title: Meropenem-clavulanate has high in vitro activity against multidrug-resistant Mycobacterium tuberculosis.
abstract: 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.
authors.affiliation: Unit of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Department of Infectious Diseases, Karolinska University Hospital Solna, Stockholm, Sweden. Electronic address: lina.davies-forsman@karolinska.se.
authors.forename: L
authors.initials: L
authors.lastname: Davies Forsman
authors.affiliation: Department of Clinical Microbiology, MTC, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: C G
authors.initials: CG
authors.lastname: Giske
authors.affiliation: Unit of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Department of Infectious Diseases, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Bruchfeld
authors.affiliation: Department of Medical Microbiology, Linköping University Hospital, Linköping, Sweden; Department of Clinical Microbiology and Infectious Diseases, Kalmar County Hospital, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Schön
authors.affiliation: Unit for Highly Pathogenic Bacteria, Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Juréen
authors.affiliation: Department of Clinical Microbiology, MTC, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Microbiology, The University of the West Indies, Kingston, Jamaica.
authors.forename: K
authors.initials: K
authors.lastname: Ängeby
mesh_terms: D061605:Administration, Intravenous; D000995:Antitubercular Agents / Q000494:pharmacology*; D019818:Clavulanic Acid / Q000494:pharmacology*; D006801:Humans; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000302:isolation & purification; D013845:Thienamycins / Q000494:pharmacology*; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000382:microbiology*; D065093:beta-Lactamase Inhibitors / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D013845:Thienamycins; D065093:beta-Lactamase Inhibitors; D019818:Clavulanic Acid; D000077731:Meropenem
keywords: Carbapenem; In vitro susceptibility; MIC; β-Lactamase inhibitor