The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin.

OBJECTIVE: To assess the relative contribution of intestinal and hepatic CYP3A inhibition to the interaction between the prototypic CYP3A substrates midazolam and clarithromycin. METHODS: On day 1, 16 volunteers (eight men and eight women; age range, 20 to 40 years; weight range, 45 to 100 kg) received simultaneous doses of midazolam intravenously (0.05 mg/kg over 30 minutes) and orally (4 mg of a stable isotope, 15N3-midazolam). Starting on day 2, 500 mg clarithromycin was administered orally twice daily for 7 days. On day 8, intravenous and oral doses of midazolam were administered 2 hours after the final clarithromycin dose. Blood and urine samples were assayed for midazolam, 15N3-midazolam, and metabolites by gas chromatography-mass spectrometry. RESULTS: There was no significant (p > 0.05) difference in the urinary excretion of 1'-hydroxymidazolam after intravenous and oral dosing on day 1 or day 8, indicating that the oral dose was completely absorbed into the gut wall. The oral clearance of midazolam was found to be significantly greater in female subjects (1.9 +/- 1.0 versus 1.0 +/- 0.3 L/hr/kg; p < 0.05) than in male subjects but not systemic clearance (0.35 +/- 0.1 versus 0.44 +/- 0.1 L/hr/kg). For women not receiving oral contraceptives (n = 6) a significant gender-related difference was observed for systemic and oral clearance and for area under the curve and elimination half-life after oral administration. A significant (p < 0.05) reduction in the systemic clearance of midazolam from 28 +/- 9 L/hr to 10 +/- 3 L/hr occurred after clarithromycin administration. Oral midazolam availability was significantly increased from 0.31 +/- 0.1 to 0.75 +/- 0.2 after clarithromycin dosing. Likewise, intestinal and oral availability were significantly increased from 0.42 +/- 0.2 to 0.83 +/- 0.2 and from 0.74 +/- 0.1 to 0.90 +/- 0.04, respectively. A significant correlation was observed between intestinal and oral availability (n = 32, r = 0.98, p < 0.05). After clarithromycin administration, a significant correlation was observed between the initial hepatic or intestinal availability and the relative increase in hepatic or intestinal availability, respectively. Female subjects exhibited a greater extent of interaction after oral and intravenous dosing than male subjects (p < 0.05). CONCLUSION: These data indicate that in addition to the liver, the intestine is a major site of the interaction between oral midazolam and clarithromycin. Interindividual variability in first-pass extraction of high-affinity CYP3A substrates such as midazolam is primarily a function of intestinal enzyme activity.

Prevention of experimental Haemophilus ducreyi infection: a randomized, controlled clinical trial.

Human subjects were infected with Haemophilus ducreyi. All subjects developed papules and were randomized to treatment with a single dose of azithromycin (1 g) or ciprofloxacin (500 mg). At weekly intervals, volunteers were reinoculated with H. ducreyi, and drug concentrations were measured in peripheral blood mononuclear cells (PBMC). When papules developed, the subjects were treated with antibiotics and dismissed from the study. Eight of the ciprofloxacin-treated subjects developed papules 1 week after the initial treatment, and the ninth subject developed disease 2 weeks after treatment. The 9 azithromycin-treated subjects developed papules 4-10 weeks (mean, 6.8) after the initial treatment (P < .001). Azithromycin was detected in PBMC for 3-6 weeks (mean, 4). Pre- and posttreatment lesions had histology typical of experimental chancroid or were culture positive. Azithromycin prevents experimental chancroid for nearly 2 months. These findings have implications for strategies to prevent chancroid.

Increased bloodstream infection rates in surgical patients associated with variation from recommended use and care following implementation of a needleless device.

OBJECTIVE: To determine if an apparent increase in bloodstream infections (BSIs) in patients with central venous catheters (CVCs) was associated with the implementation of a needleless access device. DESIGN: Retrospective cohort study using a derived CVC-days factor for estimating appropriate denominator data. SETTING: A 350-bed urban, acute, tertiary-care hospital. METHODS: BSI surveillance data were obtained, and high-risk areas for BSIs were determined. A random 5% sample of medical records was used to estimate CVC days, and a cohort study was conducted to compare BSI rates before and during needleless device use. A survey was conducted of nursing needleless-device practices. RESULTS: The surgical intensive-care unit (SICU), the medical intensive-care unit, and the solid organ transplant unit (OTU) were identified as high-risk units. Using existing surveillance BSI data and the estimated CVC days, the catheter-related BSI rates in the high-risk surgical patients were significantly higher during the needleless-device period compared with the preneedleless-device period (SICU, 9.4 vs 5.0/1,000 CVC days; OTU, 13.6 vs 2.2/1,000 CVC days). A survey of the nurses revealed that 60% to 70% were maintaining the needleless devices correctly. CONCLUSION: We observed a significant increase in the BSI rate in two surgical units, SICU and OTU, associated with introduction of a needleless device. This increase occurred shortly after the needleless device was implemented and was associated with nurses' unfamiliarity with the device, and needless-device use and care practices different from the manufacturer's recommendations.

Use of an estimation method to derive an appropriate denominator to calculate central venous catheter-associated bloodstream infection rates.

An outbreak investigation was conducted to determine if an increase in bloodstream infections (BSIs) in patients with central venous catheters (CVC) had occurred. Because other methods of obtaining CVC days were not feasible, we used an estimation method based on a random 5% sample of medical records to determine the proportion of days that a CVC was present for each of three patient units. This calculated ratio was used to estimate the total CVC days for each unit. A cohort study was conducted in which the BSI rates before and during needleless device use were compared. This article describes the methods used to calculate this estimated denominator and discusses the need for such a denominator to be used by infection control practitioners when prospective collection of CVC days is not possible.

Determination of cytochrome P450 3A4/5 activity in vivo with dextromethorphan N-demethylation.

Dextromethorphan is used widely in vivo to phenotype the polymorphically expressed cytochrome P450 (CYP) 2D6. Dextromethorphan is N-demethylated in vitro to 3-methoxymorphinan by human CYP3A4/5. We examined whether the dextromethorphan/3-methoxymorphinan urinary metabolic ratio (MR) could be used as an in vivo probe of CYP3A. Urinary excretion of 3-methoxymorphinan was excretion rate-limited in extensive metabolizers of CYP2D6, which necessitated a longer urine collection, 0 to 72 hours, to obtain true MR values for CYP3A. The urine excretion of dextromethorphan and 3-methoxymorphinan was delayed in poor metabolizers of CYP2D6 but appeared to be formation rate-limited. The delayed excretion in poor metabolizers necessitated longer urine collection intervals, 0 to 11 days, to estimate the true CYP3A MR and 0 to 8 days to estimate the true CYP2D6 MR. However, a 72-hour collection in poor metabolizers was used as an index of the true dextromethorphan/3-methoxymorphinan MR. Rifampin (300 mg b.i.d. for 7 days) significantly reduced the 0- to 72-hour dextromethorphan/3-methoxymorphinan MR consistent with an 830% (+/- 1808%) induction of CYP3A activity (n = 8), whereas erythromycin (250 mg q.i.d. for 7 days) significantly increased the dextromethorphan/3-methoxymorphinan MR, corresponding to a 34% +/- 44% inhibition of activity (n = 7) in extensive metabolizers and poor metabolizers. The changes in CYP3A activity were independent of CYP2D6 phenotype and were also observed after 24- and 48-hour urine collections in extensive metabolizers and poor metabolizers. In addition, MRs reflecting CYP2D6 and CYP3A were not significantly correlated. We conclude that the commonly used antitussive dextromethorphan can be used as an in vivo marker of CYP3A and CYP2D6 activity.

Delayed onset of angioedema with angiotensin-converting enzyme inhibitors: case report and review of the literature.

The angiotensin-converting enzyme inhibitors have gained widespread application in the management of hypertension and congestive heart failure, and after myocardial infarction. They are generally considered safe drugs, but there are a number of reports of angioedema associated with their use. In general, angioedema occurs within hours to days after initiation of therapy, and only a limited number of reports document a delayed onset. Our patient experienced angioedema after 14 months of therapy with benazepril.

Combination gel-inflatable mammary prosthesis: appearance at CT.

The combination gel-inflatable prosthesis is commonly used in breast reconstruction surgery following mastectomy for cancer. Since patients with this type of implant may be examined with computed tomography (CT) for possible pulmonary metastatic disease, recognition of the CT appearance is important in order to avoid the erroneous diagnosis of an infected prosthesis. A case is presented in which the CT appearance of a double-lumen prosthesis was misinterpreted as an infected prosthesis.