Efficacy and Safety of Piperacillin Tazobactam Systematic Review and Meta analysis

Introduction

Piperacillin-tazobactam (PTZ) is one of the most frequently utilized antibiotic agents for empirical Gram- negative bacteria coverage and remains active against a large proportion of extended-spectrum-beta-lactamase-producing Gram-negative bacteria [1] (ESBL-GN.) The efficacy of PTZ, its similar safety profile and the possibility of its use as monotherapy decreasing the need for combined antibiotic treatments, make the drug an attractive option in clinical practice [1, 2].

Carbapenems have been considered the most effective therapy for serious infections caused by resistant Gram negative bacteria; however, increased use has selection pressure for carbapenem resistance, an emerging threat which has contributed to increased selective pressure of multi-resistant Enterobacteriaceae [2, 3, 4, 5]. To counterbalance this, PTZ is proposed as a carbapenem-sparing agent to reduce the incidence of multidrug-resistant bacteria and super infections [2].

With all these previous considerations, physicians have to prescribe the most appropriate empirical antibiotic therapy for Gram-negative infections.

To clarify this, we carried out a systematic review (SR) to evaluate if PTZ is associated with a lower rate of treatment failure compared with other antibiotics.

Results

Literature search identified a total of 2264 related papers of which only 11 fulfilled inclusion criteria, and thus, were included in the SR. Figure 1 shows the results of the articles’ selection process and Table 2 summarizes the main characteristics of the included articles.

Click to enlarge

Only 4 trials out of 11 were double-blind [7, 8, 9, 10]. The rest were open-label, single blind or no blindness. Two RCT included patients treated for diabetic foot infections [8, 11] four comprised patients with intra-abdominal infections [10, 12, 13, 14] one focused on oncology patients with treated for febrile neutropenia [15] and four compared patients treated for other types of infections [9, 7, 16, 17].

The pooled incidence of treatment failure of the PTZ group was 13.32% and of the comparator group, 17.55%. Table 3 shows the pooled RR (CI95%) for the risk of failure, the effect size of each study and the results of the sensitivity analysis.

No relevant heterogeneity was detected (Q-test 14.93; DF 9; p 0.09. I2 35%). Pooled RR failure risk rate was 25% less using PTZ than other comparators (0.75; CI 95% 0.59- 0.95) (Graphic 1).

Click to enlarge

Graphic 1: Forest plot: Treatment failure risk in individual and combined studies.

Cumulative metaanalysis (Graphic 2) illustrates that as the sample size increases, the effect size achieves more relevance and accuracy, showing a consistent trend toward less risk of treatment failure using PTZ.

Click to enlarge

Graphic 2: Cummulative meta-analysis: Treatment failure rate.

The sensitivity analysis shows that [12] (5.56%) is the most influential study and the least, [14] (-0.85%). Both used the same comparator (imipinem-cilastin) and for the same indication (intraabdominal infections). The planned subgroup analyses according blindness, reveals that the pooled RR in double blind studies (n 1210 patients), is 0.91;

CI 95% 0.61 to 1.35, while that of the open label studies (n 1135), 0.67; CI 95% 0.49 to 0.90. The difference between them was not statistically significant, yielding a p value of 0.23 (Z statistic 1.20). No risk of bias of publication was detected (Graphic 3).

Graphic 3 Egger Test: Risk of bias publication.

Adverse events: Nor heterogeneity nor publication bias was detected in this comparison. Treatment groups had similar rates of adverse events (15.75% vs. 14.28%) (Pooled RR 1.02; CI95% 0.81-1.29).

Discussion

We conducted this SR to assess in children and adults, with all sorts of bacterial infections, the comparative effectiveness and safety of PTZ against available comparators.

Some authors state that PTZ is another treatment option to carbapenems, but limited to mild infections or urinary tract infections [6, 18, 19].

This SR analyzed PTZ vs another antibiotic comparator in a wide type of infections, including intaabdominal infections, febrile neutropenia, infections in diabetic patients, nosocomial pneumonia, all of which cannot be considered minor clinical threats.

Our results suggest that PTZ leads to a lower rates of treatment failure and is well tolerated, consistent with the good safety profile of the beta-lactam class [1, 2, 3, 4, 5]. The cumulative metaanalysis showed a clear trend that the risk of treatment failure is lower for PTZ than for comparators, and that the incidence of adverse events was not different.

A strength of our study is that, to the best of our knowledge, this is the first systematic review and metanalysis on the efficacy and safety of PTZ that includes only properly randomized controlled trials minimizing selection bias. This means that given the precautions taken to minimize selection bias by including only properly RCT, the clinician, who must often prescribe antibiotic treatments before having the microbiological results, can be confident that the risk of failure with empirical PTZ is lower than if another antibiotic is indicated.

Concerns arose, when it was found that all RCT studies were conducted in a diversity of underlying diseases, with some antibiotic comparators that are not typically indicated in clinical practice for treatment of these pathologies, using different doses and follow-up periods, with some infections not being microbiologically documented or in absence of ESBL-GN, some studies with few participants and mostly having treated adults. However, no significant heterogeneity was identified in the study.

On the other hand, it is not possible to totally rule out that the obtained results are not linked to the bias protection grade of the adopted design.

Further studies are needed to better understand the role of PTZ in empiric treatment of patients in intensive care settings, with ESBL-GN microbiologically documented infections and particularly, in children.

Conclusions

PTZ can be considered an adequate antibiotic option for empirical treatment of serious infections due to gram negative bacterias.

Summary points

Piperacillin tazobactan (PTZ) is an antibiotic frequently used in medical practice for the treatment of Gram negative infections. The present SR suggests that PTZ has a lower risk of therapeutic failure than other antibiotics, while the safety profiles are the same.