Ertapenem versus piperacillin/tazobactam for the treatment of complicated infections: a meta-analysis of randomized controlled trials

The treatment of complicated infections such as complicated intra-abdominal infections (cIAIs), acute pelvic infections (APIs) and complicated skin and skin-structure infections (cSSSIs) is a challenge for clinicians. They are most often polymicrobial or mixed infections which caused by pathogens involving a mixture of gram-positive and gram-negative aerobic and anaerobic organisms including staphylococcus, streptococci, enterococci, Enterobacteriaceae, anaerobic coccobacilli, anaerobic bacilli [1‐4].

The outcome of complicated infections depends on the timely diagnosis and treatment which involves appropriate antimicrobial therapy directing to the residual infecting microorganisms. Absent or inadequate antibiotic therapy results in both increased failure rates and mortality. Empiric antimicrobial treatment of the complicated infection requires parenteral coverage of a broad spectrum of potential pathogens, often including β-lactam/β-lactamase inhibitor combination, carbapenems, cephalosporins with anaerobic coverage, or combination therapy consisting of a cephalosporin, fluoroquinolone, or aminoglycoside plus an anti-anaerobic agent [5‐7].

Ertapenem (Merck & Co., Inc., USA), a long-acting and once-daily parenteral carbapenem, was approved for the treatment of complicated infections such as cIAIs, APIs, cSSSIs. It is rapidly bactericidal against most of the predominant intra-abdominal, skin/skin-structure and pelvic pathogens, including many that produce extended-spectrum or AmpC β-lactamase producing Enterobacteriaceae which are resistant to cephalosporins and β-lactam/β-lactamase inhibitor combination [8‐10]. It is an appealing option for the treatment of these complicated infections not only because of its spectrum of antimicrobial activity, but also its convenient dosing schedule, and sounds a useful alternative for combination and/or multidosed antibiotic regimens for the empiric treatment.

Although ertapenem has limited activity in vitro against enterococci and Pseudomonas aeruginosa which may be encountered in cIAIs, APIs and cSSSIs, several randomized controlled trials (RCTs) suggested that ertapenem is at least as effective as piperacillin/tazobactam, a β-lactam/β-lactamase inhibitor combination agent that is routinely used in the treatment of these complicated infections [11‐16]. Aiming to compare more conclusively the efficacy and safety of ertapenem with piperacillin/tazobactam in these complicated infections, we undertook a system review with meta-analysis of relevant RCTs.

This systematic review with a meta-analysis compared the efficacy and safety of ertapenem with piperacillin/tazobactam in patients with complicated infections including cIAIs, APIs and cSSSIs. The main result of this meta-analysis with regard to the primary efficacy outcome (clinical treatment success) suggested that no difference existed between the treatment arms (Figure 2). The secondary outcome analysis produced finding consistent with the primary outcome (Figure 2, 3). In the ertapenem treatment arms, the drug related clinical adverse events mainly were gastrointestinal and the drug related laboratory adverse events consisted primarily of elevations in liver enzymes (transaminases and alkaline phosphatase) and thrombocytosis. The safety analysis regarding to the drug related clinical and laboratory adverse events both proved no difference between the compared treatment arms (Figure 4). Likewise, post hoc analysis of trials comparing ertapenem treatment with piperacillin/tazobactam, in patients with cIAIs, APIs and cSSSIs, also have not revealed any significant differences, regarding the efficacy and safety outcomes examined [20].

An earlier meta-analysis performed by Falagas et al [21]had provided evidence that ertapenem was comparable to other recommended antimicrobial regimens (piperacillin/tazobactam, ceftriaxone plus metronidazole and ticarcillin/clavulanic acid) for the treatment of cIAIs. The focus of our meta-analysis was to compare the efficacy and safety of ertapenem with piperacillin/tazobactam, a well-established therapeutic agent, in patients with complicated infections. APIs, cSSSIs and cIAIs are most often polymicrobial infections. They have similarities both in aetiological organisms involving a mixture of gram-positive, gram-negative anerobic and anaerobic organisms such as staphylococcus, streptococci, enterococci, Enterobacteriaceae, anaerobic coccobacilli, anaerobic bacilli, and in empiric antimicrobial treatment that requires parenteral coverage of a broad spectrum of potential pathogens including an extended-spectrum cephalosporin plus an agent active against anaerobes including an extended-spectrum cephalosporin plus an agent active against anaerobes, such as metronidazole or clindamycin, or a β-lactam/β-lactamase inhibitor combination. Piperacillin/tazobactam, a β-lactam/β-lactamase inhibitor combination agent, has been well studied and is approved in the treatment of complicated infection including cIAIs, APIs, and cSSSIs [22]. So in the present meta-analysis, we included RCTs performed on APIs and cSSSIs, in addition to those performed on cIAIs.

It should be pointed out that ertapenem, although highly active in vitro against methicillin-susceptible staphylococci and most clinically important Enterobacteriaceae, streptococci and anaerobes which are the most common causal pathogens in cIAIs, APIs and cSSSIs, is not against non-fermentative gram-negative bacilli, such as Pseudomonas aeruginosa, which are important nosocomial pathogens, particularly in intensive care units, or enterococci, which in the setting of a polymicrobial infection are of questionable pathogenicity[23, 24]. Notably, in our meta-analysis ertapenem had a comparable efficacy (Figure 2, 3) to piperacillin/tazobactam, an agent possessing antienterococcal and good antipseudomonal activity. Clinical and microbiologic success rates for patients infected with Pseudomonas aeruginosa or enterococci were generally similar in each relevant RCT, and the high favorable response rates implied routine enterococcal or pseudomonal coverage was not essential, which was consistent with previous study [25‐27] and the current recommendations from the Surgical Infection Society [28] and the Infectious Disease Society of America [29]. However, this finding should be interpreted with caution, given that it is based on a rather small total number of patients in our meta-analysis.

Although the present evidence suggests ertapenem had similar efficacy and safety profile with piperacillin/tazobactam in the treatment of complicated infections such as cIAIs, APIs and cSSSIs, several unique characteristics make it as an alternative to piperacillin/tazobactam. Firstly, ertapenem may mitigate the emergence of resistant strains. Previous studies indicated that there were fewer instances of emergence of resistant Enterobacteriaceae and extended-spectrum β-lactamase producing Enterobacteriaceae in the colonizing bowel flora of ertapenem-treated patients with cIAIs than receiving piperacillin/tazobactam or ceftriaxone plus metronidazole, and there were no differences between groups in the prevalence of imipenem-resistant Pseudomonas in the colonizing bowel flora after completion of therapy [30, 31]. This may be attributed to the limited development of microbial resistance to carbapenems and the targeted spectrum of ertapenem [32]. Secondly, once-daily dosing of ertapenem may offer benefits compared with agents that require multiple dosing or combination therapy, including patient convenience and comfort, and a lower risk of medication errors [32]. Thirdly, compared with piperacillin/tazobactam given four times daily i.v., ertapenem given once daily i.v. was associated with lower drug and supply costs and less time and labor devoted to the preparation and administration of i.v. therapy[33].

In contrast to the earlier meta-analysis [21], we examined 6 high quality RCTs (Four RCTs had a Jadad score of 5, one had 4 and one had 3), focused on direct comparison of treatments with ertapenem and piperacillin/tazobactam as monotherapy, precluding the interference of other drugs, and included RCTs performed on APIs and cSSSIs in addition to cIAIs. The efficacy and safety outcome of our meta-analysis were defined similarly in the individual trial. Furthermore, the same administration route and doses of ertapenem (1 g once daily, i.v.) was used to compare with recommended dose of piperacillin/tazobactam in patients of the included RCTs. So the similar treatment schedule and evaluation criteria of the included trials provided greater statistical confidence for our meta-analysis.

The meta-analysis is not without limitations. First, the clinical treatment success analysis based on the data defined as cure or improvement of signs and symptoms may not be as accurate as complete cure. Four of the 6 overall included studies provided mixed data regarding the outcome of clinical treatment success. This may hinder a meaningful separate meta-analysis of complete cure. Second, in 3 RCTs performed on cIAIs, patients with severe infections (APACHE II score > 30 or of a life-threatening degree) were excluded, so the finding of this meta-analysis should be interpreted with caution on severe infections. Third, most included RCTs excluded patients with infections caused by pathogens known to be resistant to study treatment, which may interfere with the finding. Finally, all of the 6 included trials, including the one nonblinded study, were supported by the branding pharmaceutical company of ertapenem, a factor that might generate bias in the assessment of outcomes. Nevertheless, the sensitivity analysis limited to double-blind RCTs was performed in our meta-analysis, resulting in findings consistent with those of the primary analysis.

Despite the limitations, the efficacy of ertapenem 1 g once daily was statistically equivalent to recommended dose of piperacillin/tazobactam, and was generally well tolerated. The present evidence suggests that the clinical use of ertapenem is associated with decreased emergence of antimicrobial resistance and lower costs. The once-daily dosing of ertapenem may be a useful alternative for combination and/or multidosed antibiotic regimens for the empiric treatment. However, there is rather limited evidence for the efficacy of ertapenem compared to piperacillin/tazobactam, in patients with severe complicated infections caused by one or more pathogens.