistent pathogens (one each of Citrobacter freundii and E. coli, both from patients with CUTI) developed resistance to ceftriaxone, and four (three E. coli, one Proteus mirabilis), all from patients with CUTI who were switched from ceftriaxone to oral ciprofloxacin, had developed resistance to ciprofloxacin.


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Table 4.  Primary outcome and eradication ratesa per pathogen for the most commonly isolated Enterobacteriaceae,b by type of infection
 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Enteric Gram-negative bacilli were the most commonly isolated pathogens from patients enrolled in seven rigorously designed, double-blind comparative clinical trials of common community-acquired infections, confirming their important role in CUTI, and intra-abdominal, acute pelvic and skin/skin structure infections. As expected, most intra-abdominal, acute pelvic and skin/skin structure infections were polymicrobial. Although assessing the relative contribution of each isolate in such mixed infections is not possible, Enterobacteriaceae are generally considered to be significant pathogens, and the antimicrobial regimen selected should be effective against them. Enterobacteriaceae were also isolated as pathogens in a select population of patients with CAP. The clinical efficacy of ertapenem in these 1167 patients was equivalent to that of piperacillin–tazobactam for deep tissue (intra-abdominal, acute pelvic and skin/skin structure) infections and to ceftriaxone in CUTI including acute pyelonephritis. The clinical outcome of enteric Gram-negative CAP in a small number of patients treated with ertapenem was also excellent.

High bacterial eradication rates for Enterobacteriaceae were observed in patients treated with ertapenem (90%) and, importantly, no baseline pathogen subsequently isolated had developed resistance to ertapenem. In contrast, two patients in the ceftriaxone group (both with CUTI) had persistent Enterobacteriaceae (one with C. freundii and one with E. coli) that had become resistant to ceftriaxone. Additionally, 11 patients with CUTI who improved clinically during parenteral therapy and were switched to oral ciprofloxacin had persistent Enterobacteriaceae (eight E. coli, two K. pneumoniae and one P. mirabilis) that had developed resistance to ciprofloxacin. These data support the concept that the development of resistance in Enterobacteriaceae while on therapy may be influenced by the therapeutic agent.2224 However, the numbers were small, and although the isolates met the study definition of persistence acquiring resistance, molecular typing to confirm that the baseline and post-therapy isolates were identical was not performed, and it is possible that the post-therapy isolate represented a new strain of the same species.

Against the enteric Gram-negative pathogens in this report, ertapenem was more active in vitro than either ceftriaxone or piperacillin–tazobactam. Likewise, other investigators have found that ertapenem has excellent in vitro activity against the majority of Enterobacteriaceae, including isolates that produce extended-spectrum ß-lactamases and are resistant to third-generation cephalosporins and ß-lactam/ß-lactamase inhibitor combination agents.911,25 In vitro, ertapenem is also highly active, and in clinical trials has been shown to be effective against other bacteria commonly responsible for community-acquired intra-abdominal, pelvic and skin/skin structure infection and CAP, including methicillin-susceptible Staphylococcus aureus, ß-haemolytic streptococci and many Streptococcus pneumoniae, Haemophilus influenzae and anaerobes.1218 Although ertapenem has limited activity against non-fermentative Gram-negative bacilli, such isolates are most often associated with nosocomial infections and were infrequently isolated from patients in the ertapenem clinical trials.1218

In each of the seven clinical trials included in this report, ertapenem was generally well tolerated and had an overall safety profile similar to ceftriaxone or piperacillin–tazobactam.1218 Diarrhoea (5.5%), infused vein complication (3.7%), nausea (3.1%), headache (2.2%), vaginitis in females (2.1%), phlebitis/thrombophlebitis (1.3%) and vomiting (1.1%) were the clinical adverse events most commonly reported in patients treated with ertapenem, and transient, mild to moderate aminotransferase elevations were the most frequently reported laboratory adverse event. The incidence of these adverse experiences was comparable to the incidence in the ceftriaxone and piperacillin–tazobactam groups.

In these studies, ertapenem 1 g once a day was highly effective for treatment of patients with serious enteric Gram-negative infections, including deep tissue infections and CUTIs. Additionally, resistance to ertapenem was not observed to have developed during treatment of these infections.


    Acknowledgements
 
These data were presented in part at the Forty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 2002. Funding was provided by Merck & Co., Inc.


    Footnotes
 
* Correspondence address. Merck & Co., Inc., 10 Sentry Parkway, BL3-4, Blue Bell, PA 19422, USA. Tel: +1-484-344-2481; Fax: +1-484-344-3404; E-mail: gail_woods{at}merck.com Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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