Musculoskeletal injury associated with fluoroquinolone antibiotics.

With the expanded use of fluoroquinolones and increasing number of reports of tendon injury linked to these agents, clinicians must be aware of the frequency and strength of this association. In the past, pefloxacin and ciprofloxacin were most frequently implicated, but tendon injury is reported with most fluoroquinolones. As many as half of patients with fluoroquinolone-associated tendinopathy experience tendon rupture, and almost one third have received long-term corticosteroids. Tendon injury is mostly reported in the lower extremities, but injury in the upper extremities, including the hand, has also been reported. Management is similar regardless of the location of the injury. Use of fluoroquinolones requires careful patient assessment and follow-up in view of this complication with potential for sequelae.

The pharmacokinetics of nelfinavir and M8 during pregnancy and post partum.

OBJECTIVE: The objective of this study was to explore the pharmacokinetics of nelfinavir and its active metabolite hydroxy-t-butylamidenelfinavir (M8) during pregnancy and post partum. METHODS: Eleven human immunodeficiency virus type 1-infected pregnant women receiving 1250 mg nelfinavir twice daily were enrolled. Pharmacokinetics of nelfinavir and M8 were assessed over a 12-hour period during pregnancy (median, 32 weeks' gestation; range, 31-36 weeks) and post partum (median, 8 weeks post partum; range, 6-15 weeks). Drug concentrations were analyzed by HPLC coupled to tandem mass spectroscopy, and pharmacokinetic parameters were calculated by use of noncompartmental methods. RESULTS: The median area under the plasma concentration-time curve from 0 to 12 hours (AUC 0-12), the maximal plasma concentration (C max), and the concentration at the end of the dosing interval (C 12) for nelfinavir post partum were 33.5 h . microg/mL, 5.80 microg/mL, and 1.40 microg/mL, respectively. The values for the geometric mean ratio (GMR) (third trimester/post partum) for the nelfinavir AUC 0-12 , C max , and C 12 were 0.76 (90% confidence interval [CI], 0.54-1.06), 0.81 (90% CI, 0.57-1.15), and 0.43 (90% CI, 0.25-0.76), respectively. The GMR values for the M8 AUC 0-12 , C max , and C 12 were 0.32 (90% CI, 0.18-0.55), 0.31 (90% CI, 0.19-0.51), and 0.30 (90% CI, 0.14-0.64), respectively. The median ratio values of the AUC 0-12 of M8 and nelfinavir (M8/nelfinavir) during the third trimester and post partum were 11% and 27%, respectively (GMR, 0.42 [90% CI, 0.33-0.53]). CONCLUSIONS: Nelfinavir exposure was reduced during pregnancy, and the reduction was statistically significant for C 12 . M8 concentrations were about 70% lower during pregnancy compared with post partum, suggesting either induction of hepatic cytochrome P450 (CYP) 3A4 or inhibition of CYP2C19, or both, during pregnancy. Because 8 of 11 women had subtherapeutic nelfinavir trough concentrations during pregnancy, the safety and efficacy of therapeutic drug monitoring should be investigated.

Fluoroquinolone-associated tendinopathy: a critical review of the literature.

With the expanded use of fluoroquinolones for the treatment of community-acquired respiratory infections and reports of tendon injury linked to the use of these agents, we reviewed the literature to investigate the frequency and strength of this association. Ninety-eight case reports were available for review. The incidence of tendon injury associated with fluoroquinolone use is low in a healthy population but increases in patients who have renal dysfunction, who are undergoing hemodialysis, or who have received renal transplants. Pefloxacin and ciprofloxacin were most frequently implicated, but tendon injury was reported with most fluoroquinolones. The median duration of fluoroquinolone treatment before the onset of tendon injury was 8 days, although symptoms occurred as early as 2 hours after the first dose and as late as 6 months after treatment was stopped. Up to one-half of patients experienced tendon rupture, and almost one-third received long-term corticosteroid therapy. Tendon injury associated with fluoroquinolone use is significant, and risk factors such as renal disease or concurrent corticosteroid use must be considered when these agents are prescribed.

Antimicrobial release kinetics from polymethylmethacrylate in a novel continuous flow chamber.

Polymethylmethacrylate is used for local delivery of antimicrobials in the treatment of musculoskeletal infections. A novel continuous flow chamber system was designed to measure in vitro antimicrobial release. Three-millimeter beads containing amikacin, gentamicin, tobramycin, or vancomycin [concentration of 7.5% (weight per weight)] were placed individually in a continuous flow chamber with a total volume of 1 mL Kreb's Ringer buffer flowing at 1 mL/hour. Effluent was sampled hourly for 24 hours and then every 2 hours up to 48 hours; antimicrobial concentrations were measured in triplicate by bioassay. The mean peak concentrations were 40.9, 30.1, 30.0, and 19.1 microg/mL; the mean areas under the concentration time curves (Time 0 to infinity) were 263, 327, 110, and 180 hours x microg/mL of antibiotic; and the mean percentages of initial amount of antimicrobial released were 11.7%, 14.5%, 6.6%, and 10.9% for tobramycin, gentamicin, amikacin, and vancomycin, respectively. The results for each polymethylmethacrylate-antimicrobial agent combination were reproducible. In contrast to other in vitro elution systems, this novel system operates under the premise that there is dynamic flow surrounding polymethylmethacrylate in vivo and permits rapid in vitro comparison of the relative release of antimicrobial agents from polymethylmethacrylate.

Bacteremia due to viridans group Streptococci with diminished susceptibility to Levofloxacin among neutropenic patients receiving levofloxacin prophylaxis.

Despite the use of levofloxacin prophylaxis during the neutropenic period after autologous peripheral blood stem cell transplantation, viridans group (VG) streptococcal bacteremia developed in 6 (16.2%) of 37 patients who underwent transplantation between 1 January and 25 February 2001 at the Mayo Clinic in Rochester, Minnesota. All 6 patients presented with fever and mucositis after a mean of 4.5 days of neutropenia, and 3 developed septic shock. All 6 VG streptococcal isolates from these patients exhibited distinct patterns on pulsed-field gel electrophoresis. All isolates had diminished susceptibility to levofloxacin, 5 to gatifloxacin, and 4 to moxifloxacin. Quinolone resistance was associated with mutations in the quinolone resistance-determining region of GyrA and (for 1 isolate) of ParC. The use of levofloxacin may select VG streptococci with diminished susceptibility to levofloxacin and other quinolones with enhanced activity against gram-positive organisms and, therefore, may not be optimal for preventing VG streptococcal bacteremia in neutropenic patients.