3児の親さん薬剤師のブログ

とある薬剤師です。感染症治療を考える素材をちょこっと提供。https://note.mu/twin1980。

Should Piperacillin-Tazobactam Be Used as Definitive Therapy against Enterobacteriaceae Harboring Inducible AmpC β-Lactamases?

Amp C とPip/TazについてのAAC報告とレター

 

 


 

abstract

 

In vivo induction of AmpC beta-lactamases produces high-level resistance to many beta-lactam antibiotics in Enterobacteriaceae, often resulting in the need to use carbapenems or cefepime (FEP). The clinical effectiveness of piperacillin-tazobactam (TZP), a weak inducer of AmpC beta-lactamases, is poorly understood. Here, we conducted a case-control study of adult inpatients with bloodstream infections (BSIs) due to Enterobacter, Serratia, or Citrobacter species from 2009 to 2015 to assess outcomes following treatment with TZP compared to FEP or meropenem (MEM). We collected clinical data and screened all isolates for the presence of ampC alleles by PCR. Primary study outcomes were 30-day mortality and persistent bacteremia at ≥72 h from the time of treatment initiation. Of 493 patients with bacteremia, 165 patients met the inclusion criteria, of which 88 were treated with TZP and 77 with FEP or MEM. To minimize differences between covariates, we carried out propensity score matching, which yielded 41 matched pairs. Groups only differed by age, with patients in the TZP group significantly older (P = 0.012). There were no significant differences in 30-day mortality, persistent bacteremia, 7-day mortality, or treatment escalation between the two treatment groups, including in the propensity score-matched cohort. PCR amplification and sequencing of ampC genes revealed the presence of ampC in isolates with cefoxitin MICs below 16 μg/ml, in particular in Serratia spp., and demonstrated that these alleles were highly genetically diverse. Taken together, TZP may be a valuable treatment option for BSIs due to AmpC beta-lactamase-producing Enterobacteriaceae, diminishing the need for broader-spectrum agents. Future studies are needed to validate these findings.

 

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f:id:akinohanayuki:20170902095553p:plain

 

f:id:akinohanayuki:20170902095618p:plain

 

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レター

 

We read the recent paper by Cheng et al. with interest and commend the authors for assessing the clinically important question of whether piperacillin-tazobactam can be used as definitive therapy for bacteremia caused by Enterobacteriaceae harbor- ing inducible AmpC -lactamases. However, we disagree with the main conclusions of the paper, namely, that definitive therapy with piperacillin-tazobactam is no different than definitive therapy with either cefepime or meropenem.

In the propensity score-matched cohort, both 30-day mortality and persistent bacteremia were numerically doubled in patients receiving piperacillin-tazobactam versus those receiving cefepime or meropenem, although the reported odds ratio (OR) for 30-day mortality is 0.5. Similarly, unadjusted 30-day mortality was lower for recipients of piperacillin-tazobactam in the overall cohort, but the reported odds ratio for 30-day mortality is 1.16. Could the control group or mortality have been misclassified in these analyses? Although the lack of statistical significance for the comparison does not change, the qualitative interpretation of the findings is fundamentally reversed.

An additional consideration lies in the use of propensity score-based modeling. Although propensity scores may increase precision and reduce bias when assessing relatively uncommon events, standard multivariable logistic regression models may outperform propensity score-based models when a sufficient number of events are observed. In this case, the more limited propensity score-matched cohort included only 82 of the original 165 patients and reduced the observed mortality events from 18 to 9. Under these conditions, the use of propensity score matching may have increased model bias and, through reduction of the number of patients, led to a loss of power and a possible type 2 error. Was a standard multivariable logistic regression model that adjusted for severity of illness considered?

The numerical increase in mortality and persistent bacteremia are consistent with the results of a recent study performed by Harris and colleagues addressing risk factors for recurrence in patients with monomicrobial Enterobacter species bacteremia. In this study, the univariate odds of recurrence were nearly doubled for those who received piperacillin-tazobactam or ticarcillin-clavulanate compared to those who re- ceived carbapenems (OR, 1.83; 95% confidence interval [CI], 0.64 to 5.21; P 0.26). Although only 21 patients received definitive therapy with a -lactam or -lactamase inhibitor and the finding was not statistically significant, taken together, these two studies lead to significant concerns regarding the use of piperacillin-tazobactam as 

definitive therapy for bacteremia caused by Enterobacteriaceae with inducible AmpC -lactamases. Further research is needed to define the role of piperacillin-tazobactam as a treatment for these challenging infections.

 

感想

 

Amp C に対する選択肢が広がる可能性は嬉しいです。

エビデンスが蓄積されれば、セフェピムとカルバペネムに間になるのでしょうか?

しかし、Pip/TAZを直ちに使用したいとは思いません。

 
なお、
現在における、Amp Cに対する我々の考え方は、以下の通りです。
 
  1. 「患者さんの状態を見て」重症でなく、感受性があれば第3世代。
  2. MISがすでに高ければ、セフェピム。
  3. 重症なら、カルバペネム。

 

 


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