Biology subjects

Gumbo, T.

Publications and source records attributed to Gumbo, T..

5 recordsLinked to original sources

bioRxiv2026

Novel regimens for treatment of Mycobacterium avium lung disease based on advanced in vitro systems and the mathematics of basis functions

Azithromycin plus ethambutol plus rifabutin (azithromycin-ethambutol-rifabutin) is the standard-of-care (SOC) for Mycobacterium avium-complex lung disease. The SOC achieves sustained sputum culture conversion in only 43-53% of patients, after an average of 18 months of therapy. Recent quantitative analyses ranked omadacycline, ceftriaxone, and minocycline highest for microbial kill. Azithromycin-minocycline-ethambutol, azithromycin-omadacycline-ethambutol, epetraborole-omadacycline-ethambutol, ceftriaxone-omadacycline-rifabutin, and the SOC were compared in the intracellular hollow fiber system model of M. avium lung disease (HFS-MAC). HFS-MAC units were treated once daily for 28 days to mimic the intrapulmonary pharmacokinetics of each drug. The ceftriaxone concentrations measured in the HFS-MAC were only 1% of those achieved in the lung by standard clinical doses. Changes in the bacterial burden were described using basis functions (BF). For liquid cultures, BF 1 (BF1) was described by a linear regression-based slope, with steepest kill slope (95% Confidence interval) of 7.87 (1.52 to14.23) by ceftriaxone-omadacycline-rifabutin versus 1.04 (-0.84 to 2.92) for SOC. For the CFU/mL readout, the BF1 steepest non-linear kill slope was for ceftriaxone-omadacycline-rifabutin of 0.55 (0.35 to 0.98) log10 CFU/mL/day versus 0.16 (0.07 to 0.25) log10 CFU/mL/day for the SOC. Thus, ceftriaxone-omadacycline-rifabutin is potentially better than the SOC, even though further ceftriaxone dose optimization is required. BF2 described rebound growth and drug-resistant subpopulation growth, and demonstrated that contrary to popular belief, SOC rebound was best explained by ethambutol-resistance (r2>0.99, p=0.01) and not by azithromycin-resistance (r2=0.27, p=0.32), questioning ethambutols role in the SOC. The BF framework is potentially easy to adapt for modeling other anti-infective agents across many infectious diseases.

microbiology↗

bioRxiv2025

Sulbactam-Durlobactam Plus Ceftriaxone Dosing and Novel Treatment Regimens for Mycobacterium abscessus Lung Disease

BackgroundIDSA guideline-based therapy achieves sputum culture conversion rates in 20-34% of patients with Mycobacterium abscessus (MAB) lung disease (LD). Double-{beta}-lactam combinations have been proposed to improve cure, based on time-kill curves. MethodsWe performed minimum inhibitory concentrations (MICs) experiments followed by hollow fiber system model of MAB-LD (HFS-MAB) exposure-effect studies with sulbactam-durlobactam administered every 8h (q8h), q12h, and q24h, to identify target exposures. Next, the sulbactam-durlobactam target exposure plus ceftriaxone was administered in the HFS-MAB inoculated with three different MAB isolates, as was the sulbactam-durlobactam-ceftriaxone combination with epetraborole and omadacycline (SDCEO).{gamma} -slopes (kill-speed) were calculated for all regimens. The minimal sulbactam-durlobactam clinical doses that achieved target exposure were identified using Monte Carlo experiments. ResultsCeftriaxone reduced sulbactam-durlobactam MICs by 8-tube dilutions. In the HFS-MAB, sulbactam-durlobactam microbial kill and antimicrobial resistance were linked to % time concentration persists above MIC (%TMIC), with target exposure of 50%. Sulbactam-durlobactam killed 3.85 log10 CFU/mL below day 0 burden (B0) with regrowth. Sulbactam-durlobactam plus ceftriaxone killed without regrowth and demonstrated Bliss additivity.{gamma} of bacterial population in >95% of virtual subjects were 2.28 (0.97-4.80) log10 CFU/mL/day for sulbactam-durlobactam-ceftriaxone and 2.91 (1.65-4.93) log10 CFU/mL/day for SDCEO. The optimal sulbactam-durlobactam dose co-administered with ceftriaxone was 2G q8h for creatinine clearance >90 mL/min, 2G q12h for 60-90 mL/min, 1G q12h for [≥]30 to <60 mL/min, and 1G q24h for <30 mL/min. ConclusionSulbactam-durlobactam-ceftriaxone achieved the highest microbial kill encountered so far in the HFS-MAB. Sulbactam-durlobactam-ceftriaxone should be tested as the backbone for novel treatment shortening regimens.

pharmacology and toxicology↗

bioRxiv2025

Tigecycline pharmacodynamics in the hollow fiber system of Mycobacterium avium-complex lung disease, and the utility of MICs and time-kill studies in drug development

BackgroundGuideline-based therapy (GBT) drugs for Mycobacterium avium-complex (MAC) lung disease (LD) were chosen in part because they have low MICs. Despite these low MICs, GBT achieves six-month sustained sputum culture conversion in only 43% of patients. MethodsFirst, we co-incubated tigecycline with MAC for seven days in time-kill studies and calculated the exposure mediating 50% of maximal effect (Emax) or EC50. Next, we performed tigecycline exposure-effect studies in the hollow fiber system of MAC (HFS-MAC) inoculated with the reference ATCC#700898 isolate. Third, we performed an exposure-effect study in the HFS-MAC inoculated with 5 different isolates. Finally, the target exposure (EC80) was used to identify a clinical dose of inhaled tigecycline for MAC-LD in 10,000 subject Monte Carlo experiments (MCE). ResultsIn time-kill studies the EC50 was 0-24h area under the concentration-time curve-to-MIC (AUC0-24/MIC) of 62.24 for extracellular and 0.14 for intracellular MAC (p<0.001). In the HFS-MAC inoculated with ATCC#700898, the EC50 statistically differed between sampling days by 2,370.7%. However, studies with five different isolates demonstrated a stable and robust day-to-day EC50 (%CV=18.18%), with an EC80 AUC0-24/MIC of 33.65. The Emax was 4.84 log10 CFU/mL. In MCE, tigecycline inhalational doses of 35-40 mg/day achieved the EC80 target in >90% of virtual patients, with and an MIC breakpoint of 256 mg/L. ConclusionTime-kill studies do not inform on PK/PD target exposures or extent of kill. Inclusion of multiple MAC isolates in HFS-MAC studies improves precision of pharmacokinetic/pharmacodynamic parameter estimates. Tigecycline via the inhalational route could contribute to treatment of MAC-LD.

pharmacology and toxicology↗

bioRxiv2025

Systematic and quantitative analyses of pre-clinical Mycobacterium avium Lung Disease Tools for Drug Development and Transition from Animal Models to New Approach Methodologies

Animal and new approach methodologies such as the hollow fiber system model [HFS] are used for Mycobacterium avium-complex [MAC] lung disease [LD] preclinical drug development. Our objective was to perform a systematic review to benchmark these pre-clinical tools. We performed a literature search to identify preclinical pharmacokinetics/pharmacodynamics [PK/PD] studies for MAC-LD. Preferred Reporting Items for Systematic Reviews and Meta-analyses was used for bias minimization. Twenty HFS-MAC and 3 mouse studies met PK/PD inclusion criteria. We created a novel quality score tool based on predictors of clinical response, design optimization, and information theory. The quality score was judged high in 10%, good in 50%, adequate in 30%, and poor in 10% of studies. Monte Carlo experiments for PK/PD target attainment were reported in 61% of studies. On repetitive sampling, the PK/PD target exposure estimate varied significantly between sampling days in 76% of studies. The solution was ordinary differential equations with parameter outputs such as {gamma} [nonlinear kill-slope] and time-to-extinction applied to both HFS-MAC and patients sputa CFU/mL output. Next, we ranked the antibiotics by extent of microbial kill as fold-improvement over guideline-based therapy. The three top ranked drugs for microbial kill were omadacycline [69-fold], tedizolid [19-fold], and ceftriaxone [8-fold]. We recommend the HFS-MAC as tractable for exposure-effect and dose-fractionation studies, ranking antibiotics effect, and for translation to clinical doses. The analyses inform us of HFS-MAC recommendations for regulatory authorities and drug developers, including quality scores for optimal PK/PD design for target identification, resistance suppression, and choice of the best novel regimen.

pharmacology and toxicology↗

bioRxiv2022

Novel tuberculosis combination regimens of two and three-months therapy duration

The tuberculosis treatment duration is 4-6 months, but can be 18-20 months with multidrug resistance. Ultrashort regimens that cure regardless of resistance status ["pan-tuberculosis regimens"] would be a major step towards global tuberculosis control. Starting with seven drugs [bedaquiline, delamanid, pretomanid, OPC-167832, sutezolid, moxifloxacin, and pyrazinamide] in clinical testing, we calculated that there were thousands of possible novel combinations to evaluate. We used mathematical and pharmacokinetics/pharmacodynamic-based hollow fiber modeling to reduce this complexity to nine combinations, which we tested. Each regimens fast and slow growth bacteria kill-slope trajectories and times-to-extinction were estimated and translated to minimum required therapy duration in patients. Sputum microbial kill trajectories of two combination regimens that have undergone clinical testing were correctly predicted by this approach. Four pan-tuberculosis regimens were predicted to achieve relapse-free cure after 2-3 months therapy in patients. The kill-slopes were used to design expedited clinical trials that minimize patients risks.

pharmacology and toxicology↗