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Clinical pharmacology and lesion penetrating properties of second- and third-line antituberculous agents used in the management of multidrug-resistant (MDR) and extensively-drug resistant (XDR) tuberculosis.

ABSTRACT: Failure of first-line chemotherapy to cure tuberculosis (TB) patients occurs, in part, because of the development of resistance to isoniazid (INH) and rifampicin (RIF) the two most sterilizing agents in the four-drug regimen used to treat primary infections. Strains resistant to both INH and RIF are termed multidrug-resistant (MDR). Treatment options for MDR patients involve a complex array of twenty different drugs only two classes of which are considered to be highly effective (fluoroquinolones and aminoglycosides). Resistance to these two classes results in strains known as extensively drug-resistant (XDR) and these types of infections are becoming increasingly common. Many of the remaining agents have poorly defined pharmacology but nonetheless are widely used in the treatment of this disease. Several of these agents are known to have highly variable exposures in healthy volunteers and little is known in the patients in which they must be used. Therapeutic drug monitoring (TDM) is infrequently used in the management of MDR or XDR disease yet the clinical pharmacokinetic studies that have been done suggest this might have a large impact on disease outcome. We review what is known about the pharmacologic properties of each of the major classes of second- and third-line antituberculosis agents and suggest where judicious use of TDM would have the maximum possible impact. We summarize the state of knowledge of drug-drug interactions (DDI) in these classes of agents and those that are currently in clinical trials. Finally we consider what little is known about the ability of TB drugs to reach their ultimate site of action--the interior of a granuloma by penetrating the diseased lung area. Careful consideration of the pharmacology of these agents is essential if we are to avoid further fueling the growing epidemic of highly drug-resistant TB and critical in the development of new antituberculosis drugs.

SUBMITTER: Dartois V

PROVIDER: S-EPMC6344931 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Clinical pharmacology and lesion penetrating properties of second- and third-line antituberculous agents used in the management of multidrug-resistant (MDR) and extensively-drug resistant (XDR) tuberculosis.

Dartois Véronique V Barry Clifton E CE

Current clinical pharmacology 20100501 2

Failure of first-line chemotherapy to cure tuberculosis (TB) patients occurs, in part, because of the development of resistance to isoniazid (INH) and rifampicin (RIF) the two most sterilizing agents in the four-drug regimen used to treat primary infections. Strains resistant to both INH and RIF are termed multidrug-resistant (MDR). Treatment options for MDR patients involve a complex array of twenty different drugs only two classes of which are considered to be highly effective (fluoroquinolone ...[more]

PMID: 20156156

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Project description:Nosocomial infections caused by extensively drug-resistant (XDR) or Pan-Drug resistant (PDR) Acinetobacter (A.) baumannii have recently increased dramatically creating a medical challenge as therapeutic options became very limited. The aim of our study was to investigate the antibiotic-resistance profiles and evaluate the various combinations of ciprofloxacin (CIP) or levofloxacin (LEV) with antimicrobial agents and non-antimicrobial agents to combat antimicrobial resistance of XDR A. baumannii. A total of 100 (6.25%) A. baumannii clinical isolates were recovered from 1600 clinical specimens collected from hospitalized patients of two major university hospitals in Upper Egypt. Antimicrobial susceptibility tests were carried out according to CLSI guidelines. Antimicrobial susceptibility testing of the respective isolates showed a high percentage of bacterial resistance to 19 antimicrobial agents ranging from 76 to99%. However, a lower percentage of resistance was observed for only colistin (5%) and doxycycline (57%). The isolates were categorized as PDR (2; 2%), XDR (68; 68%), and multi-drug resistant (MDR) (30; 30%). Genotypic analysis using ERIC-PCR on 2 PDR and 32 selected XDR isolates showed that they were not clonal. Combinations of CIP or LEV with antibiotics (including, ampicillin, ceftriaxone, amikacin, or doxycycline) were tested on these A. baumannii non-clonal isolates using standard protocols where fractional inhibitory concentrations (-FICs) were calculated. Results of the respective combinations showed synergism in 23.5%, 17.65%, 32.35%, 17.65% and 26.47%, 8.28%, 14.71%, 26.47%, of the tested isolates, respectively. CIP or LEV combinations with either chlorpromazine (CPZ) 200 μg/ml, propranolol (PR) in two concentrations, 0.5 mg/ml and 1.0 mg/ml or diclofenac (DIC) 4 mg/ml were carried out and the MIC decrease factor (MDF) of each isolate was calculated and results showed synergism in 44%, 50%, 100%, 100% and 94%, 85%, 100%, 100%, of the tested isolates, respectively. In conclusion, combinations of CIP or LEV with CPZ, PR, or DIC showed synergism in most of the selected PDR and XDR A. baumannii clinical isolates. However, these combinations have to be re-evaluated in vivo using appropriate animal models infected by XDR- or PDR- A. baumannii.

Dataset Information

Clinical pharmacology and lesion penetrating properties of second- and third-line antituberculous agents used in the management of multidrug-resistant (MDR) and extensively-drug resistant (XDR) tuberculosis.

Publications

Clinical pharmacology and lesion penetrating properties of second- and third-line antituberculous agents used in the management of multidrug-resistant (MDR) and extensively-drug resistant (XDR) tuberculosis.

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