Baylor Research Institute

Srivastava, S., Chapagain, M., van Zyl, J., Deshpande, D. and Gumbo, T. (2021). “Vancomycin’s potency against Mycobacterium tuberculosis in the hollow fiber system model.” J Glob Antimicrob Resist Jan 25;S2213-7165(21)00017-5. [Epub ahead of print].

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OBJECTIVE: To determine if inhaled vancomycin formulation, that allow deposition of high intrapulmonary 0-24hr area under the concentration-time curve [AUC(0-24)], could be optimized for treatment of tuberculosis. We also explored vancomycin synergy and antagonism with D-cycloserine and benzylpenicillin. METHODS: First, we determined MIC of the Mycobacterium tuberculosis [Mtb] laboratory strains H37Ra, and H37Rv, two drug susceptible and nine multidrug resistant clinical strains. Second, in the hollow fiber system model of TB [HFS-TB] using Mtb H37Ra strain, we recapitulated vancomycin intrapulmonary pharmacokinetics of eight different doses administered twice daily over 28 days, mimicking 6 hr half-life. Third, using the HFS-TB, vancomycin was tested in combination with D-cycloserine and benzylpenicillin to determine the synergy or antagonism between the drugs having the target in the same pathway. RESULTS: Vancomycin MICs in drug susceptible Mtb clinical isolates was 12 and 48 mg/L, but >96 mg/L in all MDR isolates. In the HFS-TB, vancomycin killed 3.9 ± 0.6 log(10) CFU/mL Mtb. Concentration mediating 50% kill [EC(50)] was calculated as AUC(0-24)/MIC of 184.6 ± 106.5. Compared to day 0 bacterial burden, 1.0 and 2.0 log(10) CFU/mL kill was achieved by an AUC(0-24)/MIC of 168 and 685, respectively. Acquired-vancomycin resistance developed to all vancomycin doses tested in the HFS-TB. In the HFS-TB, vancomycin was antagonistic to benzylpenicillin, which works downstream to glycopeptides in peptidoglycan synthesis, but was synergistic with D-cycloserine, which inhibits upstream D-Ala-D-Ala ligase and alanine racemase. CONCLUSION: Our proof-of-concept studies show that vancomycin optimal exposure target for Mtb kill could be achieved via the inhalational route drug delivery. Addition of drugs such as D-cycloserine that are synergistic with vancomycin may lower the vancomycin concentrations required to kill Mtb.

Gumbo, T., Sherman, C.M., Deshpande, D., Alffenaar, J.W. and Srivastava, S. (2021). “Mycobacterium tuberculosis sterilizing activity of faropenem, pyrazinamide and linezolid combination and failure to shorten the therapy duration.” Int J Infect Dis Feb 5;104:680-684. [Epub ahead of print].

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BACKGROUND: Faropenem (F), an orally bioavailable β-lactam, kills Mycobacterium tuberculosis (Mtb) without the help of a β-lactamase inhibitor. This study explored the sterilizing effect of adding F once or twice daily to a linezolid (L) plus pyrazinamide (Z) backbone regimen. METHODS: In vitro studies were performed using the hollow fiber model of tuberculosis (HFS-TB) to compare the kill rates of: 1) ZL two-drug combination; 2) F administered once daily plus ZL (F(1)ZL); 3) F administered twice-daily plus once daily ZL (F(2)ZL); 4) F(2)ZL with high-dose Z (F(2)Z(hi)L); 5) standard therapy of isoniazid, rifampin and Z; and 6) non-treated controls. The study was performed over 56 days with three HFS-TB replicates for each regimen. RESULTS: Mtb in the non-treated HFS-TB grew at a rate of 0.018 ± 0.007 log(10) CFU/mL/day. The exponential kill rates for standard therapy were 6.6-13.2-fold higher than ZL dual therapy. The F(1)ZL and F(2)ZL regimens ranked third. The pre-existing isoniazid-resistant sub-population in the inoculum (1.34 ± 0.57 log(10) CFU/mL) grew to 4.21 ± 0.58 log(10) CFU/mL in 56 days in non-treated HFS-TB. However, no isoniazid-resistant sub-population was recorded in any of the FZL combination regimens. CONCLUSION: Due to the slow kill rate compared to standard therapy, FZL regimens are unlikely to shorten therapy duration. Efficacy of these regimens against drug-resistant tuberculosis needs to be determined.

Bell, K.R., Fogelberg, D., Barber, J., Nakase-Richardson, R., Zumsteg, J.M., Dubiel, R., Dams-O’Connor, K. and Hoffman, J.M. (2021). “The effect of phototherapy on sleep during acute rehabilitation after traumatic brain injury: a randomized controlled trial.” Brain Inj Jan 17;1-9. [Epub ahead of print].

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Objective: To examine the impact of bright white light (BWL) exposure on sleep quality in persons with recent traumatic brain injury (TBI). Design: Randomized, controlled device-sham study Setting: 3 TBI Model System inpatient rehabilitation units Participants: 131 participants (mean 40.9 years, 68% male) Intervention: Intervention group (N = 65) received BWL (1260 lux at 20 inches, 440-480 nanometers length) for 30 minutes each morning at 12-24 inches from the face. Control group (N = 66) received red light (<450 lux, no light between 440 and 480 nanometers) for the same period. Planned intervention was maximum of 10 treatments or until discharge. Main Outcome Measure: Sleep duration and quality using actigraphic recording. Results: There were no differences found between groups on the primary outcomes nor on the secondary outcomes (sleepiness, mood, cooperation with therapy). Conclusion: BWL treatment during acute rehabilitation hospitalization does not appear to impact sleep or measures commonly associated with sleep. While studies have indicated common complaints of sleep difficulties after TBI, we were unable to document an effect for phototherapy as a treatment. With growing evidence of the effect of sleep on neural repair and cognition, further study is needed to understand the nature and treatment of sleep disorders after TBI. Clinicaltrials.gov Identifier: NCT02214212.

Walters, D.C., Jansen, E.E.W., Salomons, G.S., Arning, E., Ashcraft, P., Bottiglieri, T., Roullet, J.B. and Gibson, K.M. (2021). “Preferential accumulation of the active S-(+) isomer in murine retina highlights novel mechanisms of vigabatrin-associated retinal toxicity.” Epilepsy Res 170: 106536.

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((S)-(+)/(R)-(-)) vigabatrin (Sabril(R); γ-vinyl GABA), an antiepileptic irreversibly inactivating GABA-transaminase, was administered to male C57Bl6 J mice via continuous infusion (0, 40, 80 mg/kg/d) for 12 days. Our study design pooled retina, eye (minus retina), whole brain and plasma from n = 24 animals for each dose to provide n = 8 triplicates per treatment group. Hypothesizing that (S)-(+) VGB (active isomer) would preferentially accumulate in retina, we determined VGB isomers, comprehensive amino acids, and pharmacokinetic parameters. In brain, eye and plasma, the ((S)-(+)/(R)-(-)) ratio varied from 0.73 to 1.29 and 13.3 in retina, accompanied by a partition coefficient (tissue/plasma, ((S)-(+);(R)-(-))) of 5.8;0.34, 0.63;0.49, and 0.51;0.34 in retina, eye and brain, respectively. Racemic VGB (nmol/g; plasma, nmol/mL, range of means for dose) content was: retina, 25-36; eye (minus retina), 4.8-8.0; brain, 3.1-6.8 and plasma, 8.7-14.9. GABA tissue content (nmol/g) was 1246-3335, 18-64 and 2615-3200 as a function of VGB dose for retina, eye (minus retina) and brain, respectively. The retinal glial cell toxin 2-aminoadipic acid also increased with VGB dose (76-96 nmol/g). Partitioning of active (S)-(+) VGB to retina suggests the involvement of a stereospecific transporter, the identification of which could reveal new therapeutic paradigms that might mitigate VGB’s well-known retinal toxicity and expand its clinical utility.

Walters, D.C., Jansen, E.E.W., Salomons, G.S., Arning, E., Ashcraft, P., Bottiglieri, T., Roullet, J.B. and Gibson, K.M. (2020). “Preferential accumulation of the active S-(+) isomer in murine retina highlights novel mechanisms of vigabatrin-associated retinal toxicity.” Epilepsy Res Dec 29;170:106536. [Epub ahead of print].

Full text of this article.

((S)-(+)/(R)-(-)) vigabatrin (Sabril(R); γ-vinyl GABA), an antiepileptic irreversibly inactivating GABA-transaminase, was administered to male C57Bl6 J mice via continuous infusion (0, 40, 80 mg/kg/d) for 12 days. Our study design pooled retina, eye (minus retina), whole brain and plasma from n = 24 animals for each dose to provide n = 8 triplicates per treatment group. Hypothesizing that (S)-(+) VGB (active isomer) would preferentially accumulate in retina, we determined VGB isomers, comprehensive amino acids, and pharmacokinetic parameters. In brain, eye and plasma, the ((S)-(+)/(R)-(-)) ratio varied from 0.73 to 1.29 and 13.3 in retina, accompanied by a partition coefficient (tissue/plasma, ((S)-(+);(R)-(-))) of 5.8;0.34, 0.63;0.49, and 0.51;0.34 in retina, eye and brain, respectively. Racemic VGB (nmol/g; plasma, nmol/mL, range of means for dose) content was: retina, 25-36; eye (minus retina), 4.8-8.0; brain, 3.1-6.8 and plasma, 8.7-14.9. GABA tissue content (nmol/g) was 1246-3335, 18-64 and 2615-3200 as a function of VGB dose for retina, eye (minus retina) and brain, respectively. The retinal glial cell toxin 2-aminoadipic acid also increased with VGB dose (76-96 nmol/g). Partitioning of active (S)-(+) VGB to retina suggests the involvement of a stereospecific transporter, the identification of which could reveal new therapeutic paradigms that might mitigate VGB’s well-known retinal toxicity and expand its clinical utility.