Sterilizing Effect of Ertapenem-Clavulanate in a Hollow-Fiber Model of Tuberculosis and Implications on Clinical Dosing

Abstract

Carbapenems are now being explored for treatment of multidrugresistant tuberculosis (MDR-TB), especially in conjunction with clavulanate. Clinical use is constrained by the need for multiple parenteral doses per day and the lack of knowledge of the optimal dose for sterilizing effect. Our objective was to identify the ertapenem exposure associated with optimal sterilizing effect and then design a once-a-day dose for clinical use. We utilized the hollow-fiber system model of tuberculosis in a 28-day exposure-response study of 8 different ertapenem doses in combination with clavulanate. The systems were sampled at predetermined time points to verify the concentration-time profile and identify the total bacterial burden. Inhibitory sigmoid maximum-effect (E max ) modeling was used to identify the relationship between total bacterial burden and the drug exposure and to identify optimal exposures. Contrary to the literature, ertapenem-clavulanate combination demonstrated good microbial kill and sterilizing effect. In a dose fractionation hollow-fiber study, efficacy was linked to percentage of the 24-h dosing interval of ertapenem concentration persisting above MIC (%T MIC ). We performed 10,000 MDR-TB patient computer-aided clinical trial simulations, based on Monte Carlo methods, to identify the doses and schedule that would achieve or exceed a %T MIC of Ն40%. We identified an intravenous dosage of 2 g once per day as achieving the target in 96% of patients. An ertapenem susceptibility breakpoint MIC of 2 mg/liter was identified for that dose. An ertapenem dosage of 2 g once daily is the most suitable to be tested in a phase II study of sterilizing effect in MDR-TB patients. KEYWORDS Mycobacterium tuberculosis, ertapenem, hollow-fiber infection model, MDR-TB, pharmacodynamics, pharmacokineticsT he emergence of drug-resistant tuberculosis (TB), especially multidrug-resistant TB (MDR-TB), extensively drug-resistant TB (XDR-TB), and virtually incurable TB (termed totally drug-resistant TB by some), is a global emergency that threatens to undermine many gains of chemotherapy (1-4). As a result, there is currently a four-pronged effort to combat this problem: (i) identification of new small molecules to kill drug-resistant Mycobacterium tuberculosis, (ii) repurposing of antimicrobial drugs not currently used to treat TB into TB therapeutics, (iii) host-directed therapy, and (iv) use of pharmacokinetics/pharmacodynamics (PK/PD) science to optimize efficacy while suppressing emergence of acquired drug resistance (5-8). Carbapenems, extensively used to treat Gram-negative bacteria over the last 30 years, have also been shown to be effective

Evaluation of Carbapenems for Treatment of Multi- and Extensively Drug-Resistant Mycobacterium tuberculosis

“…Another study showed that ertapenem was unstable, degrading faster than the doubling time of M. tuberculosis in the growth medium used, suggesting that previous published MICs of ertapenem are likely to be falsely high (43). In a hollow-fiber model with supplementation of ertapenem in a broth microdilution test, ertapenem showed a MIC of 0.6 ml/liter (44). A 28-day exposure-response hollow-fiber-model TB study tested 8 different doses of ertapenem in combination with clavulanate and identified the ertapenem exposure associated with optimal sterilizing effect for clinical use.…”

“…A 28-day exposure-response hollow-fiber-model TB study tested 8 different doses of ertapenem in combination with clavulanate and identified the ertapenem exposure associated with optimal sterilizing effect for clinical use. Monte Carlo simulation with 10,000 MDR-TB patients identified a susceptibility breakpoint MIC a of 2 mg/liter for an intravenous dose of 2 g once a day that achieved or exceeded 40% T free Ͼ MIC (44). Faropenem.…”

“…Subsequently, studies addressing the inactivation mechanism of LDT provided the underlying evidence to support the hypothesis of activity of carbapenems against M. tuberculosis (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). In spite of this, a series of in vitro studies have been carried out, some of which detected an effect and some of which did not (8,(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48). Only later was it recognized that these confusing results are probably explained by the chemical instability of carbapenems in culture media at the temperatures typically used in in vitro studies, and many previously published in vitro studies are likely to have reported falsely high MICs (43).…”

Meropenem Combined with Ciprofloxacin Combats Hypermutable Pseudomonas aeruginosa from Respiratory Infections of Cystic Fibrosis Patients

“…Presently, the complex and costly attributes of the set up and operation of the dynamic HFIM hinders the incorporation of numerous different strains. Thus, recently published HFIM studies mostly entail one strain and replicate (41)(42)(43)(44)(45)(46). We are not aware of any previous dynamic studies that have evaluated the antibacterial effects of the meropenem with ciprofloxacin combination for CF patients with hypermutable P. aeruginosa in the HFIM.…”

Pharmacokinetic/Pharmacodynamic Background and Methods and Scientific Evidence Base for Dosing of Second-line Tuberculosis Drugs

“…Starting in 2002, PK/PD designs were also used in tuberculosis preclinical PK/PD studies in mouse and Guinea pig models and the hollow-fiber system model of tuberculosis (HFS-TB) [11][12][13][14][15][16][17][18]. These studies established the relationship between PK/PD exposure and microbial kill, based on the inhibitory sigmoid E max model, as well as for acquired drug resistance (ADR), based on a new quadratic function model [12][13][14][15][16][17][18][19][20][21][22][23][24]. The PK/PD relationships were later demonstrated to be invariant in patients with tuberculosis [18,25,26].…”