Combination therapy for carbapenem-resistant Enterobacteriaceae: increasing evidence, unanswered questions, potential solutions

Abstract

Carbapenem-resistant Enterobacteriaceae (CRE) are associated with a high mortality rate and are an increasing problem worldwide. In this mini-review, we consider the growing number of observational studies in favour of combination therapy but highlight the absence of randomised control trials. We discuss the importance of data on minimum inhibitory concentrations (MICs), both for surveillance and for individual patient management. We examine the issues surrounding the use of carbapenems, polymyxins and tigecycline in the treatment of CRE. When and how should we be using carbapenems? Which polymyxin is best? Is tigecycline much maligned? Further studies are urgently needed to validate drug combinations, doses and ratios to maximise efficacy whilst reducing drug exposure and adverse effects.

Prevalence and antibiotics susceptibility patterns of carbapenem resistant Enterobacteriaceae

“…Falagas ME et al 48 study suggests the use of combined antibiotics may offer a comparative advantage over monotherapy. 48 Nabarro LB et al 49 Study conclude there is increasing evidence to support the use of combination therapy to treat infections that cause by CRE. 49 Fredborg M et al 50 study conclude meropenem triple combinations with a polymyxin and rifampin exhibited highest synergistic activity against carbapenem producing Enterobacteriaceae.…”

Rapid susceptibility profiling of carbapenem-resistant Klebsiella pneumoniae

“…We postulate that broth microdilution over-simplifies the test method and overestimates the dose required to demonstrate antimicrobial efficacy. Highly resistant bacterial sub-populations have been implicated in failed meropenem monotherapy before 28, 31 . These bacteria may respond to meropenem combination therapy provided sufficient breakthrough growth has not occurred 28, 31 .…”

“…Highly resistant bacterial sub-populations have been implicated in failed meropenem monotherapy before 28, 31 . These bacteria may respond to meropenem combination therapy provided sufficient breakthrough growth has not occurred 28, 31 . Identification of these features of bacterial susceptibility in a shorter time could become the basis of more timely antimicrobial treatment guidance 28, 29, 31 .…”

“…These bacteria may respond to meropenem combination therapy provided sufficient breakthrough growth has not occurred 28, 31 . Identification of these features of bacterial susceptibility in a shorter time could become the basis of more timely antimicrobial treatment guidance 28, 29, 31 . While our method eliminates the necessity of the secondary culture step required for either broth microdilution or other growth-dependent quantitative susceptibility determination 27 , further advances are needed to purify bacteria directly from patient samples so that laboratory results are available to the physician within a shorter time frame, particularly for patients with sepsis and other severe infections.…”

Phenotypic and Genotypic Methods for Determination of Carbapenemase Producing Enterobacteriaceae Isolates

“…Karbapenemaz üreten Enterobacteriaceae suşları ise karbapenemlerin etkilerinin zayıf olduğu, mortalitesi yüksek, yoğun ve çeşitli kombine antibiyoterapiyle tedavi edilmeye çalışılan infeksiyonlara neden olmaktadırlar (16,41) . Çeşitli salgınlar ve küresel sporadik vakalarla karbapenem dirençli suşla-rın yayılımı, direnç mekanizmalarının araştı-rılması ve dirençli suşlarla kolonize hastaların izolasyonu gibi çalışmaları beraberinde getirmiştir (1,42) .…”