***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    ***EXAMPLES*** 
    Input: Objectives To identify the pyrazinamide MIC above which st and ard combination therapy fails . Methods MICs of pyrazinamide were determined for Mycobacterium tuberculosis isolates , cultured from 58 patients in a previous r and omized clinical trial in Cape Town , South Africa . The MICs were determined using BACTEC MGIT 960 for isolates that were collected before st and ard treatment with isoniazid , rifampicin , pyrazinamide and ethambutol commenced . Weekly sputum collection s were subsequently made for 8 weeks in order to culture M. tuberculosis in Middlebrook broth medium . Classification and regression tree ( CART ) analysis was utilized to identify the pyrazinamide MIC predictive of sputum culture results at the end of pyrazinamide therapy . The machine learning-derived susceptibility breakpoints were then confirmed using st and ard association statistics that took into account confounders of 2 month sputum conversion . Results The pyrazinamide MIC range was 12.5 to > 100 mg/L for the isolates prior to therapy . The epidemiological 95 % cut-off value was > 100 mg/L. The 2 month sputum conversion rate in liquid cultures was 26 % by stringent criteria and 48 % by less stringent criteria . CART analysis identified an MIC breakpoint of 50 mg/L , above which patients had poor sputum conversion rates . The relative risk of poor sputum conversion was 1.5 ( 95 % CI : 1.2–1.8 ) for an MIC > 50 mg/L compared with an MIC ≤50 mg/L. Conclusions We propose a pyrazinamide susceptibility breakpoint of 50 mg/L for clinical decision making and for development of rapid susceptibility assays . This breakpoint is identical to that identified using computer-aided simulations of hollow fibre system output BACKGROUND It is believed that nonadherence is the proximate cause of multidrug-resistant tuberculosis ( MDR-tuberculosis ) emergence . The level of nonadherence associated with emergence of MDR-tuberculosis is unknown . Performance of a r and omized controlled trial in which some patients are r and omized to nonadherence would be unethical ; therefore , other study design s should be utilized . METHODS We performed hollow fiber studies for both bactericidal and sterilizing effect , with inoculum spiked with 0.5 % rifampin- and isoniazid-resistant isogenic strains in some experiments . St and ard therapy was administered daily for 28 - 56 days , with extents of nonadherence varying between 0 % and 100 % . Sizes of drug-resistant population s were compared using analysis of variance . We also explored the effect of pharmacokinetic variability on MDR-tuberculosis emergence using computer-aided clinical trial simulations of 10 000 Cape Town , South Africa , tuberculosis patients . RESULTS Therapy failure was only encountered at extents of nonadherence ≥60 % . Surprisingly , isoniazid- and rifampin-resistant population s did not achieve ≥1 % proportion in any experiment and did not achieve a higher proportion with nonadherence . However , clinical trial simulations demonstrated that approximately 1 % of tuberculosis patients with perfect adherence would still develop MDR-tuberculosis due to pharmacokinetic variability alone . CONCLUSIONS These data , based on a pre clinical model , demonstrate that nonadherence alone is not a sufficient condition for MDR-tuberculosis emergence Possible masking of tuberculosis ( TB ) in treatment of community-acquired respiratory infection by newer fluoroquinolones has not been examined in r and omised controlled trials . We undertook a r and omised , open-label controlled trial involving adults with community-acquired pneumonia or infective exacerbation of bronchiectasis encountered in government chest clinics in Hong Kong . 427 participants were assigned by r and om permutated blocks of 20 to receive either amoxicillin clavulanate ( n = 212 ) or moxifloxacin ( n = 215 ) . Participants were followed for 1 yr for active pulmonary TB . Excluding three participants with positive baseline culture , 13 developed active pulmonary TB : 10 ( 4.8 % ) out of 210 were given amoxicillin clavulanate , and three ( 1.4 % ) out of 214 were given moxifloxacin . The difference was significant by both proportion and time-to-event analysis . Post hoc analysis showed a significant decrease in the proportion with active pulmonary TB from 4.8 % to 2.4 % and 0 % among participants given amoxicillin clavulanate ( n = 210 ) , moxifloxacin for predominantly 5 days ( n = 127 ) and 10 days ( n = 87 ) , respectively . The log rank test for trend also showed a significant difference between the three subgroups . Regression models reaffirmed the linear effect ; the adjusted odds ratio ( 95 % confidence interval ) of active pulmonary TB after moxifloxacin exposure up to predominantly 10 days was 0.3 ( 0.1–0.9 ) . Newer fluoroquinolones appear to mask active pulmonary TB The identification of multidrug resistant ( MDR ) , extensively and totally drug resistant Mycobacterium tuberculosis ( Mtb ) , in vulnerable sites such as Mumbai , is a grave threat to the control of tuberculosis . The current study aim ed at explaining the rapid expression of MDR in Directly Observed Treatment Short Course ( DOTS ) compliant patients , represents the first study comparing global transcriptional profiles of 3 pairs of clinical Mtb isolates , collected longitudinally at initiation and completion of DOTS . While the isolates were drug susceptible ( DS ) at onset and MDR at completion of DOTS , they exhibited identical DNA fingerprints at both points of collection . The whole genome transcriptional analysis was performed using total RNA from H37Rv and 3 locally predominant spoligotypes viz . MANU1 , CAS and Beijing , hybridized on MTBv3 ( BuG@S ) microarray , and yielded 36 , 98 and 45 differentially expressed genes respectively . Genes encoding transcription factors ( sig , rpoB ) , cell wall bio synthesis ( emb genes ) , protein synthesis ( rpl ) and additional central metabolic pathways ( ppdK , pknH , pfkB ) were found to be down regulated in the MDR isolates as compared to the DS isolate of the same genotype . Up regulation of drug efflux pumps , ABC transporters , trans-membrane proteins and stress response transcriptional factors ( whiB ) in the MDR isolates was observed . The data indicated that Mtb , without specific mutations in drug target genes may persist in the host due to additional mechanisms like drug efflux pumps and lowered rate of metabolism . Furthermore this population of Mtb , which also showed reduced DNA repair activity , would result in selection and stabilization of spontaneous mutations in drug target genes , causing selection of a MDR strain in the presence of drug pressures . Efflux pump such as drrA may play a significant role in increasing fitness of low level drug resistant cells and assist in survival of Mtb till acquisition of drug resistant mutations with least fitness cost BACKGROUND Based on a hollow-fiber system model of tuberculosis , we hypothesize that microbiologic failure and acquired drug resistance are primarily driven by low drug concentrations that result from pharmacokinetic variability . METHODS Clinical and pharmacokinetic data were prospect ively collected from 142 tuberculosis patients in Western Cape , South Africa . Compartmental pharmacokinetic parameters of isoniazid , rifampin , and pyrazinamide were identified for each patient . Patients were then followed for up to 2 years . Classification and regression tree analysis was used to identify and rank clinical predictors of poor long-term outcome such as microbiologic failure or death , or relapse . RESULTS Drug concentrations and pharmacokinetics varied widely between patients . Poor long-term outcomes were encountered in 35 ( 25 % ) patients . The 3 top predictors of poor long-term outcome , by rank of importance , were a pyrazinamide 24-hour area under the concentration-time curve ( AUC ) ≤ 363 mg·h/L , rifampin AUC ≤ 13 mg·h/L , and isoniazid  AUC ≤ 52 mg·h/L. Poor outcomes were encountered in 32/78 patients with the AUC of at least 1 drug below the identified threshold vs 3/64 without ( odds ratio = 14.14 ; 95 % confidence interval , 4.08 - 49.08 ) . Low rifampin and isoniazid peak and AUC concentrations preceded all cases of acquired drug resistance . CONCLUSIONS Low drug AUCs are predictive of clinical outcomes in tuberculosis patients ABSTRACT Tuberculous meningitis ( TBM ) is the most lethal form of tuberculosis , and new treatments that improve outcomes are required . We r and omly assigned adults with TBM to treatment with st and ard antituberculosis treatment alone or in combination with ciprofloxacin ( 750 mg/12 h ) , levofloxacin ( 500 mg/12 h ) , or gatifloxacin ( 400 mg/24 h ) for the first 60 days of therapy . Fluoroquinolone concentrations were measured with plasma and cerebrospinal fluid ( CSF ) specimens taken at predetermined , r and omly assigned times throughout treatment . We aim ed to describe the pharmacokinetics of each fluoroquinolone during TBM treatment and evaluate the relationship between drug exposure and clinical response over 270 days of therapy ( Controlled Trials number IS RCT N07062956 ) . Sixty-one patients with TBM were r and omly assigned to treatment with no fluoroquinolone ( n = 15 ) , ciprofloxacin ( n = 16 ) , levofloxacin ( n = 15 ) , or gatifloxacin ( n = 15 ) . Cerebrospinal fluid penetration , measured by the ratio of the plasma area under the concentration-time curve from 0 to 24 h ( AUC0–24 ) to the cerebrospinal fluid AUC0–24 , was greater for levofloxacin ( median , 0.74 ; range , 0.58 to 1.03 ) than for gatifloxacin ( median , 0.48 ; range , 0.47 to 0.50 ) or ciprofloxacin ( median , 0.26 ; range , 0.11 to 0.77 ) . Univariable and multivariable analyses of fluoroquinolone exposure against a range of different treatment responses revealed worse outcomes among patients with lower and higher plasma and CSF exposures than for patients with intermediate exposures ( a U-shaped exposure-response ) . TBM patients most likely to benefit from fluoroquinolone therapy were identified , along with exposure-response relationships associated with improved outcomes . Fluoroquinolones add antituberculosis activity to the st and ard treatment regimen , but to improve outcomes of TBM , they must be started early , before the onset of coma Background : Moxifloxacin ( MFX ) is a potent drug for multidrug resistant tuberculosis(TB ) treatment and is also useful if first-line agents are not tolerated . Therapeutic drug monitoring may help to prevent treatment failure . Obtaining a full concentration-time curve of MFX for therapeutic drug monitoring is not feasible in most setting s. Developing a limited-sampling strategy based on population pharmacokinetics ( PK ) may help to overcome this problem . Methods : Steady-state plasma concentrations after the administration of 400 mg of MFX once daily were determined in 21 patients with TB , using a vali date d liquid chromatography-t and em mass spectrometry method . A one-compartment population model was generated and crossvali date d. Monte Carlo data simulation ( n = 1000 ) was used to calculate limited-sampling strategies . The correlation between predicted MFX AUC0 - 24h ( area under the concentration-time curve 0 to 24 hours ) and observed AUC0 - 24h was investigated by Bl and -Altman analysis . Finally , the predictive performance of the final model was tested prospect ively using MFX profiles from patients with TB receiving 400 , 600 , or 800 mg once daily . Results : Median minimum inhibitory concentration of Mycobacterium tuberculosis isolates was 0.25 mg/L ( interquartile range : 0.25 - 0.5 mg/L ) . The geometric mean AUC0 - 24h was 24.5 mg·h/L ( range : 8.5 - 72.2 mg·h/L ) , which result ed in a geometric mean AUC0 - 24h/minimum inhibitory concentration ratio of 72 ( range : 21 - 321 ) . PK analysis , based on PK profiles of 400 mg of MFX once daily , result ed in a crossvali date d population PK model with the following parameters : apparent clearance ( Cl ) 18.5 ± 8.6 L/h per 1.85 m2 , Vd 3.0 ± 0.7 L/kg corrected lean body mass , Ka 1.15 ± 1.16 h−1 , and F was fixed at 1 . After the Monte Carlo simulation , the best predicting strategy for MFX AUC0 - 24h for practical use was based on MFX concentrations 4 and 14 
    Output:
    
The HFS-TB model is highly accurate at forecasting optimal drug exposures , doses , and dosing schedules for use in the clinic