meropenem and Tuberculosis--Multidrug-Resistant

Carbapenems (ertapenem, imipenem, meropenem) are used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB), even if the published evidence is limited, particularly when it is otherwise difficult to identify the recommended four active drugs to be included in the regimen. No systematic review to date has ever evaluated the efficacy, safety, and tolerability of carbapenems.. A search of peer-reviewed, scientific evidence was carried out, aimed at evaluating the efficacy/effectiveness, safety, and tolerability of carbapenem-containing regimens in individuals with pulmonary/extra-pulmonary disease which was bacteriologically confirmed as M/XDR-TB. We used PubMed to identify relevant full-text, English manuscripts up to the 20 December 2015, excluding editorials and reviews.. Seven out of 160 studies satisfied the inclusion criteria: two on ertapenem, one on imipenem, and four on meropenem, all published between 2005 and 2016. Of seven studies, six were retrospective, four were performed in a single center, two enrolled children, two had a control group, and six reported a proportion of XDR-TB cases higher than 20%. Treatment success was higher than 57% in five studies with culture conversion rates between 60% and 94.8%.. The safety and tolerability is very good, with the proportion of adverse events attributable to carbapenems below 15%.

Topics: Antitubercular Agents; beta-Lactams; Carbapenems; Clinical Studies as Topic; Ertapenem; Extensively Drug-Resistant Tuberculosis; Humans; Imipenem; Meropenem; Thienamycins; Treatment Outcome; Tuberculosis, Multidrug-Resistant

The efficacy and toxicity of several drugs now used to treat multidrug-resistant tuberculosis (MDR-TB) have not been fully evaluated. We searched three databases for studies assessing efficacy in MDR-TB or safety during prolonged treatment of any mycobacterial infections, of drugs classified by the World Health Organization as having uncertain efficacy for MDR-TB (group 5). We included 83 out of 4002 studies identified. Evidence was inadequate for meropenem, imipenem and terizidone. For MDR-TB treatment, clarithromycin had no efficacy in two studies (risk difference (RD) -0.13, 95% CI -0.40-0.14) and amoxicillin-clavulanate had no efficacy in two other studies (RD 0.07, 95% CI -0.21-0.35). The largest number of studies described prolonged use for treatment of non-tuberculous mycobacteria. Azithromycin was not associated with excess serious adverse events (SAEs). Clarithromycin was not associated with excess SAEs in eight controlled trials in HIV-infected patients (RD 0.00, 95% CI -0.02-0.02), nor in six uncontrolled studies in HIV-uninfected patients, whereas six uncontrolled studies in HIV-infected patients clarithromycin caused substantial SAEs (proportion 0.20, 95% CI 0.12-0.27). For most group 5 drugs we found inadequate evidence of safety for prolonged use or for efficacy for MDR-TB, although macrolides appeared to be safe in prolonged use.

Topics: Amoxicillin; Antitubercular Agents; Azithromycin; Cilastatin; Clarithromycin; Clavulanic Acid; HIV Infections; Humans; Imipenem; Isoxazoles; Macrolides; Meropenem; Mycobacterium tuberculosis; Oxazolidinones; Randomized Controlled Trials as Topic; Thienamycins; Thioridazine; Treatment Outcome; Tuberculosis, Multidrug-Resistant; World Health Organization

Meropenem in combination with β-lactamase inhibitors (BLIs) and other drugs was tested to identify alternative treatment regimens for multidrug-resistant tuberculosis (MDR-TB).. The following were performed: (1) MIC experiments; (2) static time-kill studies (STKs) with different BLIs; and (3) a hollow fibre model system of TB (HFS-TB) studies with meropenem-vaborbactam combined with human equivalent daily doses of 20 mg/kg or 35 mg/kg rifampin, or moxifloxacin 400 mg, or linezolid 600 mg vs. bedaquiline-pretonamid-linezolid (BPaL) for MDR-TB. The studies were performed using Mycobacterium tuberculosis (M. tuberculosis) H37Rv and an MDR-TB clinical strain (named M. tuberculosis 16D) that underwent whole genome sequencing. Exponential decline models were used to calculate the kill rate constant (K) of different HFS-TB regimens.. Adding meropenem-vaborbactam could potentially restore the efficacy of isoniazid and rifampin against MDR-TB. The meropenem-vaborbactam-moxifloxacin backbone regimen has implications for creating a new effective MDR-TB regimen.

Topics: Antitubercular Agents; beta-Lactamase Inhibitors; Humans; Isoniazid; Linezolid; Meropenem; Moxifloxacin; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Multidrug-Resistant

The prevalence of multidrug resistant (MDR) tuberculosis (TB) with additional resistance to fluoroquinolones or second-line injectables (MDRFQ/SLI)/extensively drug-resistant TB (XDR-TB) in children is high in Mumbai. There are limited therapeutic options available in management of such children. Carbapenems, although approved for this indication, requires 2 to 3 daily injections, which are cumbersome. Bedaquilline (Bdq) and Delamanid (Dlm), the new antitubercular drugs still remain inaccessible to this subset of patients caused by conditional approvals. Hence, newer strategies to combat MDRFQ/SLI/XDR-TB needs to be explored.. To study feasibility and interim outcomes of a "salvage regimen" using home-based carbapenem therapy through peripherally inserted central catheter as part of a longer (18-20 months) optimized background regimen including Dlm or Bdq or both in pediatric MDRFQ/SLI/XDR-TB patients who failed a standard MDR-TB regimen under the National Tuberculosis Elimination Programme in Mumbai, India.. Retrospective descriptive analysis study. National Tuberculosis Elimination Programme medical records of all MDRFQ/SLI/XDR-TB patients enrolled at the pediatric TB clinic at BJ Wadia Hospital for Children, Mumbai who were initiated on such "salvage regimen" during the period between April 2018 and December 2020 were retrospectively studied. Treatment outcomes and adverse events were described.. Of the 15 patients enrolled, mean age of the patient population was 12.53 ± 2.47 years and the female:male ratio was 13:2. Seven patients had XDR-TB while 8 patients had MDRFQ/SLI. Most common adverse event noted was dyselectrolytemia (3 patients). Catheter-related complications were reported in 5 patients and included catheter blockage, leak, and thrombosis. Sputum culture conversion was reported in all of the patients. One child mortality was reported and 2 patients were lost to follow up during study period.. Home-based meropenem therapy using peripherally inserted central catheter is feasible with few adverse effects. This can be a promising strategy in the management of MDRFQ/SLI/XDR-TB when an effective oral regimen cannot be otherwise constituted and needs to be explored further.

Topics: Adolescent; Antitubercular Agents; Child; Extensively Drug-Resistant Tuberculosis; Feasibility Studies; Female; Humans; Male; Meropenem; Nitroimidazoles; Oxazoles; Retrospective Studies; Treatment Outcome; Tuberculosis, Multidrug-Resistant

The rise of antibiotic-resistant

Topics: Anti-Bacterial Agents; Humans; Meropenem; Mycobacterium tuberculosis; Structure-Activity Relationship; Tuberculosis, Multidrug-Resistant

Topics: Adult; Ambulatory Care; Antitubercular Agents; Humans; Infusions, Intravenous; Male; Meropenem; Treatment Outcome; Tuberculosis, Multidrug-Resistant

The increased incidence of drug-resistant TB is a major challenge for effective TB control. Limited therapeutic options and poor treatment outcomes of DR-TB may increase drug-resistance rates. The objective of the study is to retrospectively compare MDR-TB and pre-XDR-TB treatment regimens and outcomes in two large TB reference centres in Italy from January 2000 to January 2015.. A retrospective, multicentre study was conducted at the Regional TB Reference Centre Villa Marelli Institute (Milan) and at the Reference Center for MDR-TB and HIV-TB, Eugenio Morelli Hospital (Sondalo). The supra-national Reference Laboratory in Milan performed DST. Inclusion criteria were: age ≥ 18 and culture-confirmed diagnosis of MDR- or pre-XDR TB. Chi-square or Fisher exact test was used to detect differences in the comparison between treatment outcomes, therapeutic regimens, and drug-resistances. Computations were performed with STATA 15.. A total of 134 patients were selected. Median (IQR) age at admission was 33 (26-41) years and 90 patients (67.2%) were male. Pulmonary TB was diagnosed in 124 (92.5%) patients. MDR- and pre-XDR-TB cases were 91 (67.9%) and 43 (32.1%), respectively. The WHO shorter MDR-TB regimen could have been prescribed in 16/84 (19.1%) patients. Treatment success was not statistically different between MDR- and pre-XDR-TB (81.3% VS. 81.4%; P = 0.99). Mortality in MDR-TB and pre-XDR-TB groups was 4.4 and 9.3%, respectively (P = 0.2). Median duration of treatment was 18 months and a total of 110 different regimens were administered. Exposure to linezolid, meropenem, and amikacin was associated with a better outcome in both groups (P = 0.001, P < 0.001, and P = 0.004, respectively).. Tailored treatment regimens based on DST results can achieve successful outcomes in patients with pre-XDR-TB.

Topics: Adult; Amikacin; Antitubercular Agents; Drug Resistance, Bacterial; Extensively Drug-Resistant Tuberculosis; Female; Humans; Italy; Laboratories, Hospital; Linezolid; Male; Meropenem; Retrospective Studies; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Topics: Amoxicillin-Potassium Clavulanate Combination; Clavulanic Acid; Follow-Up Studies; Humans; Meropenem; Tuberculosis, Multidrug-Resistant

Topics: Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Clavulanic Acid; Humans; Meropenem; Tuberculosis, Multidrug-Resistant

Topics: Amoxicillin-Potassium Clavulanate Combination; Extensively Drug-Resistant Tuberculosis; Fanconi Syndrome; Humans; Meropenem; Tuberculosis, Multidrug-Resistant

The second-line drugs recommended to treat drug-resistant TB are toxic, expensive and difficult to procure. Given increasing resistance, the need for additional anti-TB drugs has become more urgent. But new drugs take time to develop and are expensive. Some commercially available drugs have reported anti-mycobacterial activity but are not routinely used because supporting laboratory and clinical evidence is sparse.. We analysed 217 MDR M. tuberculosis isolates including 153 initial isolates from unique patients and 64 isolates from follow-up specimens during the course of treatment. The resazurin microdilution assay was performed to determine MICs of trimethoprim/sulfamethoxazole, mefloquine, thioridazine, clofazimine, amoxicillin/clavulanate, meropenem/clavulanate, nitazoxanide, linezolid and oxyphenbutazone. Isoniazid was used for validation. We calculated the MIC 50 and MIC 90 as the MICs at which growth of 50% and 90% of isolates was inhibited, respectively.. The MIC 50 s, in mg/L, for initial isolates were as follows: trimethoprim/sulfamethoxazole, 0.2/4; mefloquine, 8; thioridazine, 4; clofazimine, 0.25; amoxicillin/clavulanate, 16/8; meropenem/clavulanate, 1/2.5; nitazoxanide, 16; linezolid, 0.25; and oxyphenbutazone, 40. The MIC 90 s, in mg/L, for initial isolates were as follows: trimethoprim/sulfamethoxazole, 0.4/8; mefloquine, 8; thioridazine, 8; clofazimine, 0.5; amoxicillin/clavulanate, 32/16; meropenem/clavulanate, 8/2.5; nitazoxanide, 16; linezolid, 0.25; and oxyphenbutazone, 60. By comparison, the MIC 90 of isoniazid was >4 mg/L, as expected. There was no evidence that previous treatment affected susceptibility to any drug.. Most drugs demonstrated efficacy against M. tuberculosis . When these MICs are compared with the published pharmacokinetic/pharmacodynamic profiles of the respective drugs in humans, trimethoprim/sulfamethoxazole, meropenem/clavulanate, linezolid, clofazimine and nitazoxanide appear promising and warrant further clinical investigation.

Topics: Amoxicillin-Potassium Clavulanate Combination; Antitubercular Agents; beta-Lactamase Inhibitors; Clavulanic Acid; Clofazimine; Drug Discovery; Drug Resistance, Multiple, Bacterial; Humans; Leprostatic Agents; Meropenem; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Thienamycins; Tuberculosis, Multidrug-Resistant

β-Lactams are the most widely used antibacterials. Among β-lactams, carbapenems are considered the last line of defense against recalcitrant infections. As recent developments have prompted consideration of carbapenems for treatment of drug-resistant tuberculosis, it is only a matter of time before

Topics: Amino Acid Sequence; Amino Acid Substitution; Anti-Bacterial Agents; Bacterial Proteins; Base Sequence; beta-Lactam Resistance; Cephalosporins; Clavulanic Acid; DNA, Intergenic; Gene Expression; Genetic Loci; Humans; Meropenem; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Open Reading Frames; Protein Binding; Thienamycins; Tuberculosis, Multidrug-Resistant

Topics: Antibiotics, Antitubercular; Child; Clavulanic Acid; Drug Therapy, Combination; Humans; Meropenem; Tuberculosis, Multidrug-Resistant

The combination of β-lactams and β-lactamase inhibitors has been shown to have potent in vitro activity against multidrug-resistant tuberculosis (MDR-TB) isolates. In order to identify the most potent β-lactam-β-lactamase inhibitor combination against MDR-TB, we selected nine β-lactams and three β-lactamase inhibitors, which belong to different subgroups. A total of 121 MDR-TB strains were included in this study. Out of the β-lactams used herein, biapenem was the most effective against MDR-TB and had an MIC50 value of 8 μg/ml. However, after the addition of clavulanate or sulbactam, meropenem exhibited the most potent anti-MDR-TB activity with an MIC50 value of 4 μg/ml. For meropenem, 76 (62.8%), 41 (33.9%), and 22 (18.2%) of the 121 MDR-TB strains were subjected to a synergistic effect when the drug was combined with sulbactam, tazobactam, or clavulanate, respectively. Further statistical analysis revealed that significantly more strains experienced a synergistic effect when exposed to the combination of meropenem with sulbactam than when exposed to meropenem in combination with tazobactam or clavulanate, respectively (P < 0.01). In addition, a total of 10.7% (13/121) of isolates harbored mutations in the blaC gene, with two different nucleotide substitutions: AGT333AGG and ATC786ATT. For the strains with a Ser111Arg substitution in BlaC, a better synergistic effect was observed in the meropenem-clavulanate and in the amoxicillin-clavulanate combinations than that in a synonymous single nucleotide polymorphism (SNP) group. In conclusion, our findings demonstrate that the combination of meropenem and sulbactam shows the most potent activity against MDR-TB isolates. In addition, the Ser111Arg substitution of BlaC may be associated with an increased susceptibility of MDR-TB isolates to meropenem and amoxicillin in the presence of clavulanate.

Topics: Amoxicillin; Anti-Bacterial Agents; beta-Lactamases; Clavulanic Acid; Drug Combinations; Drug Resistance, Multiple, Bacterial; Drug Synergism; Gene Expression; Humans; Meropenem; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Sulbactam; Thienamycins; Tuberculosis, Multidrug-Resistant

No large study has ever evaluated the efficacy, safety and tolerability of meropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to evaluate the therapeutic contribution, effectiveness, safety and tolerability profile of meropenem/clavulanate added to a background regimen when treating MDR- and XDR-TB cases.Patients treated with a meropenem/clavulanate-containing regimen (n=96) showed a greater drug resistance profile than those exposed to a meropenem/clavulanate-sparing regimen (n=168): in the former group XDR-TB was more frequent (49% versus 6.0%, p<0.0001) and the median (interquartile range (IQR)) number of antibiotic resistances was higher (8 (6-9)versus 5 (4-6)). Patients were treated with a meropenem/clavulanate-containing regimen for a median (IQR) of 85 (49-156) days.No statistically significant differences were observed in the overall MDR-TB cohort and in the subgroups with and without the XDR-TB patients; in particular, sputum smear and culture conversion rates were similar in XDR-TB patients exposed to meropenem/clavulanate-containing regimens (88.0% versus 100.0%, p=1.00 and 88.0% versus 100.0%, p=1.00, respectively). Only six cases reported adverse events attributable to meropenem/clavulanate (four of them then restarting treatment).The nondifferent outcomes and bacteriological conversion rate observed in cases who were more severe than controls might imply that meropenem/clavulanate could be active in treating MDR- and XDR-TB cases.

Topics: Adult; Antitubercular Agents; Clavulanic Acid; Extensively Drug-Resistant Tuberculosis; Female; Humans; Male; Meropenem; Retrospective Studies; Thienamycins; Treatment Outcome; Tuberculosis, Multidrug-Resistant

No large study to date has ever evaluated the effectiveness, safety and tolerability of imipenem/clavulanate versus meropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to compare the therapeutic contribution of imipenem/clavulanate versus meropenem/clavulanate added to background regimens to treat MDR- and XDR-TB cases.84 patients treated with imipenem/clavulanate-containing regimens showed a similar median number of antibiotic resistances (8 versus 8) but more fluoroquinolone resistance (79.0% versus 48.9%, p<0.0001) and higher XDR-TB prevalence (67.9% versus 49.0%, p=0.01) in comparison with 96 patients exposed to meropenem/clavulanate-containing regimens. Patients were treated with imipenem/clavulanate- and meropenem/clavulanate-containing regimens for a median (interquartile range) of 187 (60-428) versus 85 (49-156) days, respectively.Statistically significant differences were observed on sputum smear and culture conversion rates (79.7% versus 94.8%, p=0.02 and 71.9% versus 94.8%, p<0.0001, respectively) and on success rates (59.7% versus 77.5%, p=0.03). Adverse events to imipenem/clavulanate and meropenem/clavulanate were reported in 5.4% and 6.5% of cases only.Our study suggests that meropenem/clavulanate is more effective than imipenem/clavulanate in treating MDR/XDR-TB patients.

Topics: Adult; Antitubercular Agents; Clavulanic Acid; Cohort Studies; Comparative Effectiveness Research; Drug Resistance, Bacterial; Extensively Drug-Resistant Tuberculosis; Female; Humans; Imipenem; Male; Meropenem; Middle Aged; Sputum; Thienamycins; Time Factors; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Mycobacterium tuberculosis remains a global health threat largely due to the lengthy duration of curative antibiotic treatment, contributing to medical nonadherence and the emergence of drug resistance. This prolonged therapy is likely due to the presence of M. tuberculosis persisters, which exhibit antibiotic tolerance. Inorganic polyphosphate [poly(P)] is a key regulatory molecule in the M. tuberculosis stringent response mediating antibiotic tolerance. The polyphosphate kinase PPK1 is responsible for poly(P) synthesis in M. tuberculosis, while the exopolyphosphatases PPX1 and PPX2 and the GTP synthase PPK2 are responsible for poly(P) hydrolysis. In the present study, we show by liquid chromatography-tandem mass spectrometry that poly(P)-accumulating M. tuberculosis mutant strains deficient in ppx1 or ppk2 had significantly lower intracellular levels of glycerol-3-phosphate (G3P) and 1-deoxy-xylulose-5-phosphate. Real-time PCR revealed decreased expression of genes in the G3P synthesis pathway in each mutant. The ppx1-deficient mutant also showed a significant accumulation of metabolites in the tricarboxylic acid cycle, as well as altered arginine and NADH metabolism. Each poly(P)-accumulating strain showed defective biofilm formation, while deficiency of ppk2 was associated with increased sensitivity to plumbagin and meropenem and deficiency of ppx1 led to enhanced susceptibility to clofazimine. A DNA vaccine expressing ppx1 and ppk2, together with two other members of the M. tuberculosis stringent response, M. tuberculosis rel and sigE, did not show protective activity against aerosol challenge with M. tuberculosis, but vaccine-induced immunity enhanced the killing activity of isoniazid in a murine model of chronic tuberculosis. In summary, poly(P)-regulating factors of the M. tuberculosis stringent response play an important role in M. tuberculosis metabolism, biofilm formation, and antibiotic sensitivity in vivo.

Topics: Acid Anhydride Hydrolases; Animals; Antitubercular Agents; Biofilms; Citric Acid Cycle; Clofazimine; Disease Models, Animal; Drug Resistance, Bacterial; Gene Expression; Glycerophosphates; Isoenzymes; Isoniazid; Meropenem; Mice; Mycobacterium tuberculosis; Naphthoquinones; Phosphotransferases (Phosphate Group Acceptor); Polyphosphates; Thienamycins; Tuberculosis Vaccines; Tuberculosis, Multidrug-Resistant; Vaccines, DNA; Xylose

We investigated the activity of meropenem-clavulanic acid (MEM-CLA) against 68 Mycobacterium tuberculosis isolates. We included predominantly multi- and extensively drug-resistant tuberculosis (MDR/XDR-TB) isolates, since the activity of MEM-CLA for resistant isolates has previously not been studied extensively. Using Middlebrook 7H10 medium, all but four isolates showed an MIC distribution of 0.125 to 2 mg/liter for MEM-CLA, below the non-species-related breakpoint for MEM of 2 mg/liter defined by EUCAST. MEM-CLA is a potential treatment option for MDR/XDR-TB.

Topics: Antitubercular Agents; Clavulanic Acid; Meropenem; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Thienamycins; Tuberculosis, Multidrug-Resistant

XDR (extensively drug-resistant) and pre-XDR tuberculosis (TB) seriously compromise prognosis and treatment possibilities, and inevitably require the use of group V drugs (World Health Organization). The progress of all patients with XDR and pre-XDR TB seen in a specialized unit during 2012 and 2013 and treated with regimens that included at least 6 months of meropenem-clavulanate (MPC), capreomycin, moxifloxacin, linezolid, clofazimine, high-dose isoniazid, PAS, and bedaquiline in 1 case, were retrospectively analysed. Ten patients were treated, 9 with an extensive pattern of resistance to at least 6 drugs, and 1 because of adverse reactions and drug interactions leading to a similar situation. Eight of the 10 patients treated achieved bacteriological sputum conversion (2 consecutive negative monthly cultures) over a period of 2-7 months, while 2 died. No adverse reactions attributable to prolonged administration of MPC were observed.

Topics: Adult; Antitubercular Agents; Argentina; Clavulanic Acid; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Female; Humans; Male; Meropenem; Middle Aged; Mycobacterium tuberculosis; Peru; Retrospective Studies; Sputum; Thienamycins; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Uruguay; Young Adult

To evaluate the in vitro effectiveness of multiple breakpoint concentrations of newer antituberculosis agents (Linezolid and Meropenem) against Multi Drug-Resistant Tuberculosis (MDR-TB) isolates.. A descriptive cross-sectional study.. Microbiology Department, Armed Forces Institute of Pathology (AFIP), Rawalpindi, from September 2011 to August 2013.. A total of 100 MDR-TB isolates recovered during the study period were subjected to susceptibility testing against multiple breakpoint concentrations of Linezolid (LZD) and Meropenem (MER). The breakpoint concentration used for LZD were 0.5, 1.0 and 2.0 µg/ml, while for MER were 4.0, 8.0 and 16 µg/ml. Mycobacterial Growth Indicator Tube (MGIT) 960 system was used to carry out drug susceptibility testing as per recommended protocol.. At break point concentration of 0.5 µg/ml, 80 out of 100 (80%) MDR-TB isolates were susceptible to LZD while at breakpoint concentration of 1.0 µg/ml and 2.0 µg/ml, 96/100, (96%) of MDR-TB isolates were susceptible. For MER, at breakpoint concentrations of 4.0 µg/ml no MDR-TB isolate was susceptible, while at 8.0 µg/ml 3/100, (3%) and at 16.0 µg/ml 11/100, (11%) of MDR-TB isolates were susceptible.. LZD was found to have excellent in vitro efficacy as 96% of MDR-TB isolates were susceptible at breakpoint concentration of 1.0 µg/ml or more. In case of MER it was found that in vitro susceptibility improved as the break point concentrations were increased.

Topics: Antitubercular Agents; Cross-Sectional Studies; Humans; Linezolid; Meropenem; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pakistan; Thienamycins; Tuberculosis, Multidrug-Resistant

With the relentless increase in multidrug- and extensively-drug resistant tuberculosis (MDR/XDR-TB), new treatment strategies are necessary. Favorable results have been reported by combining a β-lactam antibiotic and a β-lactamase inhibitor. The β-lactamase encoded by the blaC gene of Mycobacterium tuberculosis (MTB) is the major mechanism of resistance to β-lactam antibiotics (e.g., penicillin). Meropenem, a β-lactam antibiotic of the carbapenem group, is a relatively weak substrate for the β-lactamase of MTB. The β-lactamase inhibitor clavulanate irreversibly inactivates the β-lactamase encoded by the blaC gene, thus making the combination of meropenem and clavulanate an interesting treatment alternative for MTB. However, very few isolates of MTB have been tested for this drug combination and few clinical reports exist. Thus, the present study investigates the in vitro activity of meropenem-clavulanate for drug-resistant MTB isolates, including MDR/XDR-TB.. The minimum inhibitory concentration (MIC) distribution of meropenem-clavulanate was determined using Middlebrook 7H10, including MDR and XDR strains of MTB (n=68). Meropenem was prepared in a stock solution with a final concentration range of 0.002-512mg/L. Clavulanate was added at a fixed concentration of 64mg/L, to avoid a decline of the β-lactamase to insufficient levels during the experiment. All isolates were evaluated after three weeks of growth. The pan-susceptible strain H37Rv was used as a control.. There was a Gaussian MIC-distribution between 0.125 and 2mg/L of meropenem-clavulanate (expressed as the concentration of meropenem), but four isolates had very high MIC levels (16 and 32mg/L), which is likely to be out of reach in clinical doses (Fig. 1). The susceptibility of the isolates to meropenem-clavulanate was not correlated to the level of resistance to first- or second-line anti-tuberculous drugs. The MIC of the pan-susceptible control strain H37Rv was 1mg/L of meropenem, when combined with clavulanate.. The present study shows that meropenem-clavulanate has low MICs against MTB in vitro, including MDR and XDR-TB isolates. Meropenem has good tissue penetration and low protein-binding, but requires an intravenous access and is relatively expensive. Meropenem-clavulanate may be a treatment option in selected cases of MDR/XDR-TB, although further clinical studies are warranted.

Topics: Administration, Intravenous; Antitubercular Agents; beta-Lactamase Inhibitors; Clavulanic Acid; Humans; Meropenem; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Thienamycins; Tuberculosis, Multidrug-Resistant

Meropenem, a broad-spectrum parenteral β-lactam antibiotic, in combination with clavulanate has recently shown efficacy in patients with extensively drug-resistant tuberculosis. As a result of meropenem's short half-life and lack of oral bioavailability, the development of an oral therapy is warranted for TB treatment in underserved countries where chronic parenteral therapy is impractical. To improve the oral absorption of meropenem, several alkyloxycarbonyloxyalkyl ester prodrugs with increased lipophilicity were synthesized and their stability in physiological aqueous solutions and guinea pig as well as human plasma was evaluated. The stability of prodrugs in aqueous solution at pH 6.0 and 7.4 was significantly dependent on the ester promoiety with the major degradation product identified as the parent compound meropenem. However, in simulated gastrointestinal fluid (pH 1.2) the major degradation product identified was ring-opened meropenem with the promoiety still intact, suggesting the gastrointestinal environment may reduce the absorption of meropenem prodrugs in vivo unless administered as an enteric-coated formulation. Additionally, the stability of the most aqueous stable prodrugs in guinea pig or human plasma was short, implying a rapid release of parent meropenem.

Topics: Animals; Drug Stability; Guinea Pigs; Humans; Hydrogen-Ion Concentration; Meropenem; Prodrugs; Thienamycins; Tuberculosis, Multidrug-Resistant; Water

Clinical experience on meropenem-clavulanate to treat tuberculosis (TB) is anecdotal (according to case reports on 10 patients). The aim of our case-control study was to evaluate the contribution of meropenem-clavulanate when added to linezolid-containing regimens in terms of efficacy and safety/tolerability in treating multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB cases after 3 months of second-line treatment. 37 cases with MDR-/XDR-TB were prescribed meropenem-clavulanate (3 g daily dose) in addition to a linezolid-containing regimen (dosage range 300-1200 mg·day(-1)), designed according to international guidelines, which was prescribed to 61 controls. The clinical severity of cases was worse than that of controls (drug susceptibility profile, proportion of sputum-smear positive and of re-treatment cases). The group of cases yielded a higher proportion of sputum-smear converters (28 (87.5%) out of 32 versus nine (56.3%) out of 16; p=0.02) and culture converters (31 (83.8%) out of 37 versus 15 (62.5%) out of 24; p=0.06). Excluding XDR-TB patients (11 (11.2%) out of 98), cases scored a significantly higher proportion of culture converters than controls (p=0.03). One case had to withdraw from meropenem-clavulanate due to increased transaminase levels. The results of our study provide: 1) preliminary evidence on effectiveness and safety/tolerability of meropenem-clavulanate; 2) reference to design further trials; and 3) a guide to clinicians for its rationale use within salvage/compassionate regimens.

Topics: Acetamides; Adult; Antitubercular Agents; Case-Control Studies; Clavulanic Acid; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Female; Humans; Linezolid; Male; Meropenem; Middle Aged; Oxazolidinones; Thienamycins; Treatment Outcome; Tuberculosis, Multidrug-Resistant

To: (i) assess if amoxicillin/clavulanate is a useful option for the management of multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB); (ii) assess if meropenem/clavulanate is active against Mycobacterium tuberculosis at concentrations achievable in vivo; and (iii) determine whether there was inhibition of meropenem/clavulanate activity in the presence of amoxicillin.. Twenty-eight M. tuberculosis strains (7 susceptible, 2 monoresistant, 16 MDR and 3 XDR) were included in the study and tested against different concentrations of meropenem, meropenem/clavulanate, amoxicillin/meropenem, amoxicillin/clavulanate and amoxicillin/meropenem/clavulanate using the Bactec 960 MGIT(®) system.. All 28 strains were resistant to meropenem at the highest concentration tested (5 mg/L). Although 24 strains were susceptible to amoxicillin/clavulanate, 7 strains were susceptible only to 7.2/2.5 mg/L amoxicillin/clavulanate, 10 strains were susceptible to 3.6/2.5 mg/L amoxicillin/clavulanate, 6 strains were susceptible to 1.8/2.5 mg/L amoxicillin/clavulanate and 1 strain was susceptible to 0.9/2.5 mg/L amoxicillin/clavulanate. Therefore, 4/28 strains (14.29%) were resistant to the highest concentration of amoxicillin tested (7.2 mg/L); all of them were MDR. All of the 11 strains resistant to amoxicillin or susceptible only to 7.2 mg/L amoxicillin increased their susceptibility to amoxicillin/clavulanate after the addition of meropenem. The addition of clavulanate to meropenem reduced the MIC of meropenem by an average of over 1.8 dilutions.. The combination of amoxicillin/clavulanate plus meropenem is active against MDR/XDR-TB in vitro, and this triple therapy could be a useful therapy for MDR/XDR-TB and possibly help to reduce the development of further resistance. The drug susceptibility technique used here is routinely used, with modification, in mycobacteriology laboratories.

Topics: Amoxicillin; Anti-Bacterial Agents; beta-Lactams; Clavulanic Acid; Drug Synergism; Humans; Meropenem; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Thienamycins; Tuberculosis, Multidrug-Resistant

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Humans; Meropenem; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Thienamycins; Tuberculosis, Multidrug-Resistant