ABSTRACT
Hearing loss and nephrotoxicity are associated with prolonged treatment duration and higher dosage of amikacin and kanamycin. In our tuberculosis center, we used therapeutic drug monitoring (TDM) targeting preset pharmacokinetic/pharmacodynamic (PK/PD) surrogate endpoints in an attempt to maintain efficacy while preventing (oto)toxicity. To evaluate this strategy, we retrospectively evaluated medical charts of tuberculosis (TB) patients treated with amikacin or kanamycin in the period from 2000 to 2012. Patients with culture-confirmed multiresistant or extensively drug-resistant tuberculosis (MDR/XDR-TB) receiving amikacin or kanamycin as part of their TB treatment for at least 3 days were eligible for inclusion in this retrospective study. Clinical data, including maximum concentration (Cmax), Cmin, and audiometry data, were extracted from the patients' medical charts. A total of 80 patients met the inclusion criteria. The mean weighted Cmax/MIC ratios obtained from 57 patients were 31.2 for amikacin and 12.3 for kanamycin. The extent of hearing loss was limited and correlated with the cumulative drug dose per kg of body weight during daily administration. At follow-up, 35 (67.3%) of all patients had successful outcome; there were no relapses. At a median dose of 6.5 mg/kg, a correlation was found between the dose per kg of body weight during daily dosing and the extent of hearing loss in dB at 8,000 Hz. These findings suggest that the efficacy at this lower dosage is maintained with limited toxicity. A randomized controlled trial should provide final proof of the safety and efficacy of TDM-guided use of aminoglycosides in MDR-TB treatment.
Subject(s)
Amikacin/pharmacokinetics , Antitubercular Agents/pharmacokinetics , Drug Monitoring , Extensively Drug-Resistant Tuberculosis/drug therapy , Hearing Loss/diagnosis , Kanamycin/pharmacokinetics , Mycobacterium tuberculosis/drug effects , Adult , Amikacin/adverse effects , Amikacin/blood , Antitubercular Agents/adverse effects , Antitubercular Agents/blood , Area Under Curve , Audiometry , Biological Availability , Drug Administration Schedule , Drug Dosage Calculations , Extensively Drug-Resistant Tuberculosis/blood , Extensively Drug-Resistant Tuberculosis/microbiology , Female , Hearing Loss/chemically induced , Hearing Loss/pathology , Humans , Kanamycin/adverse effects , Kanamycin/blood , Male , Microbial Sensitivity Tests , Mycobacterium tuberculosis/growth & development , Retrospective StudiesABSTRACT
Little is known about plasma drug concentrations relative to quantitative susceptibility in patients with multidrug-resistant tuberculosis (MDR-TB). We previously described a TB drug activity (TDA) assay that determines the ratio of the time to detection of plasma-cocultured Mycobacterium tuberculosis versus control growth in a Bactec MGIT system. Here, we assess the activity of individual drugs in a typical MDR-TB regimen using the TDA assay. We also examined the relationship of the TDA to the drug concentration at 2 h (C2) and the MICs among adults on a MDR-TB regimen in Tanzania. These parameters were also compared to the treatment outcome of sputum culture conversion. Individually, moxifloxacin yielded superior TDA results versus ofloxacin, and only moxifloxacin and amikacin yielded TDAs equivalent to a -2-log killing. In the 25 patients enrolled on a regimen of kanamycin, levofloxacin, ethionamide, pyrazinamide, and cycloserine, the C2 values were found to be below the expected range for levofloxacin in 13 (52%) and kanamycin in 10 (40%). Three subjects with the lowest TDA result (<1.5, a finding indicative of poor killing) had significantly lower kanamycin C2/MIC ratios than subjects with a TDA of ≥1.5 (9.8 ± 8.7 versus 27.0 ± 19.1; P = 0.04). The mean TDAs were 2.52 ± 0.76 in subjects converting to negative in ≤2 months and 1.88 ± 0.57 in subjects converting to negative in >2 months (P = 0.08). In Tanzania, MDR-TB drug concentrations were frequently low, and a wide concentration/MIC range was observed that affected plasma drug activity ex vivo. An opportunity exists for pharmacokinetic optimization in current MDR-TB regimens, which may improve treatment response.
Subject(s)
Antitubercular Agents/blood , Mycobacterium tuberculosis/drug effects , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Pulmonary/drug therapy , Adolescent , Adult , Amikacin/blood , Amikacin/pharmacokinetics , Amikacin/therapeutic use , Antitubercular Agents/pharmacokinetics , Antitubercular Agents/therapeutic use , Cycloserine/blood , Cycloserine/pharmacokinetics , Cycloserine/therapeutic use , Ethionamide/blood , Ethionamide/pharmacokinetics , Ethionamide/therapeutic use , Female , Fluoroquinolones/blood , Fluoroquinolones/pharmacokinetics , Fluoroquinolones/therapeutic use , Humans , Kanamycin/blood , Kanamycin/pharmacokinetics , Kanamycin/therapeutic use , Levofloxacin/blood , Levofloxacin/pharmacokinetics , Levofloxacin/therapeutic use , Male , Microbial Sensitivity Tests , Middle Aged , Moxifloxacin , Mycobacterium tuberculosis/growth & development , Ofloxacin/blood , Ofloxacin/pharmacokinetics , Ofloxacin/therapeutic use , Pyrazinamide/blood , Pyrazinamide/pharmacokinetics , Pyrazinamide/therapeutic use , Sputum/microbiology , Tanzania , Tuberculosis, Multidrug-Resistant/blood , Tuberculosis, Multidrug-Resistant/microbiology , Tuberculosis, Pulmonary/blood , Tuberculosis, Pulmonary/microbiologyABSTRACT
Antioxidant therapy protects against aminoglycoside-induced ototoxicity in animal models. A clinically suitable antioxidant must not affect the therapeutic efficacy of aminoglycosides or exhibit any side effects of its own. In addition, the treatment should be inexpensive and convenient in order to be implemented in developing countries where the use of aminoglycosides is most common. Standardized Salviae miltiorrhizae extracts (Danshen) are used clinically in China and contain diterpene quinones and phenolic acids with antioxidant properties. We combined in vitro and in vivo approaches to investigate the effect of a clinically approved injectable Danshen solution on aminoglycoside-induced free radical generation and ototoxicity. In vitro, Danshen inhibited gentamicin-dependent lipid peroxidation (formation of conjugated dienes from arachidonic acid), as well as the gentamicin-catalyzed formation of superoxide (in a lucigenin-based chemiluminescence assay) and hydroxyl radicals (oxidation of N,N-dimethyl-p-nitrosoaniline). Danshen extracts were then administered to adult CBA mice receiving concurrent treatment with kanamycin (700 mg/kg of body weight twice daily for 15 days). Auditory threshold shifts induced by kanamycin (approximately 50 dB) were significantly attenuated. Danshen did not reduce the levels in serum or antibacterial efficacy of kanamycin. These results suggest that herbal medications may be a significantly underexplored source of antidotes for aminoglycoside ototoxicity. Such traditional medicines are widely used in many developing countries and could become an easily accepted and inexpensive protective therapy.
Subject(s)
Anti-Bacterial Agents/adverse effects , Drugs, Chinese Herbal/pharmacology , Gentamicins/adverse effects , Hearing Loss/chemically induced , Hearing Loss/prevention & control , Kanamycin/adverse effects , Phenanthrenes/pharmacology , Abietanes , Animals , Anti-Bacterial Agents/blood , Auditory Threshold/drug effects , Cochlea/drug effects , Cochlea/pathology , Drug Interactions , Evoked Potentials, Auditory, Brain Stem/drug effects , Free Radical Scavengers/pharmacology , Hearing Loss/metabolism , Hydroxyl Radical/metabolism , Kanamycin/blood , Lipid Peroxidation/drug effects , Male , Mice , Mice, Inbred CBA , Oxidants/adverse effects , Oxidants/metabolism , Superoxides/metabolismABSTRACT
This study documents an important change in the kanamycin in susceptibilites of Escherichia coli strains cultivated from neonates. Whereas some nurseries have in the past experienced resistance rates as high as 70 per cent recent survelliance of seven North American nurseries demonstrated that 90 percent or more of E. coli strains are currently susceptible to kanamycin. Pharmacokinetic studies of 65 babies treated with either 7.5 or 10 mg/kg kanamycin doses revealed that peak serum values varied with dosage, birthweight, and chronologic age. Peak serum levels were below the desired therapeutic range in many babies treated with 7.5 mg/kg doses of kanamycin every 12 hours. Concentrations in cerebrospinal fluid specimens from 21 infants were 0.5 to 12 mu/ml after 7.5 mg/kg kanamycin doses. Calculated distribution volumes, plasma clearances, and serum half-life values were used in formulating a revised kanamycin in dosage and frequency of administration schedule.