From the Guidelines
For infections showing efflux pump-mediated colistin resistance in India, the most effective alternative treatment option is ceftazidime/avibactam, due to its strong recommendation and moderate certainty of evidence, as supported by recent studies 1. When considering treatment options, it's crucial to prioritize those that have demonstrated efficacy against multidrug-resistant bacteria, particularly in the context of efflux pump-mediated resistance. The use of ceftazidime/avibactam is backed by observational studies that show a higher rate of clinical success and lower mortality compared to traditional antibiotic regimens, including those that include colistin 1. Some key points to consider in the treatment of such infections include:
- The importance of novel β-lactam agents like ceftazidime/avibactam and meropenem/vaborbactam as first-line treatment options for infections caused by KPC-producing carbapenem-resistant Enterobacterales (CRE) 1.
- The potential for imipenem/relebactam and cefiderocol to be considered as alternative treatments, although the evidence for their use is currently conditional and based on low certainty of evidence 1.
- The need to consider the site of infection, local epidemiology, and the emergence of resistance when selecting a treatment regimen 1.
- The importance of monitoring renal function, especially when using certain antibiotics like colistin or aminoglycosides, which can have nephrotoxic effects 1. Given the complexity of treating infections with efflux pump-mediated colistin resistance, it's essential to stay updated with the latest clinical guidelines and evidence-based recommendations to ensure the best possible outcomes for patients.
From the FDA Drug Label
Tigecycline is less affected by the two major tetracycline-resistance mechanisms, ribosomal protection and efflux Tigecycline resistance in some bacteria (e.g., Acinetobacter calcoaceticus-Acinetobacter baumannii complex) is associated with multi-drug resistant (MDR) efflux pumps. The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for tigecycline against isolates of similar genus or organism group 1There have been reports of the development of tigecycline resistance in Acinetobacter infections seen during the course of standard treatment. Such resistance appears to be attributable to an MDR efflux pump mechanism
Alternative treatment options for infections showing efflux pump-mediated colistin resistance in India may include tigecycline, as it is less affected by efflux pump mechanisms and has been shown to be active against certain bacteria that may exhibit colistin resistance, such as Acinetobacter baumannii. However, monitoring for relapse of infection is important, and susceptibility testing should be performed to determine the effectiveness of tigecycline against the specific bacterial isolate 2.
- Key considerations:
- Tigecycline is not affected by certain resistance mechanisms, such as beta-lactamases or macrolide efflux pumps
- Tigecycline resistance may still occur through other mechanisms, such as MDR efflux pumps
- Clinical significance of in vitro data is unknown, and efficacy of tigecycline in treating clinical infections caused by certain bacteria has not been established in adequate and well-controlled clinical trials
From the Research
Alternative Treatment Options for Infections Showing Efflux Pump-Mediated Colistin Resistance in India
- The use of efflux pump inhibitors (EPIs) has been proposed as a potential strategy to combat efflux pump-mediated colistin resistance in India 3, 4, 5, 6.
- A study published in 2018 found that the EPI CCCP was able to reverse colistin resistance in a collection of 93 Gram-negative bacteria with known and unknown colistin resistance mechanisms, including isolates with mcr-1 plasmid-mediated colistin resistance 3.
- Another study published in 2015 investigated the role of efflux pump-mediated fluoroquinolone resistance in nosocomial isolates of Pseudomonas aeruginosa from a tertiary referral hospital in north-east India, and found that 23% of the isolates showed efflux-mediated fluoroquinolone resistance 4.
- A review published in 2001 discussed the inhibition of efflux pumps as a novel approach to combat drug resistance in bacteria, and highlighted the potential benefits of efflux pump inhibitors in improving the clinical performance of various antibiotics 5.
- A study published in 2019 found that the combinatorial use of a MarR inhibitor with an efflux pump inhibitor was able to restore colistin sensitivity in a colistin-resistant E. coli strain, and demonstrated the potential of this approach in vitro and in vivo 6.
- The use of aztreonam, ceftazidime/avibactam, and colistin combination has also been proposed as a viable treatment option for patients with infections caused by metallo-beta-lactamase (MBL)-producing Enterobacteriaceae, which are often resistant to colistin 7.
Mechanisms of Efflux Pump-Mediated Colistin Resistance
- Efflux pumps are a major mechanism of resistance to colistin, and can be inhibited by EPIs such as CCCP and BC1 3, 6.
- The L-Ara-4-N pathway and the MgrB protein have been implicated in colistin resistance, and mutations in these genes can contribute to reduced colistin susceptibility 6.
- The MarR protein is a regulator of the AcrAB efflux pump, and inhibition of MarR by salicylate can increase the expression of the AcrAB efflux pump and reduce colistin susceptibility 6.
Future Directions
- Further research is needed to identify new EPIs that can be used in humans, and to develop combination therapies that can effectively restore colistin sensitivity in colistin-resistant bacteria 3, 6.
- The use of whole-genome sequencing and molecular characterization of efflux pumps can help to identify the molecular mechanisms of efflux pump-mediated colistin resistance, and inform the development of targeted therapies 6.