Antibiotic combinations that exploit heteroresistance to multiple drugs effectively control infection

Abstract

Antibiotic resistant bacteria are a significant threat to human health, with one estimate suggesting they will cause 10 million worldwide deaths per year by 2050, surpassing deaths due to cancer 1. Since new antibiotic development can take a decade or longer, it is imperative to effectively use currently available drugs. Antibiotic combination therapy offers promise for treating highly resistant bacterial infections, but the factors governing the sporadic efficacy of such regimens have remained unclear. Dogma suggests that antibiotics ineffective as monotherapy can be effective in combination 2. Here, using carbapenemresistant Enterobacteriaceae (CRE) clinical isolates, we revealed the underlying basis for the majority of effective combinations to be heteroresistance. Heteroresistance is a poorly understood mechanism of resistance reported for different classes of antibiotics 3-6 in which only a subset of cells are phenotypically resistant 7. Within an isolate, the subpopulations resistant to different antibiotics were distinct, and over 88% of CRE isolates exhibited heteroresistance to multiple antibiotics ("multiple heteroresistance"). Combinations targeting multiple heteroresistance were efficacious, whereas those targeting homogenous resistance

Synergetic Effects of Combined Treatment of Colistin With Meropenem or Amikacin on Carbapenem-Resistant Klebsiella pneumoniae in vitro

“…Treatment of the bacteria with MEM at 4,000 µg/L exhibited a bacteriostatic effect on 3 CRKP isolates and treatment of the bacteria with AMK at 8,000 µg/L inhibited the growth of 3 CRKP isolates. Our observed phenotype of the CRKP isolates was consistent with what has recently been reported in the United states, indicating the hetero-resistance of CRKP isolates to the drugs contributes to bacteriostatic effect and regrowth (Band et al, 2018(Band et al, , 2019. Therefore, combination therapy is needed not only to fight the multiple-drug resistant CRKP isolates but also to prevent the emergence of the resistance during the treatment.…”

“…It has been reported that the mortality rates can be as high as 40-50% in patients with CRKP infections (Patel et al, 2008). The pathogens often harbor multiple drug-resistant genes that cause the bacteria hetero-resistance to antibiotics in addition to β-bactams (Band et al, 2018(Band et al, , 2019, severely limiting alternative treatment options and increasing therapeutic cost (Huang et al, 2018;Santos and Secoli, 2019). The development of new antimicrobial agents to combat new CRKP isolates is extremely time-consuming, and therapeutic replacement with novel alternative agents may cause potential toxicities.…”

“…The development of new antimicrobial agents to combat new CRKP isolates is extremely time-consuming, and therapeutic replacement with novel alternative agents may cause potential toxicities. Recently, Band et al reported that two multidrug-resistant CRKP isolates exhibiting colistin hetero-resistance, a phenomenon in which only a subpopulation of genetically identical bacterial is resistant to the drug (Band et al, 2018(Band et al, , 2019. Therefore, the use of combination therapy of two or more antibiotics instead of monotherapy in CRKP-infected patients is a feasible option, and the efficacy of such combinations to kill the hetero-resistant CRKP isolates remains to be determined.…”

Peer Review #3 of "Genomic diversity of prevalent Staphylococcus epidermidis multidrug-resistant strains isolated from a Children’s Hospital in México City in an eight-years survey (v0.4)"

“…In the SE collection, only the S07 strain was susceptible to oxacillin (6 g/ml) in plate assays, despite the detection of mecA in the genome. Altogether, these results indicate that most of the SE strains (15) studied here are MRSE, identified by the presence of the mecA gene; any phenotypic inconsistencies could be due to lack of expression of the mecA, heteroresistance, or the limitation of the current antibiotic susceptibility testing methods (Band et al 2019;Harrison et al 2019;Nicoloff et al 2019).…”

Heterogeneous Strategies to Eliminate Intracellular Bacterial Pathogens

“…For example, the emergence of "superbugs" such as methicillin-resistant Staphylococcus aureus (MRSA) (Lakhundi and Zhang, 2018;Turner et al, 2019), vancomycin resistant Enterococcus (VRE) (Courvalin, 2006), MCR positive Enterobacteriaceae (Liu et al, 2016), and high-level tigecycline resistance in E. coli (He et al, 2019;Sun et al, 2019) is accelerating and resulting in the growing failure of antibiotic treatment. Alarmingly, except for genetically encoded antibiotic resistance (Blair et al, 2015) and antibiotic heteroresistance (a transient antibiotic resistance due to gene amplifications) (Band et al, 2019;Nicoloff et al, 2019), bacteria have evolved multi-approaches to withstand antibiotic therapy such as antibiotic tolerance (Dhar and Mckinney, 2007;Kim, 2007). This is a biology phenomenon that describes bacteria that are genetically susceptible, but phenotypically tolerant to antibiotic treatment (Brauner et al, 2016).…”