Revisiting the mutant prevention concentration to guide dosing in childhood tuberculosis

Jaganath, Devan; Schaaf, H. Simon; Donald, Peter R.

doi:10.1093/jac/dkx051

Cited by 5 publications

(6 citation statements)

References 92 publications

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“…Their results confirm that resistant mutants are enriched when bacteria were exposed to concentrations that fall within the MSW. While the MPC and MSW have been widely described in M. tuberculosis in adults as defined values (Rodriguez et al, 2004), in one review of the antibiotic dosing used in child tuberculosis, it was found that the heterogeneity of MICs could result in a range of MPCs (Jaganath et al, 2017). Multiple studies using Streptococcus pneumonia (Li et al, 2002; Drlica, 2003; Zinner et al, 2003) and Haemophilus influenzae (Li et al, 2004; Metzler et al, 2004b) emphasize the variability in mutation accumulation and observe increasing MSWs with successive mutations.…”

Section: Introductionmentioning

confidence: 99%

Variation in Mutant Prevention Concentrations

et al. 2019

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Objectives:Understanding how phenotypic traits vary has been a longstanding goal of evolutionary biologists. When examining antibiotic-resistance in bacteria, it is generally understood that the minimum inhibitory concentration (MIC) has minimal variation specific to each bacterial strain-antibiotic combination. However, there is a less studied resistance trait, the mutant prevention concentration (MPC), which measures the MIC of the most resistant sub-population. Whether and how MPC varies has been poorly understood. Here, we ask a simple, yet important question: How much does the MPC vary, within a single strain-antibiotic association? Using a Staphylococcus species and five antibiotics from five different antibiotic classes—ciprofloxacin, doxycycline, gentamicin, nitrofurantoin, and oxacillin—we examined the frequency of resistance for a wide range of concentrations per antibiotic, and measured the repeatability of the MPC, the lowest amount of antibiotic that would ensure no surviving cells in a 1010 population of bacteria.Results: We found a wide variation within the MPC and distributions that were rarely normal. When antibiotic resistance evolved, the distribution of the MPC changed, with all distributions becoming wider and some multi-modal.Conclusion: Unlike the MIC, there is high variability in the MPC for a given bacterial strain-antibiotic combination.

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Section: Introductionmentioning

confidence: 99%

Variation in Mutant Prevention Concentrations

et al. 2019

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“…MPC is the lowest concentration that prevents the development of a bacterial isolate that is a single-step mutant with the least susceptibility. MSW is the drug concentration difference between the MIC and MPC, and failing to reach drug concentrations above the MPC may allow bacteria with resistance-associated mutations to grow and acquire more mutations . Bacterial resistance is complex when bacteria are exposed to low antibiotic dosages.…”

Section: Discussionmentioning

confidence: 99%

“…MSW is the drug concentration difference between the MIC and MPC, and failing to reach drug concentrations above the MPC may allow bacteria with resistance-associated mutations to grow and acquire more mutations. 39 Bacterial resistance is complex when bacteria are exposed to low antibiotic dosages. In the present study, the MPC of TGC to the CRKP clinical isolates varied from 32−64 mg/L, which was higher than that in previous studies, 32 indicating that the isolates could acquire resistance at greater dosages.…”

Section: ■ Discussionmentioning

confidence: 99%

Tigecycline–Rifampicin Restrains Resistance Development in Carbapenem-Resistant Klebsiella pneumoniae

Shi,

Xu,

Zhao

et al. 2023

ACS Infect. Dis.

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The goal of this study was to clarify the synergistic antibacterial activity of the combination of tigecycline (TGC) and rifampicin (RIF). Additionally, the study sought to investigate the impact of this combination on the development of mutational resistance and to assess its efficacy in an in vivo model using Galleria mellonella. Through a checkerboard test, we found that the combination of TGC and RIF showed synergistic antibacterial activity against carbapenem-resistant Klebsiella pneumoniae (CRKP). The fractional inhibition concentration index (FICI) was found to be ≤0.5, confirming the potency of the combination. Additionally, this synergistic effect was further validated in vivo using the G. mellonella infection model. TGC−RIF treatment had a lower mutant prevention concentration (MPC) than that of monotherapy, indicating its potential to reduce the development of mutational resistance. We observed a substantial variation in the MPCs of TGC and RIF when they were measured at different proportions in the combinations. Furthermore, during the resistant mutant selection window (MSW) test, we noticed a correlation between strains with low FICI and low MSW. The expression of efflux-pump-related genes, namely rarA and acrB, is significantly decreased in the combination therapy group. This indicates that altered expression levels of certain efflux pump regulator genes are associated with a combined decrease in bacterial mutation resistance. In conclusion, the combination of TGC and RIF effectively suppresses antibiotic resistance selection in CRKP. This study establishes a paradigm for evaluating drug-resistant mutant suppression in antimicrobial combination therapy.

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“…Various research projects have focused on the role and perspective of the veterinarian in the fight against resistance to antibiotics and its responsible use, including the methods to determine antibiotic selection and dosage (Fortané 2019 ; Martinez et al 2014 ; Trek Diagnostic Systems 2005 ). It must be borne in mind that resistance to antibiotics while not occurring in every instance of their use can drive resistance when treatments are not fully effective in eliminating bacterial infections (Gebru et al 2011 ; Jaganath, Schaaf & Donald 2017 ). Alternative tests to minimum inhibitory concentration (MIC) determinations and ongoing improvements to determine the most effective dose to treat animals are essential (Martinez et al 2014 ).…”

Section: Introductionmentioning

confidence: 99%

“…The MIC method determines the lowest concentration (in µg/mL) of an antibiotic that inhibits the growth of a given strain of bacteria and shows the interaction between the drug and the pathogen (Martinez et al 2014 ). Minimum inhibitory concentrations can, however, prove ineffective where there is a high rate of mutations in specific organisms such as tuberculosis (Jaganath et al 2017 ). With the MPC method, a higher inoculum size (10 8 coli forming unit (CFU)/mL) is used to block the growth of the least susceptible bacteria present (Coyner 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Comparing the minimum inhibitory and mutant prevention concentrations of selected antibiotics against animal isolates of Pasteurella multocida and Salmonella typhimurium

Wentzel

Biggs

Vuuren

2022

Onderstepoort j. vet. res.

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Historically, the use of antibiotics was not well regulated in veterinary medicine. The emergence of antibiotic resistance (ABR) in pathogenic bacteria in human and veterinary medicine has driven the need for greater antibiotic stewardship. The preservation of certain antibiotic classes for use exclusively in humans, especially in cases of multidrug resistance, has highlighted the need for veterinarians to reduce its use and redefine dosage regimens of antibiotics to ensure efficacy and guard against the development of ABR pathogens. The minimum inhibitory concentration (MIC), the lowest concentration of an antibiotic drug that will prevent the growth of a bacterium, is recognised as a method to assist in antibiotic dosage determination. Minimum inhibitory concentrations sometimes fail to deal with first-step mutants in bacterial populations; therefore dosing regimens based solely on MIC can lead to the development of ABR. The mutant prevention concentration (MPC) is the minimum inhibitory antibiotic concentration of the most resistant first-step mutant. Mutant prevention concentration determination as a complementary and sometimes preferable alternative to MIC determination for veterinarians when managing bacterial pathogens. The results of this study focused on livestock pathogens and antibiotics used to treat them, which had a MIC value of 0.25 µg/mL for enrofloxacin against all 27 isolates of Salmonella typhimurium. The MPC values were 0.50 µg/mL, with the exception of five isolates that had MPC values of 4.00 µg/mL. The MPC test yielded 65.52% (18 isolates) Salmonella isolates with florfenicol MICs in the sensitive range, while 11 isolates were in the resistant range. Seventeen isolates (58.62%) of Pasteurella multocida had MIC values in the susceptible range and 41.38% (12 isolates) had an intermediate MIC value. Mutant prevention concentration determinations as done in this study is effective for the antibiotic treatment of bacterial infections and minimising the development of resistance. The MPC method can be used to better control to prevent the development of antibiotic drug resistance used in animals.

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Revisiting the mutant prevention concentration to guide dosing in childhood tuberculosis

Cited by 5 publications

References 92 publications

Variation in Mutant Prevention Concentrations

Variation in Mutant Prevention Concentrations

Tigecycline–Rifampicin Restrains Resistance Development in Carbapenem-Resistant Klebsiella pneumoniae

Comparing the minimum inhibitory and mutant prevention concentrations of selected antibiotics against animal isolates of Pasteurella multocida and Salmonella typhimurium

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