Piperacillin–tazobactam as alternative to carbapenems for ICU patients

A literature search was performed via PubMed, including all records from 1990 through April 2016. The following search pattern was applied: (ESBL OR extended-spectrum β-lactamases) AND (infection) AND (cefepime OR cefoxitine OR cephamycins OR flomoxef OR BL/BLI OR Piperacillin–tazobactam OR Carbapenems OR temocillin OR alternatives). Reference lists were cross-checked to identify further publications for possible inclusion. We restricted inclusion to studies published in the English, Spanish and French languages.

We screened and included studies in three categories according to the following criteria: (1) pharmacokinetics and pharmacodynamics studies, where all studies investigating the PK/PD of the potential alternatives to carbapenems in ICU patients were included. (2) For clinical studies, we restricted inclusion to studies reporting mortality of patients receiving empirical or definitive treatment with a non-carbapenem therapy for an ESBL bacteremia in adult patients. Patients with community-, hospital- and healthcare-associated bacteremia were eligible for inclusion. (3) Finally, considering ecological studies, we included any published article reporting carbapenem-resistant Enterobacteriaceae (CRE). Among the eligible articles, studies were included if they reported on exposure to any previous antibiotic class as a risk factor associated with CRE acquisition.

Several studies suggested that ESBL-PE were susceptible to non-carbapenem beta-lactams. However, the prevalence of susceptibility depends on the species concerned, the antibiotic class and local epidemiology. ESBL-producing E. coli is usually regarded as more susceptible to all beta-lactams than ESBL-producing K. pneumoniae, piperacillin–tazobactam (Pip–Taz) being the most effective antibiotic [28]. North American data from the 2010–2014 SMART programs find that 4, 10 and 46% of ESBL-producing E. coli were susceptible to ceftriaxone, cefepime and ceftazidime, respectively [28], whereas 96–98 and 69% of ESBL-producing E. coli isolates from urinary tract [29] and from patients with pneumonia [30] were found susceptible in vitro to Pip–Taz, respectively. Conversely, only 26.9% of ESBL-producing Klebsiella spp. isolates from patients with pneumonia were susceptible to Pip–Taz [30]. Asian data on ESBL-producing E. coli find similar susceptibilities, with 1.6, 9.5, 33.4 and 84.5% isolates susceptible to cefotaxime, cefepime, ceftazidime and Pip–Taz, respectively [29]. It is noteworthy that in silico PK/PD studies aiming to evaluate the use of alternatives to carbapenems for treatment of ESBL-PE infections suggest that ESBL-Kp susceptibility is overestimated by conventional methods in comparison with E-test susceptibility testing.

According to epidemiological data, two main antibiotics could be used as an alternative to carbapenems: piperacillin and cefoxitin. Others antibiotics suggested in the literature as temocillin, ceftolozane/tazobactam and/or ceftazidime/avibactam are less tested. Our goal was to define the optimal condition for using these antibiotics for ESBL-PE-related infections in ICU.

The pharmacokinetics of piperacillin in ICU patients was quite extensively investigated. There is, however, a lack of consensus on the pharmacokinetic/pharmacodynamic target to be achieved. Indeed targets as different as obtaining a free concentration > MIC (fT > MIC) or > 4 times the MIC (fT > 4xMIC) for 50 or 100% of a dose interval have been considered [31‐36]. This is a crucial point as the dose to be administered will vary considerably according to the chosen target. There are, however, increasing data supporting a minimal efficacy criteria of fT > MIC = 100% in ICU patients, while a total trough concentration/MIC ratio of at least three was found to prevent the emergence of resistance in vitro [37‐40]. Therefore, based on these more drastic PK/PD endpoints, it seems a dose of 4.5 g TID given as intermittent infusions should not be considered any more in ICU patients with normal renal functions [32, 36]. A 4.5-g × 4 daily dose appears more convenient, provided it is administered as prolonged infusion of at least 3 h [32, 34]. Indeed, for an intermittent bolus administration, a 4gx4 dose is associated with a very low probability of target attainment, even for the lowest PK/PD target of T > MIC = 50% [32]. However, even with a 4.5-g x 4 dose given by extended 3-h infusions, around one-third of the patients may not achieve a fT > MIC = 100%, which supports the need for an individual dose adjustment using therapeutic drug monitoring [35]. Such a result strongly supports the use of continuous infusion, and since this administration mode provides a better outcome than intermittent infusion [24], we believe a 16-g daily dose given as a continuous infusion, following a 4.5-g loading dose, should be considered as a starting point in ICU patients with normal renal function. Such an approach was found relevant for the treatment of ventilator-associated pneumonia, as it allowed the achievement of alveolar concentrations > 16 mg/L (i.e., the clinical breakpoint for gram-negative bacteria).

Slightly different results were observed in morbidly obese ICU patients, for whom the elimination half-life of piperacillin seems to be increased, compared to non-obese patients, resulting in an increased fT > MIC for equivalent doses [33]. Consequently, a 4.5-g × 4 daily dose given as a 4-h extended infusion should provide satisfying trough concentrations [33].

The pharmacokinetics of piperacillin in ICU patients undergoing continuous renal replacement therapy (CRRT) was also investigated, and similar results were found in case of venovenous hemofiltration or hemodiafiltration. A 4.5-g TID dose given as 30-min infusion should provide a free concentration > MIC for the entire dosing interval in almost all patients. Extending the infusion duration to 4 h should allow the attainment of several times the MIC. However, dose requirements seem to importantly depend on the membrane used and the effluent rate that are major aspects of CRRT poorly investigated to date [41, 42]. An interesting point is that piperacillin concentration in the dialysate effluent is equal to the free plasma concentration and can therefore be used for the individual adaptation of the dose via therapeutic drug monitoring (TDM) [43]. To our knowledge, the PK of piperacillin in the context of intermittent hemodialysis was not investigated to date in ICU patients. Based on the results obtained in sepsis-free volunteers with chronic renal failure [44], a dose of 4.5 g bid could be used as a starting point, with a subsequent TDM-guided individual adjustment of the dose. Conflicting results are available about the percentage of the dose that is eliminated by a 4-h session of hemodialysis (i.e., from 10 to 50%) [45, 46]. However, because a supplemental elimination is likely to occur during hemodialysis, it seems preferable to administrate the drug just after the end of the hemodialysis session.

Cefoxitin PK in ICU patients was not investigated to date. By using the PK parameters obtained in healthy subjects, it was shown that for a 8-g daily dose of cefoxitin, only an administration by continuous infusion provided a high probability to achieve targets of fT > MIC = 100% and fT > 4 × MIC = 100% for ESBL-PE [47]. However, since PK differences are expected in ICU subjects, PK data in this population are obviously needed [48].

Concerning temocillin, a 2-g TID dose given as intermittent 30-min infusion, provides a high probability to attain fT > MIC = 100% in ICU patients with normal renal function, provided the MIC is ≤ 4 mg/L. For higher MIC, administration of the same daily dose by continuous infusion is preferable [49]. In summary, among the different antibiotics suggested as alternatives to carbapenems, Pip–Tz is the one with the most frequent published PK/PD data in ICU. High daily doses and prolonged infusion should be promoted for ESBL-PE-related infections in ICU patients.

The article selection process is shown in Fig. 1. Of the 54 articles selected initially, 23 provided data among patients treated with BL/BLIs for ESBL-producing Enterobacteriaceae-related infections (Table 1). Most of the published studies were retrospective (17/23; 73.9%), and all others were observational. Community-acquired, healthcare-associated and nosocomial infections were included without distinction. Among these 23 studies, 9 (39.1%), 6 (26%) and 7 (30.4%) evaluated antibiotic therapy as empirical therapy (ETC), definitive therapy or both, respectively. Among carbapenems, the selected molecule was available in 53% of included studies and imipenem–cilastatin was the most frequently used (45.7% of studies) followed by meropenem (35.2%) and ertapenem (19.1%).

Only 3 (13%) studies reported the doses of antibiotics [19, 20, 50] and none reported the modalities of antibiotic’s administration. Indeed administered doses in patients without renal failure were variable; however, imipenem was used in most cases at an average dose of 0.5 g every 6 h, whereas 1 g every 8 h and 1 g every 24 h were used for meropenem and ertapenem, respectively. The two species most frequently involved were E. coli and K. pneumoniae. All patients included in these studies had bacteremia, and the two most frequent sites of infection were urinary tract and intra-abdominal infection. MIC was taken into account in adjusting antibiotic therapy in 11 (47.8%) of the 23 studies.

As mentioned above, 11 studies included between 6 and 131 ICU patients. In fact, some of the same patients were included in different cohorts [12, 51]. Only 4 studies [52‐55] included patients with pneumonia caused by ESBL-PE, representing 8–50% of patients with ESBL-PE-related infections, indicating that less than 30 patients with ESBL-related pneumonia could be evaluated. Data regarding outcome for patients treated with carbapenems versus alternatives were available from 20 (86.9%) of the 23 studies including bacteremic patients. Surprisingly, potential confounding factors, such as severity of underlying diseases or of infection, were seldom reported.

Among studies including ICU patients, 6 (56%) compared BL/BLIs to carbapenems as empirical therapy. However, BL/BLIs was the only alternative compared to carbapenems in only 3 studies [12, 20, 51]. In these studies, E. coli and K. pneumoniae represented more than two-third of the isolates and MICs were taken into account in only one study [20]. The difference of mortality didn’t reach statistical significance in two studies [12, 51]. However, Ofer-friedman et al. [20] conducted a multicenter observational study including non-urinary BSI and comparing BL/BLI to carbapenem for the treatment of ESBL. In contrast to other studies, E. coli accounted for only half of the bloodstream infections; the median piperacillin MIC was 8 mg/L, and approximately half of patients required ICU care. In this study, the mortality was significantly higher in the piperacillin–tazobactam group [OR 7.9 (1.2–53)]. Thus, BL/BLIs may lead a poorer outcome than carbapenem therapy for critically ill patients with ESBL-PE infection from non-urinary sources.

Finally 7/11 (63%) studies compared BL/BLIs to carbapenems as definitive therapy, of which 4 (36.3%) compared BL/BLIs as the only alternative to carbapenems [12, 19, 20, 22, 51]. It should be noted that only one of these studies took into account MICs [20], whereas none took into account dosages and modalities of administration for assessing the effectiveness of therapy [19].

While initial research suggested the relative safety of imipenem–cilastatin on the intestinal microbiota [56], the recent analysis of rectal colonization of large number of ICU patients found that even a brief exposure to imipenem is a risk factor for carriage of resistant GNB in the intestinal flora [6].

The effect of non-carbapenem antibiotics on the emergence of multidrug-resistant bacteria and specifically carbapenem resistance is a major issue. In animal models, imipenem–cilastatin had no effect on the indigenous microflora [56]. In a mouse model, clindamycin and piperacillin–tazobactam promoted colonization, while ertapenem did not promote the establishment of intestinal colonization with KPC-Kp [57]. Also several authors highlighted the risk associated with the emergence/selection of resistant strains when using Pip–Taz. Firstly, in vitro/in vivo studies [27] suggested that Pip–Taz seems to be less resistant to the inoculum effect comparing to carbapenems. Secondly, several clinical studies [58] underlined the risk of promoting vancomycin-resistant enterococci (VRE) colonization. Finally the emergence of carbapenem-resistant PE has been documented for a variety of antibiotics in the clinical setting [59] (Table 2): Fluoroquinolones [60, 61], extended-spectrum cephalosporin [62], antipseudomonal penicillins [63] and β-lactams/β-lactamase inhibitors [64] have all been identified as risk factors for carbapenem resistance in Klebsiella pneumoniae.

Whether carbapenem is the only antibiotic class associated with the selection of carbapenem-resistant gram-negative isolates is an important issue, especially regarding the worldwide spread of carbapenemase-producing Enterobacteriaceae (CPE). These data suggest that antibiotics that disturb the intestinal anaerobic microflora and lack significant activity against KPC-Kp may promote colonization by this organism [65] (Table 3).