Pharmacokinetics of Moxifloxacin in Cerebrospinal Fluid and Plasma in Patients with Tuberculous Meningitis

Alffenaar, Jan‐Willem C.; Altena, Richard van; Bokkerink, H. J.; Luijckx, Gert Jan; Soolingen, Dick van; Aarnoutse, Rob E.; Werf, van der Tjipke

doi:10.1086/605576

Cited by 92 publications

(71 citation statements)

References 14 publications

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“…However, limited studies seem to suggest the safety of higher doses. A recent study by Ruslami et al (40) which evaluated daily 800-mg doses of moxifloxacin did not show increased toxicity, while a study by Alffenaar et al showed tolerability at 600 mg and 800 mg moxifloxacin (41). An ongoing clinical trial by Alffenaar et al is evaluating the safety of moxifloxacin at escalated doses of 600 and 800 mg (NCT01329250; http://clinicaltrials.gov /show/NCT01329250).…”

Section: Discussionmentioning

confidence: 99%

Moxifloxacin Population Pharmacokinetics and Model-Based Comparison of Efficacy between Moxifloxacin and Ofloxacin in African Patients

Zvada

Denti

Sirgel

et al. 2014

Antimicrob Agents Chemother

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h Pharmacokinetic exposure and the MIC of fluoroquinolones are important determinants of their efficacy against Mycobacterium tuberculosis. Population modeling was used to describe the steady-state plasma pharmacokinetics of moxifloxacin in 241 tuberculosis (TB) patients in southern Africa. Monte Carlo simulations were applied to obtain the area under the unbound concentration-time curve from 0 to 24 h (fAUC 0 -24 ) after daily doses of 400 mg or 800 mg moxifloxacin and 800 mg ofloxacin. The MIC distributions of ofloxacin and moxifloxacin were determined for 197 drug-resistant clinical isolates of Mycobacterium tuberculosis. For a specific MIC, the probability of target attainment (PTA) was determined for target fAUC 0 -24 /MIC ratios of >53 and >100. The PTAs were combined with the MIC distributions to calculate the cumulative fraction of response (CFR) for multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Even with the less stringent target ratio of >53, moxifloxacin at 400 mg and ofloxacin at 800 mg achieved CFRs of only 84% and 58% for multidrug-resistant isolates with resistance to an injectable drug, while the 800-mg moxifloxacin dose achieved a CFR of 98%. Using a target ratio of >100 for multidrug-resistant strains (without resistance to injectable agents or fluoroquinolones), the CFR was 88% for moxifloxacin and only 43% for ofloxacin, and the higher dose of 800 mg moxifloxacin was needed to achieve a CFR target of >90%. Our results indicate that moxifloxacin is more efficacious than ofloxacin in the treatment of MDR-TB. Further studies should determine the optimal pharmacodynamic target for moxifloxacin in a multidrug regimen and clarify safety issues when it is administered at higher doses.

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Section: Discussionmentioning

confidence: 99%

Moxifloxacin Population Pharmacokinetics and Model-Based Comparison of Efficacy between Moxifloxacin and Ofloxacin in African Patients

Zvada

Denti

Sirgel

et al. 2014

Antimicrob Agents Chemother

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“…Based on the AUC CSF /AUC S ratio, their penetration into the CSF in the absence of meningeal inflammation is much higher than that of ␤-lactam antibiotics (see Table S1.1 in the supplemental material). Fluoroquinolones are of great value for the treatment of CNS infections by Gram-negative aerobic bacilli (ciprofloxacin) and by Mycobacterium tuberculosis (moxifloxacin) (4,5). The activity of most fluoroquinolones is too low to treat Streptococcus pneumoniae meningitis (176).…”

Section: Fluoroquinolonesmentioning

confidence: 99%

“…The CSF penetrations of ethambutol and of the larger compounds streptomycin (hydrophilic) and rifampin (lipophilic; plasma protein binding rate of approximately 80%) are lower, and these compounds do not always reach CSF concentrations that are active against M. tuberculosis, in particular when meningeal inflammation is less pronounced or resolves during reconvalescence (106). When resistant strains of M. tuberculosis cause meningitis, moxifloxacin reaches high CSF concentrations in the presence and absence of meningeal inflammation and has been used successfully for this indication (4,5). The entry of isoniazid, pyrazinamide, rifampin, and streptomycin into CSF during tuberculous meningitis was not inhibited by concomitant corticosteroid treatment (20 mg dexamethasone/ day i.v.…”

Section: Antituberculosis Drugsmentioning

confidence: 99%

Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections

2010

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SUMMARY The entry of anti-infectives into the central nervous system (CNS) depends on the compartment studied, molecular size, electric charge, lipophilicity, plasma protein binding, affinity to active transport systems at the blood-brain/blood-cerebrospinal fluid (CSF) barrier, and host factors such as meningeal inflammation and CSF flow. Since concentrations in microdialysates and abscesses are not frequently available for humans, this review focuses on drug CSF concentrations. The ideal compound to treat CNS infections is of small molecular size, is moderately lipophilic, has a low level of plasma protein binding, has a volume of distribution of around 1 liter/kg, and is not a strong ligand of an efflux pump at the blood-brain or blood-CSF barrier. When several equally active compounds are available, a drug which comes close to these physicochemical and pharmacokinetic properties should be preferred. Several anti-infectives (e.g., isoniazid, pyrazinamide, linezolid, metronidazole, fluconazole, and some fluoroquinolones) reach a CSF-to-serum ratio of the areas under the curves close to 1.0 and, therefore, are extremely valuable for the treatment of CNS infections. In many cases, however, pharmacokinetics have to be balanced against in vitro activity. Direct injection of drugs, which do not readily penetrate into the CNS, into the ventricular or lumbar CSF is indicated when other effective therapeutic options are unavailable.

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“…The optimal fluoroquinolone agent and exposure for TBM treatment have not been defined. There have been case reports or small case series describing ciprofloxacin, levofloxacin, and moxifloxacin pharmacokinetics (PKs) in TBM treatment (1,2,4,7,13,38), but there are no clinical data evaluating gatifloxacin or fluoroquinolone exposure-response relationships for this patient population.…”

mentioning

confidence: 99%

Randomized Pharmacokinetic and Pharmacodynamic Comparison of Fluoroquinolones for Tuberculous Meningitis

Thwaites

Bhavnani

Chau

et al. 2011

Antimicrob Agents Chemother

119

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Pharmacokinetics of Moxifloxacin in Cerebrospinal Fluid and Plasma in Patients with Tuberculous Meningitis

Cited by 92 publications

References 14 publications

Moxifloxacin Population Pharmacokinetics and Model-Based Comparison of Efficacy between Moxifloxacin and Ofloxacin in African Patients

Moxifloxacin Population Pharmacokinetics and Model-Based Comparison of Efficacy between Moxifloxacin and Ofloxacin in African Patients

Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections

Randomized Pharmacokinetic and Pharmacodynamic Comparison of Fluoroquinolones for Tuberculous Meningitis

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