Ceftazidime-avibactam has potent sterilizing activity against highly drug-resistant tuberculosis

Deshpande, Devyani; Srivastava, Shashikant; Chapagain, Moti; Magombedze, Gesham; Martin, Katherine; Cirrincione, Kayle; Lee, Pooi S; Koeuth, Thearith; Dheda, Keertan; Gumbo, Tawanda

doi:10.1126/sciadv.1701102

Cited by 62 publications

(76 citation statements)

References 45 publications

(113 reference statements)

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“…The d-cycloserine minimum inhibitory concentrations (MICs) for Mtb H37Ra (ATCC 25177) and H37Rv (ATCC 27294) were determined using 4 methods: Sensititre MYCOTB plate, macrobroth dilution, as well as the 1% indirect proportion method using Middlebrook 7H10, and MGIT [19][20][21]. For the latter 3 methods, the concentrations 0, 0.5, 1, 2, 4, 8, 16, 32, and 64 mg/L were tested.…”

Section: Minimum Inhibitory Concentrations Of Laboratory Strainsmentioning

confidence: 99%

“…For the latter 3 methods, the concentrations 0, 0.5, 1, 2, 4, 8, 16, 32, and 64 mg/L were tested. Next, we examined the microbial kill effect of different d-cycloserine concentrations against extracellular Mtb in test tubes and intracellular Mtb in infected THP-1 cells that were activated for 72 hours with 100 nM of phorbol 12-myristate 13-acetate 12-well plates, and coincubated with drug, using protocols described previously [19,20].…”

Section: Minimum Inhibitory Concentrations Of Laboratory Strainsmentioning

confidence: 99%

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d-Cycloserine Pharmacokinetics/Pharmacodynamics, Susceptibility, and Dosing Implications in Multidrug-resistant Tuberculosis: A Faustian Deal

Deshpande

Alffenaar

Köser

et al. 2018

Clinical Infectious Diseases

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Background. d-cycloserine is used to treat multidrug-resistant tuberculosis. Its efficacy, contribution in combination therapy, and best clinical dose are unclear, also data on the d-cycloserine minimum inhibitory concentration (MIC) distributions is scant. Methods. We performed a systematic search to identify pharmacokinetic and pharmacodynamic studies performed with d-cycloserine. We then performed a combined exposure-effect and dose fractionation study of d-cycloserine in the hollow fiber system model of tuberculosis (HFS-TB). In parallel, we identified d-cycloserine MICs in 415 clinical Mycobacterium tuberculosis (Mtb) isolates from patients. We utilized these results, including intracavitary concentrations, to identify the clinical dose that would be able to achieve or exceed target exposures in 10 000 patients using Monte Carlo experiments (MCEs). Results. There were no published d-cycloserine pharmacokinetics/pharmacodynamics studies identified. Therefore, we performed new HFS-TB experiments. Cyloserine killed 6.3 log 10 colony-forming units (CFU)/mL extracellular bacilli over 28 days. Efficacy was driven by the percentage of time concentration persisted above MIC (%T MIC), with 1.0 log 10 CFU/mL kill achieved by %T MIC = 30% (target exposure). The tentative epidemiological cutoff value with the Sensititre MYCOTB assay was 64 mg/L. In MCEs, 750 mg twice daily achieved target exposure in lung cavities of 92% of patients whereas 500 mg twice daily achieved target exposure in 85% of patients with meningitis. The proposed MCE-derived clinical susceptibility breakpoint at the proposed doses was 64 mg/L. Conclusions. Cycloserine is cidal against Mtb. The susceptibility breakpoint is 64 mg/L. However, the doses likely to achieve the cidality in patients are high, and could be neurotoxic.

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Section: Minimum Inhibitory Concentrations Of Laboratory Strainsmentioning

confidence: 99%

Section: Minimum Inhibitory Concentrations Of Laboratory Strainsmentioning

confidence: 99%

d-Cycloserine Pharmacokinetics/Pharmacodynamics, Susceptibility, and Dosing Implications in Multidrug-resistant Tuberculosis: A Faustian Deal

Deshpande

Alffenaar

Köser

et al. 2018

Clinical Infectious Diseases

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“…This waxy coating contributes to drug resistance in M. tuberculosis , but is also the target of several mycobacteria-specific antibiotics 1 . The challenge of multi- and extensively-drug resistant M. tuberculosis has not adequately been met by drug discovery efforts, however recent reports suggest that β-lactams are effective at treating these drug-resistant infections 2-4 . Despite their therapeutic promise, we know relatively little about the turn-over of PG in mycobacteria, which is the eventual target of β-lactam antibiotics.…”

Section: Figurementioning

confidence: 99%

The hydrolase LpqI primes mycobacterial peptidoglycan recycling

Moynihan

Cadby

Veerapen

et al. 2018

Preprint

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30Growth and division by most bacteria requires remodeling and cleavage of their cell 31 wall. A byproduct of this process is the generation of free peptidoglycan (PG) fragments known 32 as muropeptides. These muropeptides are recycled in many model organisms, where the 33 bacteria can harness their unique nature as a signal for cell wall damage. These molecules also 34 serve as important signals for hosts where binding to specific receptors reports on the presence 35 of intracellular bacteria. Despite this critical role for muropeptides, it has long been thought that 36 pathogenic mycobacteria such as Mycobacterium tuberculosis do not recycle their PG. Herein 37 we show that M. tuberculosis and Mycobacterium bovis BCG are both able to recycle 38 components of their PG. We demonstrate that MurNAc but not GlcNAc can be metabolised by 39All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/312876 doi: bioRxiv preprint first posted online May. 3, 2018; 2 mycobacteria and that stem-peptide recycling proceeds independent of amino sugar recovery. 40In addition, we demonstrate that the core-mycobacterial gene lpqI encodes an authentic NagZ 41 β-N-acetylglucosaminidase, which is essential for recycling MurNAc. Surprisingly, loss of lpqI 42 leads to antimicrobial resistance and increased proliferation in macrophages. This supports a 43 model whereby the amount of PG released by mycobacterial cells is tightly controlled in order 44 to effectively modulate the infection process. 45

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“…En un estudio con simulaciones Monte Carlo se encontró que ceftazidima y avibactam en combinación eran capaces de lisar el bacilo tuberculoso extracelular. Se encontró que avibactam es un potente inhibidor del gen blaC, que codifica la β-lactamasa de M. tuberculosis 32 . En otra publicación, se comparó el uso de ceftarolina vs ceftazidima/avibactam para micobacterias del complejo avium intracellulare (MAC).…”

Section: Ceftazidima/avibactamunclassified

Nuevas cefalosporinas

Olarte-Luis

Cáceres-Galíndez

Cortés

2018

Rev. chil. infectol.

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Ceftazidime-avibactam has potent sterilizing activity against highly drug-resistant tuberculosis

Abstract: Ceftazidime-avibactam is highly efficacious against extensive- and multidrug-resistant strains of Mycobacterium tuberculosis.

Cited by 62 publications

References 45 publications

d-Cycloserine Pharmacokinetics/Pharmacodynamics, Susceptibility, and Dosing Implications in Multidrug-resistant Tuberculosis: A Faustian Deal

d-Cycloserine Pharmacokinetics/Pharmacodynamics, Susceptibility, and Dosing Implications in Multidrug-resistant Tuberculosis: A Faustian Deal

The hydrolase LpqI primes mycobacterial peptidoglycan recycling

Nuevas cefalosporinas

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