Abstract
Ceftolozane-tazobactam (TOL-TAZ) is a novel antibacterial with activity against Pseudomonas aeruginosa and other common Gram-negative pathogens, including extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, that are associated with complicated intra-abdominal infections (cIAIs). This prospective, double-blind, randomized, multicenter, phase II trial assessed patient clinical and microbiological responses to and the safety of TOL-TAZ plus metronidazole compared with those of meropenem. Hospitalized adults with cIAIs that required surgical intervention were randomized (2:1) to receive intravenous (i.v.) TOL-TAZ (1.5 g [containing 1,000 mg TOL and 500 mg TAZ] every 8 h [q8h]) with or without i.v. metronidazole (500 mg q8h) or i.v. meropenem (1 g q8h) for 4 to 7 days. The primary endpoint was the clinical response at the test-of-cure visit in the microbiologically modified intent-to-treat (mMITT) and microbiologically evaluable (ME) populations. Secondary measures included the patients' microbiological response and safety. In total, 82 patients received TOL-TAZ (90.2% with metronidazole), and 39 received meropenem. For the mMITT population, clinical cure was seen in 83.6% of the patients (51/61; 95% confidence interval [CI], 71.9 to 91.8) who received TOL-TAZ and 96.0% of the patients (24/25; 95% CI, 79.6 to 99.9) who received meropenem (difference, −12.4%; 95% CI, −34.9% to 11.1%); in the ME population, clinical cure was seen in 88.7% and 95.8% of the patients (difference, −7.1%; 95% CI, −30.7% to 16.9%) who received TOL-TAZ and meropenem, respectively. TOL-TAZ demonstrated microbiological success against Escherichia coli (89.5%), Klebsiella pneumoniae (100%), and P. aeruginosa (100%). The adverse event rates were similar in the groups (50.0% with TOL-TAZ and 48.8% with meropenem). TOL-TAZ in combination with metronidazole was well tolerated and resulted in clinical and microbiological success rates supportive of further clinical development in patients with cIAIs. (This study has been registered at ClinicalTrials.gov under registration no. NCT01147640.)
INTRODUCTION
Complicated intra-abdominal infections (cIAIs) are defined as infections resulting from perforation of the gastrointestinal tract that extend into the peritoneal space and are associated with either abscess formation or peritonitis (1). The management of cIAIs involves surgical control of the perforation and/or percutaneous drainage of the associated abscess with adjunctive antibiotic therapy (1). These infections are often polymicrobial and frequently involve a variety of facultative and aerobic Gram-negative pathogens, particularly Escherichia coli, Klebsiella pneumoniae, and, less frequently, Pseudomonas aeruginosa, Klebsiella oxytoca, Enterobacter spp., and Proteus mirabilis (2).
Gram-negative bacteria are highly adaptive pathogens that can acquire resistance to antibacterials through multiple mechanisms, including β-lactamase production, AmpC overexpression, decreases in outer membrane protein expression, and efflux pump upregulation (3, 4). Ongoing surveillance data from the Study for Monitoring Antimicrobial Resistance Trends (SMART) have shown that an increasing percentage of Enterobacteriaceae isolates from intra-abdominal sources are resistant to antibiotics and produce extended-spectrum β-lactamases (ESBLs) (2, 5). Furthermore, the widespread use of carbapenems may lead to further emergence of resistant strains (6–8). Therefore, new therapeutic options are needed for patients at high risk of infections caused by multidrug-resistant (MDR) pathogens, including P. aeruginosa and ESBL-producing Enterobacteriaceae strains.
Ceftolozane-tazobactam is an antibacterial consisting of ceftolozane, a novel antipseudomonal cephalosporin, with tazobactam, a well-established β-lactamase inhibitor. This antibacterial has in vitro activity against P. aeruginosa, including drug-resistant strains, and other common Gram-negative pathogens, including most ESBL-producing Enterobacteriaceae (9, 10), and it is under clinical development for the treatment of cIAIs, complicated urinary tract infections, and health care-associated pneumonia.
Ceftolozane exerts its bactericidal activity by inhibiting essential penicillin-binding proteins, resulting in the inhibition of cell wall synthesis and subsequent cell death. Tazobactam is an inhibitor of most class A β-lactamases and some class C β-lactamases that, by binding to the active sites of these enzymes, protects ceftolozane from hydrolysis and broadens coverage to include most ESBL-producing Enterobacteriaceae (10, 11). Ceftolozane-tazobactam is stable against common cephalosporin resistance mechanisms, including penicillinases, cephalosporinases, and most common class A β-lactamases (10, 11). Furthermore, ceftolozane-tazobactam has activity against some AmpC-derepressed Enterobacteriaceae spp. (10) and has the most potent antipseudomonal activity among the currently available cephalosporins (12, 13). In P. aeruginosa, ceftolozane-tazobactam is minimally affected by AmpC overexpression, increases in efflux mechanisms, and porin deficiencies (14, 15). The minimum concentration needed to inhibit 50%/90% (MIC50/90) of P. aeruginosa isolates is 0.5/2 μg/ml. Ceftolozane-tazobactam has also demonstrated activity against MDR (MIC50/90, 2/8 μg/ml) and extremely drug-resistant (XDR) (MIC50/90, 4/16 μg/ml) P. aeruginosa strains (12). Against ceftazidime-resistant Enterobacteriaceae, ceftolozane-tazobactam is 2- to 32-fold more active than ceftazidime and piperacillin-tazobactam (9), and an in vivo study in mice confirmed the activity of ceftolozane-tazobactam against ESBL-positive Enterobacteriaceae (16). Ceftolozane-tazobactam has activity against Streptococcus spp. and Bacteroides fragilis; however, its activity is limited against other anaerobes (17). A neutropenic mouse thigh infection model was used to evaluate the pharmacokinetic-pharmacodynamic (PK-PD) driver of ceftolozane. As with other β-lactams, the PK-PD index that correlated best with the therapeutic efficacy was the percentage of time above the MIC (%T>MIC). In that study, the magnitudes of the %T>MIC associated with stasis and 1-log10 kill were 24.8% and 32.2%, respectively, which were used to select the therapeutic dose (16).
In this phase II trial (ClinicalTrials.gov registration no. NCT01147640), the safety and efficacy of ceftolozane-tazobactam (1.5 g every 8 h [q8h]) in combination with metronidazole, compared with those of meropenem alone, were evaluated for the treatment of hospitalized patients with cIAIs. (Part of this research was presented at the 53rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, 10 to 13 September 2013, Denver, CO [18]).
MATERIALS AND METHODS
Study design.
A prospective, double-blind, randomized, multicenter trial was conducted from June 2010 to March 2011 at 35 sites in five countries: the United States (11 sites), Argentina (6), Russia (10), Georgia (4), and Serbia (4). The study was performed in accordance with International Conference on Harmonization/Good Clinical Practice guidelines and applicable regulatory requirements. The study protocol was approved by the institutional review board or independent ethics committee at each site, and each patient provided written informed consent.
Treatment regimens.
Patients were enrolled by investigators at each study site and randomized (2:1) via an interactive voice/Web response system, which utilized a computer-generated scheme to assign patient numbers. Once generated, the patient numbers and study drug assignments were provided to the pharmacist or designee. The patients and all of the study staff who evaluated and made decisions about the patients' care remained blinded to the treatment assignments. Patients received intravenous ceftolozane-tazobactam (1.5 g every 8 h [q8h]) plus intravenous metronidazole (500 mg q8h) or intravenous meropenem (1 g q8h) plus matching saline placebo. Meropenem was chosen as the active comparator as it is approved at the dose utilized in this trial for the treatment of adult patients with complicated appendicitis and peritonitis (19). The decision to use metronidazole in combination with ceftolozane-tazobactam was at the discretion of the prescribing physician but the combination was administered to the majority (90.2%) of the patients. The treatment group that received ceftolozane-tazobactam with metronidazole is referred to herein as the ceftolozane-tazobactam group. The duration of treatment was 4 to 7 days, but extension to 14 days was allowed for patients who did not have an adequate source control (1). The dose of ceftolozane-tazobactam that was selected for this study was based on phase I pharmacokinetic and safety studies in healthy adults (20) and the probability of target attainment (30%T>MIC) against pathogens with an MIC of up to 8 μg/ml (≥90%) (21). Randomization was stratified based on the primary site of infection (localized complicated appendicitis versus other sites of intra-abdominal infection [IAI]), since responses to therapy in these infections can differ. Patients with generalized peritonitis (even if due to appendicitis) were included in the “other site” category. This trial intended to enroll no more than 50% of patients with complicated appendicitis, and the number of such patients was monitored during the study.
Inclusion criteria.
Hospitalized male and female patients were eligible for inclusion if they were 18 to 90 years old and had evidence of cIAI requiring surgical intervention (e.g., laparotomy, laparoscopic surgery, or percutaneous draining of an abscess), provided written informed consent, and had a diagnosis of one of the following: cholecystitis (including gangrenous) with rupture or perforation, diverticular disease with perforation or abscess, appendiceal perforation or periappendiceal abscess, acute gastric or duodenal perforation (only if operated on >24 h after the occurrence), traumatic perforation of the intestine (only if operated on >12 h after the occurrence), peritonitis due to perforated viscus, IAI following a prior operative procedure, postoperative peritonitis, or intra-abdominal abscess. If a patient was enrolled preoperatively, he or she must have had radiographic evidence of bowel perforation or intra-abdominal abscess.
Exclusion criteria.
Patients with a high risk of recurrent infections due to exogenous contamination (e.g., cIAIs managed by a staged repair process) were excluded, as were those in whom systemic antibiotics had been used for >24 h in the 48-h period prior to the first dose of the study drug (unless treatment failure for cIAI with that therapy was documented). Patients with a low hematocrit level (<25%), a platelet count of <75,000/mm3, or a neutrophil count of <1,000/mm3 were also excluded from the study, as were those who were considered unlikely to survive the study period, those who had any life-threatening disease (including acute hepatic failure and hepatic disease) or immunocompromising illness, a history of antibiotic hypersensitivity or clinically significant electrocardiographic abnormalities, women who were pregnant or nursing, and patients who had any condition that could have compromised their safety during the study. Patients who had previously received imipenem, meropenem, doripenem, or cefepime for a current IAI, who required concomitant systemic antibacterials (except for vancomycin or linezolid) in addition to the study drugs, who were known to have an IAI caused by a pathogen that was resistant to meropenem, or who had previously participated in another study with ceftolozane-tazobactam were also excluded.
Analysis populations.
The modified intent-to-treat (MITT) population included all randomized patients who received at least one dose of the study drug; this was the primary population for the analysis of safety. The microbiological MITT (mMITT) population included MITT patients who had evidence of an IAI and who had an intra-abdominal pathogen at baseline (regardless of susceptibility to the study drug). The clinically evaluable (CE) population included patients who received the study drug, complied with the study protocol, did not have a missing or indeterminate clinical outcome response at the test-of-cure (TOC) visit, and had no confounding factors that interfered with the assessment of clinical outcome (e.g., use of nonstudy systemic antibiotic therapy on or after the first dose of the study drug for reasons other than treatment failure). The microbiologically evaluable (ME) population comprised patients in the CE population who had an intra-abdominal pathogen at baseline that was susceptible to the study drug received.
A sufficient number of patients were enrolled in the study groups to provide an initial analysis of the safety and efficacy of both study treatments in patients with cIAI. Assuming an evaluability rate of approximately 80% for the mMITT population, an overall sample size of 120 patients was expected to result in 64 mMITT patients in the ceftolozane-tazobactam group and 32 mMITT patients in the meropenem group.
Assessments.
All patients underwent an abdominal examination at baseline, and intra-abdominal specimens for the culture of aerobes and anaerobes were collected at the time of baseline surgical intervention, within 24 h of study drug administration. The MIC ranges of ceftolozane-tazobactam and meropenem were determined for the baseline pathogens. The baseline pathogens were considered susceptible to ceftolozane-tazobactam if the MIC was ≤8 μg/ml, intermediate if the MIC was 16 μg/ml, and resistant if the MIC was ≥32 μg/ml. The MIC cutoffs for susceptibility to meropenem and metronidazole were based on Clinical and Laboratory Standards Institute definitions (22).
Clinical outcome was assessed at the TOC visit (7 to 14 days after the last dose of the study drug) and the late follow-up (LFU) visit (21 to 28 days after the last dose of the study drug). “Clinical cure” was defined as complete resolution or significant improvement in all signs and symptoms of the infection so that no additional antibiotic or procedure was necessary. An outcome of “clinical failure” was assigned to patients who died because of their infection, who had persistent infection documented during an operative or drainage procedure, who had a postoperative surgical-site infection, or who required additional antibiotics for their infection. An outcome of “indeterminate” was assigned when study data were not available for the evaluation of efficacy, for any reason.
The primary objective was to determine the clinical response in the mMITT and ME populations at the TOC visit. Secondary objectives were to evaluate the clinical response in the CE population at the TOC visit and the clinical response in the mMITT and ME populations by patient subgroup (age, baseline acute physiology and chronic health evaluation II [APACHE II] score, and renal function). Additional secondary evaluations included the overall microbiological success (eradication or presumed eradication of the baseline pathogen) and the clinical and microbiological successes per pathogen for the ME population in each treatment group.
Safety and tolerability were assessed throughout the study by recording adverse events (AEs), changes in vital signs, laboratory results, and physical examination results.
Statistical analysis.
Inferential statistical analyses were not conducted. A two-sided 95% confidence interval (CI) was calculated, using the Clopper-Pearson method (23), for the clinical and microbiological response rates.
RESULTS
Patient disposition and baseline characteristics.
A total of 122 patients were randomized into the study, which took place between June 2010 and March 2011. In total, 83 patients were randomized to ceftolozane-tazobactam and 39 to meropenem (Fig. 1). One patient in the ceftolozane-tazobactam group did not receive the study drug, so the MITT population comprised 121 patients; 82 patients received ceftolozane-tazobactam for a mean duration of 5.7 days, and 39 patients received meropenem for a mean duration of 6 days. Most patients in the two treatment groups (94.0% and 97.4% in the ceftolozane-tazobactam and meropenem groups, respectively) completed the study treatment. The most common reason for premature discontinuation from the study treatment was an insufficient therapeutic effect (reported in 3/83 [3.6%] patients in the ceftolozane-tazobactam group and 1/39 [2.6%] patients in the meropenem group).
FIG 1.
Patient flow and study populations. Ceftolozane-tazobactam was administered in combination with metronidazole at the discretion of the prescribing physician.
Demographic characteristics of the MITT population were generally comparable between the two treatment groups, although some differences were observed (Table 1). Most patients in the two groups had baseline APACHE II scores of <10; however, more patients in the ceftolozane-tazobactam group had APACHE II scores of ≥10 (25.0% versus 14.3% in the meropenem group). In contrast, the number of patients with prior treatment failure was higher in the meropenem group than in the ceftolozane-tazobactam group.
TABLE 1.
Baseline demographics and patient characteristics of the MITT population
| Characteristic | Data for patients who received: |
|
|---|---|---|
| Ceftolozane-tazobactama (n = 82) | Meropenem (n = 39) | |
| Sex, male (n [%]) | 45 (54.9) | 24 (61.5) |
| Race, white (n [%]) | 80 (97.6) | 37 (94.9) |
| Mean (SD) age (yr) | 48.5 (18.8) | 46.4 (18.5) |
| Age, ≥65 yr (n [%]) | 19 (23.2) | 7 (17.9) |
| Mean (SD) body mass index (kg/m2) | 28.2 (8.7) | 25.8 (4.0) |
| APACHE II scoreb,c | ||
| <10 (n [%]) | 54 (75.0) | 30 (85.7) |
| ≥10 (n [%]) | 18 (25.0) | 5 (14.3) |
| Median (range) | 7 (0–18) | 6 (0–15) |
| Baseline CLCR | ||
| Normal (≥90 ml/min/1.73 m2) (n [%]) | 51 (62.2) | 23 (59.0) |
| Mild renal impairment (60 to <90 ml/min/1.73 m2) (n [%]) | 17 (20.7) | 13 (33.3) |
| Moderate renal impairment (30 to <60 ml/min/1.73 m2)d (n [%]) | 14 (17.1) | 3 (7.7) |
| Prior antibiotic treatment failure (n [%])e | 9 (11.0) | 9 (23.1) |
Ceftolozane-tazobactam was administered in combination with metronidazole at the discretion of the prescribing physician.
Not all patients had baseline acute physiology and chronic health evaluation II (APACHE II) scores obtained.
Percentages are based on those with available data.
The majority of subjects had a CLCR of 50 to 60 ml/min/1.73 m2, in compliance with the protocol.
Defined as active clinical signs and symptoms of cIAI despite >48 h of prior antibacterial therapy.
The baseline infection characteristics were similar in the two treatment groups (Table 2). The most common diagnosis was appendiceal perforation or periappendiceal abscess, followed by cholecystitis and diverticular disease. Laparotomy was the most common initial surgical intervention in both groups.
TABLE 2.
Patient diagnoses and interventions in the mMITT population
| Primary diagnosis and intervention(s) or origin | Data (n [%]a) for patients who received: |
|
|---|---|---|
| Ceftolozane-tazobactamb (n = 61) | Meropenem (n = 25) | |
| Diagnosis | ||
| Appendiceal perforation or periappendiceal abscess | 30 (49.2) | 14 (56.0) |
| Cholecystitis with rupture, perforation, or progression beyond gallbladder wall | 13 (21.3) | 4 (16.0) |
| Diverticular disease with perforation or abscess | 7 (11.5) | 4 (16.0) |
| Peritonitis due to perforated viscus, postoperative or spread from other focus | 4 (6.6) | 1 (4.0) |
| Acute gastric or duodenal perforation | 3 (4.9) | 0 |
| Traumatic perforation of the intestine | 0 | 1 (4.0) |
| Other intra-abdominal abscess | 4 (6.6) | 1 (4.0) |
| Site of origin of infection | ||
| Appendix | 31 (50.8) | 14 (56.0) |
| Biliary, cholecystitis | 12 (19.7) | 4 (16.0) |
| Colon | 9 (14.8) | 5 (20.0) |
| Stomach/duodenum | 4 (6.6) | 0 |
| Small bowel | 3 (4.9) | 1 (4.0) |
| Parenchymal, liver | 3 (4.9) | 0 |
| Parenchymal, spleen | 3 (4.9) | 0 |
| Biliary, cholangitis | 1 (1.6) | 0 |
| Other | 2 (3.3) | 0 |
| Initial intervention type | ||
| Laparotomy | 52 (85.2) | 22 (88.0) |
| Laparoscopy | 7 (11.5) | 1 (4.0) |
| Percutaneous aspiration | 4 (6.6) | 2 (8.0) |
| Other | 2 (3.3) | 0 |
Patients may have had >1 infection site and/or abdominal intervention.
Ceftolozane-tazobactam was administered in combination with metronidazole at the discretion of the prescribing physician.
Pathogens at baseline.
The incidence and distribution of intra-abdominal pathogens isolated at baseline were similar in the treatment groups. For the mMITT population, the most common pathogen isolated at baseline was E. coli, present in 41/61 (67.2%) and 19/25 (76.0%) patients in the ceftolozane-tazobactam and meropenem groups, respectively. In the mMITT population, 24/61 (39.3%) patients in the ceftolozane-tazobactam group and 9/25 (36.0%) patients in the meropenem group had a polymicrobial infection (≥2 organisms isolated at baseline).
In the mMITT population, the MIC50/90 values for ceftolozane-tazobactam against the two most commonly isolated pathogens, E. coli and Streptococcus spp., were 0.12/0.12 μg/ml and 2/4 μg/ml, respectively. For meropenem, the MIC50/90 values for these two pathogens were 0.015/0.015 μg/ml and 0.06/0.5 μg/ml, respectively. Additionally, the ceftolozane-tazobactam MICs were 0.5 μg/ml for the seven P. aeruginosa isolates and ranged from 0.12 μg/ml to 1 μg/ml for meropenem. All E. coli, Streptococcus spp., K. pneumoniae, and P. aeruginosa isolates collected at baseline were susceptible to ceftolozane-tazobactam and meropenem.
Clinical outcomes.
For the primary endpoint, clinical cure rates at the TOC visit were higher in the meropenem group than in the ceftolozane-tazobactam group for the two coprimary populations (Table 3). For the mMITT population, clinical cure was observed for 51/61 (83.6%; 95% CI, 71.9% to 91.8%) and 24/25 (96.0%; 95% CI, 79.6% to 99.9%) patients in the ceftolozane-tazobactam and meropenem groups, respectively (treatment difference, −12.4%; 95% CI, −34.9% to 11.1%). In the ME population, clinical cure was observed in 47/53 (88.7%; 95% CI, 77.0% to 95.7%) and 23/24 (95.8%; % CI, 78.9% to 99.9%) patients, respectively (treatment difference −7.1%; 95% CI, −30.7% to 16.9%).
TABLE 3.
Clinical outcome at the test-of-cure visit in the mMITT, ME, and CE populations
| Outcome | mMITT population |
ME population |
CE population |
|||
|---|---|---|---|---|---|---|
| Ceftolozane-tazobactama (n = 61) | Meropenem (n = 25) | Ceftolozane-tazobactama (n = 53) | Meropenem (n = 24) | Ceftolozane-tazobactama (n = 70) | Meropenem (n = 35) | |
| Clinical cure (n [%]) | 51 (83.6) | 24 (96.0) | 47 (88.7) | 23 (95.8) | 64 (91.4) | 33 (94.3) |
| Difference in clinical cureb (% [95% CI]) | −12.4 (−34.9 to 11.1) | −7.1 (−30.7 to 16.9) | −2.9 (−23.5 to 18.0) | |||
| Clinical failure (n [%]) | 6 (9.8) | 1 (4.0) | 6 (11.3) | 1 (4.2) | 6 (8.6) | 2 (5.7) |
| Indeterminate (n [%]) | 4 (6.6) | 0 (0.0) | NAc | NA | NA | NA |
Ceftolozane-tazobactam was administered in combination with metronidazole at the discretion of the prescribing physician.
Difference between the two treatments.
NA, not applicable; subjects with indeterminate responses were excluded from the ME and CE populations.
An outcome of clinical failure was reported for six patients in the ceftolozane-tazobactam group and one patient in the meropenem group. An outcome of “indeterminate” was observed for four patients in the ceftolozane-tazobactam group and none in the meropenem group. Patients for whom therapy failed ranged in age from 26 to 60 years and had various infection types, including spontaneous rupture of the appendix, interintestinal abscess, acute gastric perforation, and perforated colon. In the ceftolozane-tazobactam group, the reasons for clinical failure were postsurgical wound infection or persistent or recurrent infection requiring treatment with additional antibiotics. The patient in the meropenem group who experienced clinical failure required additional antibiotic therapy because of ongoing signs and symptoms of cIAI.
The clinical cure rates at the TOC visit in CE patients were 91.4% (64/70) and 94.3% (33/35) in the ceftolozane-tazobactam and meropenem groups, respectively (Table 3). The clinical relapse rates at the LFU visit in CE patients with clinical cure at the TOC visit were comparable in the two treatment groups (3.1% [2/64] in the ceftolozane-tazobactam group and 3.1% [1/32] in the meropenem group).
Clinical responses at the TOC visit in the ME population were evaluated in subgroups based on risk factors for poor response, including age, APACHE II score, and renal function. Clinical cure rates with ceftolozane-tazobactam for patients <65 and ≥65 years old were 84.6% (33/39) and 100% (14/14), respectively. For patients with APACHE II scores of <10 and ≥10, the clinical cure rates were 85.7% (30/35) and 92.3 (12/13), respectively. In patients with normal renal function (creatinine clearance [CLCR], ≥90 ml/min/1.73 m2) and mild to moderate renal impairment (CLCR, ≥30 to <90 ml/min/1.73 m2), the clinical cure rates with ceftolozane-tazobactam were 87.9% (29/33) and 90% (18/20), respectively.
Microbiological outcomes.
At the TOC visit, microbiological success rates in the ME population were 90.6% (48/53) and 95.8% (23/24) for the ceftolozane-tazobactam and meropenem groups, respectively.
The per-pathogen microbiological success rates were high in both treatment groups (Table 4), with 89.5% (34/38) and 94.7% (18/19) of E. coli infections eradicated by ceftolozane-tazobactam and meropenem, respectively. Ceftolozane-tazobactam eradicated 100% (8/8) of K. pneumoniae infections (this pathogen was not present in any patients in the meropenem group at baseline). Both treatments demonstrated a 100% microbiological success rate against P. aeruginosa. In addition, a 100% microbiological success rate was observed for all Gram-positive pathogens with each of the treatments.
TABLE 4.
Per-pathogen microbiological success rates at the test-of-cure visit for the ME populationa
| Pathogen | Success rate (no. of successes/total no. [%]b) for: |
|
|---|---|---|
| Ceftolozane-tazobactamc (n = 53) | Meropenem (n = 24) | |
| Gram-negative aerobes | ||
| Escherichia coli | 34/38 (89.5) | 18/19 (94.7) |
| Klebsiella pneumoniae | 8/8 (100.0) | 0.0 |
| Pseudomonas aeruginosa | 4/4 (100.0) | 3/3 (100.0) |
| Proteus mirabilis | 3/3 (100.0) | 0.0 |
| Acinetobacter baumannii | 1/1 (100.0) | 1/1 (100.0) |
| Otherd | 4/5 (80.0) | 3/3 (100.0) |
| Gram-positive aerobes | ||
| Streptococcus spp. | 8/8 (100.0) | 4/4 (100.0) |
| Enterococcus faecium | 5/5 (100.0) | 2/2 (100.0) |
| Enterococcus faecalis | 5/5 (100.0) | 1/1 (100.0) |
| Gemella morbillorum | 1/1 (100.0) | 1/1 (100.0) |
| Gemella bergeri | 0.0 | 1/1 (100.0) |
| Other | 0.0 | 1/1 (100.0) |
| Gram-negative anaerobes | ||
| Bacteroides (non-fragilis) | 2/2 (100.0) | 4/4 (100.0) |
| Bacteroides fragilis | 6/7 (85.7) | 1/1 (100.0) |
| Fusobacterium nucleatum | 1/1 (100.0) | 0.0 |
| Prevotella buccae | 1/2 (50.0) | 0.0 |
| Gram-positive anaerobes | ||
| Bifidobacterium adolescentis | 1/1 (100.0) | 0.0 |
| Eggerthella lenta | 0.0 | 1/1 (100.0) |
| Propionibacterium acnes | 1/1 (100.0) | 0.0 |
Microbiological success was defined as eradication or presumed eradication of the baseline pathogen.
Patients may have had more than one pathogen at baseline.
Ceftolozane-tazobactam was administered in combination with metronidazole at the discretion of the prescribing physician.
Other Gram-negative aerobes were Hafnia alvei, Citrobacter freundii, Pseudomonas fluorescens, and Citrobacter braakii.
Two of three patients in the ceftolozane-tazobactam group who were positive for ESBL-producing Enterobacteriaceae demonstrated clinical cure, whereas one patient had an indeterminate response (the subject died of urosepsis prior to the TOC visit). The patient with an ESBL infection in the meropenem group demonstrated clinical cure.
Safety.
The overall incidences of AEs that were reported after the start of therapy with the study drug were similar between patients in the ceftolozane-tazobactam and those in the meropenem groups (50.0% [41/82] versus 48.8% [19/39], respectively). The most commonly reported treatment-emergent AEs (TEAEs) in the ceftolozane-tazobactam and meropenem groups were pyrexia (14.7% and 10.3%, respectively) and nausea (6.1% and 10.3%, respectively). All other events were reported in <10% of the patients in each treatment group. The overall incidence rates of the gastrointestinal TEAEs nausea, vomiting, and diarrhea were 15.9% (13/82) in patients treated with ceftolozane-tazobactam and 25.6% (10/39) in patients treated with meropenem, and there were three TEAEs of ileus reported in patients treated with ceftolozane-tazobactam versus none in the meropenem group. The majority of TEAEs in the two treatment groups were mild to moderate in severity. The incidences of individual TEAEs reported in ≥5% of patients in each treatment group are summarized in Table 5.
TABLE 5.
Adverse events occurring in ≥5% of patients in either treatment group during the study (MITT population)
| Adverse event |
n (%) of indicated events in patients who received: |
|
|---|---|---|
| Ceftolozane-tazobactama (n = 82) | Meropenem (n = 39) | |
| Nausea | 5 (6.1) | 4 (10.3) |
| Vomiting | 4 (4.9) | 3 (7.7) |
| Diarrhea | 4 (4.9) | 3 (7.7) |
| Pyrexia | 12 (14.7) | 4 (10.3) |
| Hypertension | 4 (4.9) | 2 (5.1) |
| Phlebitis | 2 (2.4) | 2 (5.1) |
| Hypomagnesemia | 2 (2.4) | 2 (5.1) |
| Wound dehiscence | 0 (0.0) | 2 (5.1) |
| Anemia | 5 (6.1) | 1 (2.6) |
| GGT increased | 1 (1.2) | 2 (5.1) |
| ALT increased | 0 (0.0) | 3 (7.7) |
| AST increased | 0 (0.0) | 2 (5.1) |
Ceftolozane-tazobactam was administered in combination with metronidazole at the discretion of the prescribing physician.
TEAEs considered related to the study drug were less common in the ceftolozane-tazobactam group than in the meropenem group (8.5% [7/82] versus 33.3% [13/39]), with abnormal liver function tests and diarrhea being the most common drug-related TEAEs reported in the meropenem group. In the ceftolozane-tazobactam group, drug-related TEAEs, reported in one patient each, included diarrhea, nausea, vomiting, infusion-site pain, blood alkaline phosphatase level increase, gamma-glutamyl transferase (GGT) level increase, hepatic enzyme level increase, abnormal dreams, and phlebitis.
The incidence of serious AEs (SAEs) was higher in the ceftolozane-tazobactam group (17.1% [14/82]) than in the meropenem group (5.1% [2/39]). An analysis of the types of SAEs observed in the ceftolozane-tazobactam group revealed that events in 11 subjects were primarily related to treatment failure, the underlying IAI, or the surgical procedure (seroma, wound infection, intestinal perforation, ischemic colitis, cholelithiasis, acute pancreatitis, urosepsis, hematoma, peridiverticular abscess, female genital tract fistula, and renal failure/cardiorespiratory arrest). Two subjects experienced vascular and cardiac disorders related to a preexisting disease (atrial flutter/shock and atrial fibrillation), and one subject developed pneumonia 6 days after discontinuation of ceftolozane-tazobactam. None of the SAEs were reported as drug related by the investigator, and none of the patients in either treatment group had a drug-related TEAE that led to premature discontinuation of the study drug.
Three patients in the ceftolozane-tazobactam group died during the study (within 30 days of receiving the last dose). All three deaths were assessed as unrelated to ceftolozane-tazobactam. In one case, an 83-year-old female with a medical history of diabetes mellitus, chronic pancreatitis, encephalopathy, hepatitis C, ischemic heart disease with hypertension and angina, and chronic pancreatitis entered the study following a laparotomy for drainage of a retroperitoneal abscess with diffuse peritonitis caused by K. pneumoniae. After 7 days of study treatment, she was reported to be clinically improved. Three days after the end of therapy, she developed urosepsis with pulmonary edema and experienced rapid deterioration leading to death. An autopsy revealed chronic pyelonephritis with paranephric abscess and generalized peritonitis. In another situation, a 43-year-old female with a medical history of Hashimoto's disease was entered into the study following a laparotomy with Hartmann's procedure for perforation due to diverticular disease caused by E. coli, Enterobacter cloacae, and B. fragilis. After 7 days of study treatment, her treatment was reported as a clinical failure. The patient's treatment was switched to imipenem-cilastatin, and she subsequently experienced ischemic colitis with fecal discharge from the surgical wound that required resection of the colon 6 days after ceftolozane-tazobactam treatment. The patient then received vancomycin, fluconazole, and ciprofloxacin treatment, after which she developed a pulmonary embolus with cardiac arrest and died. Lastly, a 48-year-old male with a medical history of morbid obesity, myocardial infarction, hypertension, atrial fibrillation, ventricular pacemaker, diabetes mellitus, and chronic obstructive pulmonary disease experienced multiorgan failure related to septic shock prior to study entry. He was entered into the study following a small-bowel resection for a strangulated ventral hernia. As this patient's enrollment violated the protocol's inclusion/exclusion criteria (the patient had undergone an open-abdomen technique, was considered unlikely to survive the study period, and had preexisting multiorgan failure), the study drug was discontinued after two doses. The following day, the patient developed worsening renal failure, pulmonary edema, and atelectasis, and he died 7 days posttreatment from multiorgan failure due to sepsis after multiple reexplorations of the original laparotomy.
The most commonly observed clinical laboratory abnormalities were increases in liver function test results. More patients in the meropenem group than in the ceftolozane-tazobactam group had postbaseline shifts of ≥2 toxicity grades in GGT (34.2% versus 7.0%), aspartate transaminase (AST) (18.9% versus 10.6%), and alanine aminotransferase (ALT) (21.1% versus 7.0%). Shifts in hemoglobin level were reported more often in the ceftolozane-tazobactam group (14.5%) than in the meropenem group (6.1%); however, the decreases in hemoglobin levels appeared to be related to surgical intervention.
DISCUSSION
This randomized double-blind trial demonstrated that ceftolozane-tazobactam administered in combination with metronidazole is an effective treatment in patients with cIAIs, with cure rates ranging from 83.6% to 90.6% in various analysis populations. The clinical response rates observed with ceftolozane-tazobactam are consistent with those of prior studies of different antimicrobial therapies that have been evaluated for this indication (24–26).
Meropenem, the comparator in this study, is widely used to treat adult and pediatric patients with serious infections and is approved for the treatment of complicated appendicitis and peritonitis in adults (19). Comparably high rates of clinical cure were observed in patients treated with ceftolozane-tazobactam and meropenem at the TOC visit in the ME and CE populations. The larger treatment difference observed in favor of meropenem for the mMITT population (−12.4%) compared with that of the ME population (−7.1%) was partly, but not completely, driven by the higher number of patients with a missing or indeterminate clinical outcome in the ceftolozane-tazobactam group than in the meropenem group (4 versus 0, respectively), which may have been an artifact of the small sample size and 2:1 randomization in this phase II study. In the ME and CE populations, higher clinical cure rates for patients receiving ceftolozane-tazobactam and smaller treatment differences (−7.1% and −2.9%, respectively) were noted. The higher clinical cure rates observed in the ceftolozane-tazobactam arm were due to the exclusion of patients with missing outcome assessments or with an outcome assessment that was available but confounded by other factors (e.g., concomitant antibiotic use or insufficient duration of treatment). The cIAI cure rate for meropenem that was observed in the mMITT population (96%) was higher than that reported in a similar study in patients with cIAI (88.8%) (25). No consistent demographic or baseline characteristics between patients for whom treatment failed were noted, suggesting that there was no relationship between the risk factors for poor response and those for poor clinical outcome.
The incidence and distribution of baseline infecting pathogens were similar between the treatment groups and consistent with results from prior studies in patients with cIAIs (25). As expected, the most common baseline intra-abdominal pathogens overall were from Enterobacteriaceae. The four most common pathogens isolated from the mMITT population were E. coli (69.8% of patients), Streptococcus spp. (15.1%), K. pneumoniae (10.5%), and Enterococcus faecium (10.5%). The baseline Gram-negative pathogens were highly susceptible to both ceftolozane-tazobactam and meropenem. Ceftolozane-tazobactam was shown to be active against other major causative Gram-negative pathogens in cIAIs, demonstrating a 100% microbiological success rate for eradicating P. aeruginosa and K. pneumoniae. Compared with surveillance data that have demonstrated rates of ESBL-positive E. coli from patients with cIAIs ranging from 22.9% in Latin America to 9.4% and 6.0% in Europe and North America, respectively (27), a low rate of ESBL-positive pathogens was observed in this trial. Despite mixed reports on the utility of β-lactam/β-lactamase inhibitors for the treatment of patients with systemic ESBL infections (10, 28, 29), two out of three ceftolozane-tazobactam patients infected with ESBL-producing Enterobacteriaceae were classified as having clinical cures, which is consistent with an in vivo animal model of ESBL infection (16).
Ceftolozane-tazobactam administered at a dose of 1.5 g q8h via intravenous infusion was well tolerated in this population of patients, with an overall incidence of TEAEs that was comparable to that observed in patients randomized to meropenem. Although the incidence rates of SAEs (17.1%) and deaths (3.7%) were higher in the ceftolozane-tazobactam group, the overall rates observed in this study are similar to the rates of SAEs (8.9% to 14.0% [24, 25]) and deaths (2.5% to 4.9% [24, 25, 30, 31]) that were observed in previous clinical trials of patients with cIAIs. In the current study, shifts in hemoglobin levels were reported more often in the ceftolozane-tazobactam group than in the meropenem group; however, the decreases in hemoglobin levels were not related to the study drug and appeared to be related to complicated surgical procedures in high-risk patients. Liver enzyme elevations were the most common postbaseline shifts in clinical laboratory parameters, which is consistent with β-lactam therapy.
A limitation of this phase II trial was the relatively small sample size. Also, it was not designed or powered to statistically compare efficacy between the two treatment groups. Nevertheless, these results suggest that ceftolozane-tazobactam is effective in the treatment of patients with cIAIs. No clinically important unexpected safety findings were observed, and AEs were balanced between the two treatment groups. These findings support the further investigation of ceftolozane-tazobactam for the treatment of patients with serious infections caused by Gram-negative pathogens.
ACKNOWLEDGMENTS
This study was funded by Cubist Pharmaceuticals. Editorial support for the manuscript was provided by Kate Bradford, of Parexel, and funded by Cubist Pharmaceuticals.
Christopher Lucasti is a consultant to Cubist Pharmaceuticals, Cerexa, and Novexel/AstraZeneca. Ellie Hershberger, Benjamin Miller, Sara Yankelev, Judith Steenbergen, and Ian Friedland are employees of Cubist Pharmaceuticals. Joseph Solomkin is a consultant to Cubist Pharmaceuticals, Bayer, AstraZeneca, Merck, Tetraphase, Rempex, and Pfizer, and he has provided lectures supported by GSK, Bayer, Merck, and Pfizer.
Footnotes
Published ahead of print 30 June 2014
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