Should Moxifloxacin Be Used for the Treatment of Extensively Drug-Resistant Tuberculosis? An Answer from a Murine Model

ABSTRACT The prevalence of extensively drug-resistant tuberculosis (XDR-TB), defined as TB that is resistant to isoniazid, rifampin, fluoroquinolones, and aminoglycosides, is rising worldwide. The extent of Mycobacterium tuberculosis resistance to fluoroquinolones depends on the mutation in the DNA gyrase, the only target of fluoroquinolones. The MIC of moxifloxacin, the most active fluoroquinolone against M. tuberculosis, may be lower than its peak serum level for some ofloxacin-resistant strains of Mycobacterium tuberculosis. Therefore, if the MIC of moxifloxacin is lower than its peak serum level, it may be effective against XDR-TB. Our objective was to determine the efficacy of moxifloxacin in treating ofloxacin-resistant TB. We selected isogenic fluoroquinolone-resistant mutants of M. tuberculosis H37Rv in vivo. We infected Swiss mice with either wild-type H37Rv or one of three mutant strains with different MICs that are commonly seen in clinical practice. The MICs of the mutant strains ranged from below to above the peak moxifloxacin level seen in humans (3 μg/ml). Each mouse was treated with one of four moxifloxacin doses for 1 month. Moxifloxacin was effective against mutant strain GyrB D500N, with the lowest MIC (0.5 μg/ml), when the standard dose was doubled. Moxifloxacin reduced mortality in mice infected with mutant strain GyrA A90V with an intermediate MIC (2 μg/ml). However, it had no impact on the mutant strain GyrA D94G with the highest MIC (4 μg/ml). Our study underscores current WHO recommendations to use moxifloxacin when there is resistance to early-generation fluoroquinolones such as ofloxacin, restricting this recommendation to strains with moxifloxacin MICs of less than or equal to 2 μg/ml.

In Vitro and In Vivo Activities of Rifampin, Streptomycin, Amikacin, Moxifloxacin, R207910, Linezolid, and PA-824 against Mycobacterium ulcerans

ABSTRACT Seven antimicrobials were tested in vitro against 29 clinical isolates of Mycobacterium ulcerans. R207910 demonstrated the lowest MIC50 and MIC90, followed by moxifloxacin (MXF), streptomycin (STR), rifampin (RIF), amikacin (AMK), linezolid (LZD), and PA-824. All but PA-824 demonstrated an MIC90 significantly less than the clinically achievable peak serum level. Administered as monotherapy to mice, RIF, STR, AMK, MXF, R207910, and LZD demonstrated some degree of bactericidal activity, whereas PA-824 failed to prevent mortality and to reduce the mean number of CFU in the footpads. Because 4 or 8 weeks of treatment by the combinations RIF-MXF, RIF-R207910, and RIF-LZD displayed bactericidal effects similar to those of RIF-STR and RIF-AMK, these three combinations might be considered as orally administered combined regimens for treatment of Buruli ulcer. Taking into account the cost, potential toxicity, and availability, the combination RIF-MXF appears more feasible for application in the field; additional experiments with mice are warranted to define further its activity against M. ulcerans. In addition, a pilot clinical trial is proposed to test the efficacy of RIF-MXF for treatment of Buruli ulcer.

Pharmacodynamics of Amphotericin B in a Neutropenic-Mouse Disseminated-Candidiasis Model

ABSTRACT In vivo pharmacodynamic parameters have been described for a variety of antibacterials. These parameters have been studied in correlation with in vivo outcomes in order to determine which dosing parameter is predictive of outcome and the magnitude of that parameter associated with efficacy. Very little is known about pharmacodynamics for antifungal agents. We utilized a neutropenic mouse model of disseminated candidiasis to correlate pharmacodynamic parameters (percent time above MIC [T > MIC], area under the concentration time curve [AUC]/MIC ratio, and peak serum level/MIC ratio) for amphotericin B in vivo with efficacy, as measured by organism number in homogenized kidney cultures after 72 h of therapy. Amphotericin B was administered by the intraperitoneal route. Drug kinetics for amphotericin B in infected mice were nonlinear. Serum half-lives ranged from 13 to 27 h. Infection was achieved by intravenous inoculation with 106 CFU of yeast cells per ml via the lateral tail vein of neutropenic mice. Groups of mice were treated with fourfold escalating total doses of amphotericin B ranging from 0.08 to 20 mg/kg of body weight divided into 1, 3, or 6 doses over 72 h. Increasing doses produced concentration-dependent killing, ranging from 0 to 2 log10 CFU/kidney compared to the organism number at the start of therapy. Amphotericin B also produced prolonged dose-dependent suppression of growth after serum levels had fallen below the MIC. Nonlinear regression analysis was used to determine which pharmacodynamic parameter best correlated with efficacy. Peak serum level in relation to the MIC (peak serum level/MIC ratio) was the parameter best predictive of outcome, while the AUC/MIC ratio and T > MIC were only slightly less predictive (peak serum level/MIC ratio, coefficient of determination [R 2] = 90 to 93%; AUC/MIC ratio,R 2 = 49 to 69%; T > MIC, R 2 = 67 to 85%). The total amount of drug necessary to achieve various microbiological outcomes over the treatment period was 4.8- to 7.6-fold smaller when the dosing schedule called for large single doses than when the same amount of total drug was administered in 2 to 6 doses. Given the narrow therapeutic window of amphotericin B and frequent treatment failures, these results suggest the need for a reevaluation of current dosing regimens.

Use of Cefamandole in the Treatment of Soft Tissue and Skeletal Infections

Thirty-eight patients were treated with cefamandole 6–12 g/d. These included 24 patients with cellulitis and/or abscess and 14 with osteomyelitis or septic arthritis. Two patients were bacteremic. Of the patients treated, 26 had an underlying disease; 27 required some surgical procedure. Staphylococcus aureus was the most frequent bacteria isolated. Of 38 patients treated, 31 had a clinical cure, six were unevaluable, and one failed on therapy. Twelve patients developed a reaction to the drug. Average peak serum level after cefamandole 1 g iv was 30.6 μg/ml (range, 10–67 μg/ml); average peak serum level after 2 g iv was 39.9 μg/ml (range, 6.6–110 μg/ml). Cancellous bone concentrations in two patients ranged from 6 to 7 μg/ml, and cortical bone concentrations in five patients ranged from 10 to 28 μg/ml.

Pharmacokinetic Comparison of Intravenous and Oral Chloramphenicol in Patients with Haemophilus in fluenzae Meningitis

The pharmacokinetics of chloramphenicol following intravenous and oral administration were studied in 14 infants with Haemophilus influenzae meningitis. Following five days of treatment with intravenous chloramphenicol (100 mg/kg/day every six hours), oral chloramphenicol was substituted at the same dose. Multiple serum levels of chloramphenicol were determined after an intravenous dose on day 4 and after an oral dose on day 10. CSF levels were measured six hours after intravenous or oral chloramphenicol dose on those days (CSF trough). Following intravenous administration, the mean peak serum level of 15.0 µ/g ml was reached at 45 minutes. In comparison, after oral chloramphenicol in the same dosage, the mean peak serum level of 18.5 µg ml was achieved at two to three hours. The mean serum half-life of the drug (6.5 hours) was significantly longer after oral administration than after intravenous chloramphenicol (4.0 hours) (P .001). The increased serum half-life following orally administered chloramphenicol was occasionally associated with drug accumulation. In addition, mean trough CSF levels were somewhat higher when the patient received oral medication (6.6 µg/ml) compared to intravenous administration (4.2 µ/ml) (P .001). For any treatment regimen for H influenzae meningitis that includes a period of oral chloramphenicol therapy the patient should be hospitalized to ensure compliance. Because of the wide range of individual variation in serum half-life that may result in accumulation, periodic monitoring of serum chloramphenicol levels is also recommended.

Cephazolin Treatment of Pneumococcal Pneumonia and Urinary Tract Infections

Ten cases of pneumococcal pneumonia were treated with cephazolin 500 mg. q8h for at least 5 days. In every case therapy was accompanied by clinical improvement and eradication of the organism. Ten patients with E. coli bacteriuria (5 symptomatic) were treated with cephazolin 500 mg. q12h for 7 to 10 days. In every case the pathogen was eliminated during therapy but in one case bacteriologic relapse occurred following cessation of therapy. In 10 cases of bacteriuria caused by P. mirabilis, Klebsiella sp, Enterobacter, and Enterococcus, the urine became sterile during treatment, but relapse was common. Initial and final creatinine clearances obtained in 29 patients who received an average of 12.9 g. of cephazolin showed no tendency toward loss of renal function. Serial serum levels of cephazolin were determined following the first 500 mg. dose in 18 patients. The peak serum level occurred at one hour with a serum half life of approximately 2.2 hours. For 13 of these 18 patients serial serum levels were also obtained following the last dose of cephazolin. At this time the mean peak level occurred at 2 hours but again the serum half life was approximately 1.9 hours.