Genetic analysis of five sedentary fish species in middle Laranjinha River (upper Paraná River basin): A case study.

Most studies of diversity and genetic structure in neotropical fish have focused on commercial species from large rivers or their reservoirs. However, smaller tributaries have been identified as an important alternative migratory route, with independent pools of genetic diversity. In this context, the present study aimed to evaluate genetic diversity and structure in five neotropical fish species from a region of Laranjinha River in the upper Paraná River basin. PCR-RAPD (random amplified polymorphic DNA) markers were used to characterize around 40 individuals of each species distributed upstream and downstream of Corredeira Dam that interrupts the river. The descriptive index of genetic diversity (P = 30.5-82%; HE 0.122-0.312) showed that the populations have acceptable levels of genetic diversity. The values for Nei's genetic distance (DN min 0.0110 and max 0.0306) as well as the genetic structure index and the analysis of molecular variance (AMOVA, ϕST min 0.0132 and max 0.0385) demonstrated low, but significant levels of genetic structure. Bayesian analysis of assignment found two k clusters, including several individuals with mixed ancestry for all populations from the five species analyzed. These findings along with historical data on rainfall and the low dimensions of the dam studied here support the hypothesis that periodic floods enable the transit of individuals between different localities mitigating the differentiation process between populations.

Effects of AIDS and gender on steady-state plasma and intrapulmonary ethambutol concentrations.

Our objective was to study the steady-state plasma and intrapulmonary orally administered ethambutol concentrations in healthy volunteers and subjects with AIDS. Ethambutol (15 mg/kg of body weight) was administered orally once daily to 10 men with AIDS, 10 healthy men, 10 women with AIDS, and 10 healthy women. The mean (+/-standard deviation [SD]) CD4 cell count for the 20 subjects with AIDS was (350 +/- 169) x 10(6) cells per liter. Blood was obtained for drug assay 2 h after the last dose and at the completion of bronchoalveolar lavage, performed 4 h after the last dose. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) was calculated by the urea dilution method. The total number of alveolar cells (AC) was counted in a hemocytometer, and differential cell counting was performed after cytocentrifugation. Ethambutol was measured by a new, sensitive and specific liquid chromotography-mass spectrometry method. The presence of AIDS, as defined in this study, or gender was without significant effect on the concentrations of ethambutol in plasma at 2 or 4 h or in ELF at 4 h following the last dose. Plasma drug concentrations (mean +/- SD) at 2 and 4 h were 2.1 +/- 1.2 and 2.1 +/- 0.8 microg/ml, respectively, and both values were not significantly different from the concentration of ethambutol in ELF at 4 h (2.2 +/- 1.1 microg/ml). The concentration of ethambutol was significantly greater in AC in all four groups (range, 44.5 +/- 15.6 to 82.0 +/- 39.4 microg/ml) than in ELF or plasma and was approximately 30 to 240 times the reported MIC for ethambutol-susceptible strains of Mycobacterium tuberculosis. The AC ethambutol concentration (mean +/- SD) in the smoking women (97.2 +/- 32.1 microg/ml) was more than twice the concentration in all other nonsmoking subjects (45.2 +/- 16.8 microg/ml) combined (P < 0.05). Two- and 4-h concentrations of ethambutol in plasma were not affected by AIDS status or gender. The high AC/plasma and AC/ELF concentration ratios suggest that substantial antimycobacterial activity resides in these cells. The data confirm earlier observations of active transport ex vivo of ethambutol into pulmonary macrophages.

High-performance liquid chromatographic-tandem mass spectrometric method for the determination of ethionamide in human plasma, bronchoalveolar lavage fluid and alveolar cells.

We have developed and validated an accurate, sensitive, and rapid high-performance liquid chromatographic-tandem mass spectrometric method (HPLC-MS-MS) for the determination of ethionamide in plasma, bronchoalveolar fluid (BAL) and alveolar cells (AC). The retention times for ethionamide, clemastine fumarate (internal standard for plasma), promethazine (internal standard for plasma) and propranolol (internal standard for BAL and AC) were approximately 2.62, 1.21, 2.14, and 2.22 min, respectively, with a total run time of 3.2 min. Ethionamide detection for plasma was carried out on a PE Sciex API III (Perkin-Elmer, Foster City, CA, USA). BAL and cell pellets and some plasma specimens were analyzed on a Micromass Quattro LC (Micromass Co., Manchester, UK). The detection limits for ethionamide were 0.05 microg/ml for plasma, and 0.005 microg/ml for BAL supernatants and alveolar cell suspensions.

Effects of AIDS and gender on steady-state plasma and intrapulmonary ethionamide concentrations.

Ethionamide, 250 mg every 12 h for a total of nine doses, was administered to 40 adult volunteers (10 men with AIDS, 10 healthy men, 10 women with AIDS, and 10 healthy women). Blood was obtained for drug assay prior to administration of the first dose, 2 h after the last dose, and at the completion of standardized bronchoscopy and bronchoalveolar lavage, which were performed 4 h after the last dose. Ethionamide was measured in epithelial lining fluid (ELF) and alveolar cells (AC) using a new mass spectrometric method. The presence of AIDS or gender was without significant effect on the concentrations of ethionamide in plasma, AC, or ELF. Plasma concentrations (mean +/- standard deviation [SD]) were 0.97 +/- 0.65 and 0.65 +/- 0.35 microg/ml at 2 and 4 h after the last dose, respectively, and both values were significantly greater than the concentration of ethionamide in AC (0.38 +/- 0.47 microg/ml) (P < 0. 05). The concentration of ethionamide was significantly greater in ELF (5.63 +/- 3.8 microg/ml) than in AC or plasma at 2 and 4 h and was approximately 10 to 20 times the reported MIC for ethionamide-susceptible strains of Mycobacterium tuberculosis. For all 40 subjects, the ELF/plasma concentration ratios (mean +/- SD) at 2 and 4 h were 8.7 +/- 11.7 and 9.7 +/- 5.6, respectively. We conclude that the absorption of orally administered ethionamide, as measured in this study, was not affected by gender or the presence of AIDS. Ethionamide concentrations were significantly greater in ELF than in plasma or AC, suggesting that substantial antimycobacterial activity resides in this compartment.

Liquid chromatographic determination of rifampin in human plasma, bronchoalveolar lavage fluid, and alveolar cells.

A technique is presented for the measurement of rifampin in humans by reversed-phase column chromatography and postcolumn photo irradiation. The assay employs diazepam as an internal standard and provides specific, rapid, and reliable determinations for drug concentration in plasma, bronchoalveolar lavage (BAL), and alveolar cells (AC). The preparation of plasma and AC samples utilizes a simple deproteinization step, whereas BAL supernatants require a solid-phase extraction. The assay produces sharp peaks with retention times of 6.2 and 15 min for rifampin and diazepam, respectively. The detection limits for rifampin were 0.5 microgram/mL for plasma, 0.015 microgram/mL for BAL supernatants, and 0.03 microgram/mL for AC suspensions. The assay has excellent performance characteristics, making it suitable for pharmacological studies in humans, and it is being used to support a study of the intrapulmonary pharmacokinetics of rifampin.

Single-dose intrapulmonary pharmacokinetics of rifapentine in normal subjects.

The intrapulmonary pharmacokinetics of rifapentine were studied in 30 volunteers who received a single, oral dose of rifapentine (600 mg). Subgroups of five subjects each underwent bronchoscopy and bronchoalveolar lavage (BAL) at timed intervals following drug administration. Drug concentrations, including the concentration of the primary metabolite 25-desacetyl rifapentine, were determined in plasma, BAL fluid, and alveolar cells (AC) by high-pressure liquid chromatography. The concentrations in epithelial lining fluid (ELF) were calculated by the urea diffusion method. The concentration-time data were fit to two-compartment (plasma) or one-compartment (AC and ELF) models. The peak concentrations in plasma, ELF, and AC, 26.2, 3. 7, and 5.3 microg/ml, respectively, occurred at 5, 5, and 7 h after drug administration, respectively. The half-lives and areas under the curve for plasma, ELF, and AC were 18.3 h and 520 microg. h/ml, 20.8 h and 111 microg. h/ml, and 13.0 h and 133 microg. h/ml, respectively. Although the intrapulmonary rifapentine concentrations were less than the plasma rifapentine concentrations at all time periods, they remained above the proposed breakpoint for M. tuberculosis (0.5 microg/ml) for the 48-h observation period. These data provide a pharmacokinetic rationale for extended-interval dosing. The optimum dosing regimen for rifapentine will have to be determined by controlled clinical trials.

High-performance liquid chromatographic determination of pyrazinamide in human plasma, bronchoalveolar lavage fluid, and alveolar cells.

A technique is presented for the measurement of pyrazinamide in human plasma, bronchoalveolar lavage, and alveolar cells by reversed-phase column chromatography. The assay utilizes acetazolamide as an internal standard, ultraviolet detection at 268 nm, and an acetonitrile-based mobile phase. Preparation of plasma samples requires a simple deproteinization step, resulting in the development of sharp peaks with retention times of 8.4 and 17 minutes for pyrazinamide and acetazolamide, respectively. Bronchoalveolar lavage and alveolar cell suspensions require an acid extraction with ethyl acetate, evaporation to dryness, and reconstitution. This method provides specific, rapid, and reliable determinations of drug concentrations and therefore is suitable for pharmacological studies, particularly those that are designed to quantitate the intrapulmonary concentrations of pyrazinamide.

Intrapulmonary concentrations of pyrazinamide.

The objective of this study was to compare the steady-state plasma and intrapulmonary concentrations of orally administered pyrazinamide in normal volunteers and subjects with AIDS. Pyrazinamide was administered at 1 g once daily for 5 days to 40 adult volunteers (10 men with AIDS, 10 normal men, 10 women with AIDS, and 10 normal women). Subjects with AIDS and with more than four stools per day were excluded. Blood was obtained prior to administration of the first dose, 2 h after the last dose, and at the completion of bronchoscopy and bronchoalveolar lavage, which were performed 4 h after the last dose. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) recovered was calculated by the urea dilution method. The total number of alveolar cells (AC) was counted in a hemocytometer, and differential cell counting was performed after cytocentrifugation. Pyrazinamide was measured by high-performance liquid chromatography. The presence of AIDS or gender had no significant effect on the concentrations of pyrazinamide in plasma. The concentrations of pyrazinamide in ELF and AC were lower in the subjects with AIDS than in the subjects without AIDS, but the difference was not significant. The concentrations in plasma (mean +/- standard deviation) were 25.1 +/- 7.6 and 21.1 +/- 6.8 microg/ml at 2 and 4 h after the last dose, respectively, and were not significantly different from the concentration (17.4 +/- 16.9 microg/ml) in AC. The concentration of pyrazinamide in ELF was high (431 +/- 220 microg/ml) and was approximately 4 to 40 times the reported MIC for pyrazinamide-susceptible strains of Mycobacterium tuberculosis. The high concentration of pyrazinamide in ELF may contribute in part to the effectiveness of the drug in treating pulmonary tuberculosis.

Sensitive liquid chromatographic technique to measure isoniazid in alveolar cells, bronchoalveolar lavage and plasma in HIV-infected patients.

The need to monitor the effectiveness of antimicrobial drugs in treating opportunistic infections such as tuberculosis in HIV-infected patients requires the development of sensitive assays. A suitable HPLC method was developed to measure the concentration of isoniazid (INH) in plasma 1 h after a standard 300 mg dose and to detect the low levels typically found in alveolar cells obtained by bronchoalveolar lavage of subjects maintained on a standard regimen of the drug. Following extraction with a chloroform-butanol mixture, the INH was back-extracted into dilute acid which was subsequently analyzed by HPLC using a CN reversed-phase column and an acetonitrile-isopropanol based mobile phase. Another HPLC method was developed using direct injection and a polymer based column to measure minute concentrations of INH in the cell-free lavage. In both systems, detection of the drug was accomplished with a sealed coulometric detector (+0.6 V) capable of giving a consistent daily response without adjustment. When saline, cellular extracts and plasma from untreated subjects were spiked with various amounts of INH and analyzed, the lowest level of quantitation was 10, 25 and 100 ng/ml, respectively. Calibration curves showed good linearity when spiked concentrations were compared to peak areas (r=0.991, 0.993 and 0.998, respectively). Alveolar cell extracts and cell-free bronchoalveolar fluid from HIV-positive patients maintained on a standard INH regimen had detectable levels of INH 4 h after a 300 mg oral dose. The plasma INH at 1 h had a range of 0.3-7.1 microg/ml (n = 50). Precision studies with plasma spiked at 0.1, 0.5, 1.0 and 5.0 microg/ml revealed within-run coefficients of variation (C.V.s) of 8.9, 7.2, 4.2 and 4.9%, respectively and analytical recoveries of 97, 108, 108 and 98%, respectively. The day-to-day C.V.s for the plasma method were 7.6, 4.9 and 3.8% at concentrations of 0.5, 1.0 and 3.0 microg/ml, respectively. The results suggest that this rugged HPLC technique can quantitate INH in 1 h plasma with good precision and can be used to estimate the very low INH concentrations found in alveolar cells and cell-free lavage recovered from patients undergoing anti-tuberculosis therapy.

Effect of charcoal hemoperfusion on clearance of pentamidine isethionate after accidental overdose.

BACKGROUND: Pentamidine isethionate is an antimicrobial agent effective in the treatment of Pneumocystis carinii pneumonia, trypanosomiasis and leishmaniasis. Severe and fatal toxicity is reported with pentamidine use. CASE REPORT: A patient received an accidental overdose (40 times the prescribed dose) of intravenous pentamidine due to a pharmacy mixing error. Charcoal hemoperfusion was utilized to attempt to lower the serum concentration of pentamidine and lessen toxicity. RESULTS: Measurement of pentamidine concentrations in the patient's blood demonstrates a beneficial effect of hemoperfusion. CONCLUSIONS: Charcoal hemoperfusion may represent a useful modality in the management of pentamidine isethionate overdosage.

Single-dose intrapulmonary pharmacokinetics of azithromycin, clarithromycin, ciprofloxacin, and cefuroxime in volunteer subjects.

The intrapulmonary pharmacokinetics of azithromycin, clarithromycin, ciprofloxacin, and cefuroxime were studied in 68 volunteers who received single, oral doses of azithromycin (0.5 g), clarithormycin (0.5 g), ciprofloxacin (0.5 g), or cefuroxime (0.5 g). In subgroups of four subjects each, the subjects underwent bronchoscopy and bronchoalveolar lavage at timed intervals following drug administration. Drug concentrations, including those of 14-hydroxyclarithromycin (14H), were determined in serum, bronchoalveolar lavage fluid, and alveolar cells (ACs) by high-pressure liquid chromatography. Concentrations in epithelial lining fluid (ELF) were calculated by the urea diffusion method. The maximum observed concentrations (mean +/- standard deviation) of azithromycin, clarithromycin, 14H, ciprofloxacin, and cefuroxime in serum were 0.13 +/- 0.07, 1.0 +/- 0.6, 0.60 +/- 0.41, 0.95 +/- 0.32, and 1.1 +/- 0.3 microgram/ml, respectively (all at 6 h). None of the antibiotics except clarithromycin (39.6 +/- 41.1 micrograms/ml) was detectable in ELF at the 6-h bronchoscopy. The movement into and persistence in cells was different for azithromycin and clarithromycin. In ACs azithromycin was not detectable at 6 h, reached its highest concentration at 120 h, and exhibited the greatest area under the curve (7,403 micrograms.hr ml-1). The peak concentration of clarithromycin (181 +/- 94.1 micrograms/ml) was greater and occurred earlier (6 h), but the area under the curve (2,006 micrograms.hr ml-1) was less than that observed for azithromycin. 14H was detectable in ACs at 6 h (40.3 +/- 5.2 micrograms/ml) and 12 h (32.8 +/- 57.2 micrograms/ml). The peak concentration of ciprofloxacin occurred at 6 h (4.3 +/- 5.2 micrograms/ml), and the area under the curve was 35.0 micrograms.hr ml-1. The data indicate that after the administration of a single dose, azithromycin, clarithromycin, and ciprofloxacin penetrated into ACs in therapeutic concentrations and that only clarithromycin was present in ELF. The correlation of these kinetic observations with clinical efficacy or toxicity was not investigated and is unclear, but the data provide a basis for further kinetic and clinical studies.

Intrapulmonary and systemic pharmacokinetics of aerosolized pentamidine used for prophylaxis of pneumocystis carinii pneumonia in patients infected with the human immunodeficiency virus.

A study was conducted to determine the intrapulmonary and systemic pharmacokinetics of aerosolized pentamidine prophylaxis (APP) in patients infected with human immunodeficiency virus (HIV). 151 patients received high-dose (300 mg twice a month or 600 mg once a month) APP as part of a previously published clinical trial, and 29 additional patients received standard-dose (300 mg once a month) APP. Serial blood samples were obtained from the first cohort: 577 samples were obtained from 76 patients in the group given 600 mg once a month, and 554 blood samples were obtained from 75 patients in the group given 300 mg twice a month. In 9 of the 151 patients, bronchoscopy and tri-lobar (right upper, middle, and lower lobe) bronchoalveolar lavage (BAL) were performed 6 and 12 months after initiation of APP. Unilobar (right middle lobe) BAL was performed in the 29 patients infected with HIV who underwent bronchoscopy for diagnostic purposes. Pentamidine was measured using a chromatographic (HPLC) assay. The concentrations (mean +/- SD) of pentamidine in plasma in the groups given 300 mg twice a month and 600 mg once a month were 5.3 +/- 6.1 ng/mL and 8.8 +/- 9.6 ng/mL, respectively, and accumulation did not occur. The BAL supernatant and alveolar cell pentamidine concentrations were not significantly different in the 3 lobes and ranged from 16.5 +/- 7.7 ng/mL to 29.2 +/- 19.5 ng/mL and 1255 +/- 1142 ng/mg protein to 1572 +/- 1161 ng/mg protein in the group given 300 mg twice a month; and from 5.5 +/- 2.9 ng/mL to 9.4 +/- 7.7 ng/mL and 339 +/- 201 ng/mg protein to 571+/- 681 ng/mg protein in the group given 600 mg once a month. The intropulmonary concentrations of pentamidine at 6 and 12 months were not significantly different. In 18 of the 29 patients who received 1 to 7 prior monthly doses of standard APP, drug concentrations in BAL increased linearly (y = 2.05x) with the number of doses administered before bronchoscopy. These data indicate that intrapulmonary drug concentrations continue to increase for approximately 6 months after the initiation of APP, at which time steady state is achieved, and that administration of high dose APP is probably safe.

Intrapulmonary pharmacokinetics of clarithromycin and of erythromycin.

The intrapulmonary pharmacokinetics of orally administered clarithromycin (500 mg every 12 h for five doses) or erythromycin (250 mg every 6 h for nine doses) were studied in 32 healthy adult volunteers. Four of the subjects, two in the clarithromycin group and two in the erythromycin group, were smokers. Bronchoscopy, bronchoalveolar lavage, and venipuncture were performed at 4, 8, 12, 24, and 48 h after administration of the last dose of clarithromycin and at 4, 8, and 12 h after administration of the last dose of erythromycin. Clarithromycin was measured by high-performance liquid chromatography, and erythromycin was measured by a microbiological assay. No systemic sedation was used. There were no major adverse events. The concentrations of antibiotics in epithelial lining fluid (ELF) were calculated by the urea dilution method. The volumes (mean +/- standard deviation) of ELF were 1.9 +/- 2.0 ml and 1.5 +/- 0.7 ml in the clarithromycin and erythromycin groups, respectively (P > 0.05). There was no effect of smoking on the amount of bronchoalveolar lavage fluid recovered, the volume of ELF, or the number of erythrocytes present in the lavage fluid (P > 0.05 for all comparisons). The total number of alveolar cells, however, was almost threefold greater in the smokers versus that in the nonsmokers (P < 0.05). Clarithromycin was concentrated in ELF (range, 72.1 +/- 73.0 micrograms/ml at 8 h to 11.9 +/- 3.6 micrograms/ml at 24 h) and alveolar cells (range, 505.8 +/- 293.1 micrograms/ml at 4 h to 17.0 +/- 34.0 micrograms/ml at 48 h). 14-(R)-Hydroxyclarithromycin was also present in these compartments, but at lower concentrations than the parent compound. The concentrations of erythromycin in ELF and alveolar cells were low at 4, 8, and 12 h following the last dose of drug (range, 0 to 0.8 +/- microgram/ml in ELF and 0 to 0.8 +/- 1.3 microgram/ml in alveolar cells). The clinical significance of any antibiotic concentrations in these compartments in unclear. The data suggest, and we conclude, that clarithromycin may be a useful drug in the treatment of pulmonary infections, particularly those caused by intracellular organisms.

Pharmacokinetics of cefodizime in volunteers with normal or impaired renal function.

The pharmacokinetics of single, 1- or 2-g intravenous doses of cefodizime were studied in subjects with normal, impaired renal function or requiring chronic hemodialysis. Drug concentrations were measured using high-performance liquid chromatography. Forty-five subjects (20 with creatinine clearance of > or = 90 mL/min, 15 with creatine clearances between 5 and 89 mL/min, and 10 requiring chronic hemodialysis) were studied. The concentration-time curve of cefodizime was best represented by an open two-compartment model. The elimination half-lives in subjects with normal (Group 1) and impaired renal function (Group 2) or requiring chronic hemodialysis (Group 3) were 4.14 +/- 1.55, 5.10 +/- 2.24, and 10.1 +/- 6.01 hours, respectively (Group 3 versus 1 or 2, P < .05; Group 1 versus 2, P > .05). The total body (serum) clearances in the same groups were 3 +/- 0.52, 2.22 +/- 0.61, and 0.99 +/- 0.33 L/hour, respectively (Group 1 versus 2 or 3, P < .05; Group 2 versus 3, P < .05). Although renal function has an effect on the pharmacokinetics of cefodizime, its effect on the elimination half life is marginal in subjects with creatinine clearance of more than 25 mL/min. In individuals with more severe renal impairment or those requiring chronic hemodialysis, dosage adjustment would be required.

A randomized comparison of once-monthly or twice-monthly high-dose aerosolized pentamidine prophylaxis.

RESULTS: Ten of the 146 (7 percent) evaluable subjects developed PCP during the year study period, and there was no difference in the efficacy of the two regimens. Among patients receiving secondary prophylaxis, the attack rate of PCP at 1 year was 11 percent. This compares favorably with a 1-year attack rate of 19 percent in similar patients receiving standard dose (300 mg) prophylaxis and suggests, but does not prove, a dose-response effect. Concentrations of pentamidine in BAL fluid were not significantly different among the three lobes of the lung. Intrapulmonary pentamidine did not accumulate during the year of study. Aerosolized pentamidine was associated with a marginal but statistically significant increase in the residual volume, decreased flow rates, and increased airway reactivity. OBJECTIVE: The optimal regimen of aerosolized pentamidine in unknown. Published data suggest that there is a dose-response effect and that the occurrence of Pneumocystis carinii pneumonia (PCP) has been associated with prolongation of the interval between doses. The purpose of this study was to compare the efficacy, pharmacokinetics, and physiologic effects of two high-dose regimens of aerosolized pentamidine prophylaxis. DESIGN: Prospective, randomized study of 300 mg twice monthly vs 600 mg once monthly during a 1-year observation period. Pentamidine concentrations in plasma and bronchoalveolar lavage (BAL) fluid were measured and serial pulmonary function was measured. SETTING: A large teaching hospital in San Francisco. PATIENTS: One hundred fifty-one adult (age > 18 years) men with human immunodeficiency virus infection. Of 146 evaluable patients, prophylaxis was primary (no prior PCP) in 108 (75 percent) and secondary (one prior episode of PCP) in 38 (25 percent). MEASUREMENTS: Date and diagnosis of PCP, occurrence of drug toxicity, pulmonary function testing, and concentrations of pentamidine in BAL and plasma. CONCLUSIONS: The data suggest, but do not prove, that a dose-response effect has been demonstrated, and that high-dose aerosolized pentamidine may further reduce the attack rate of PCP. These preliminary observations should be confirmed in a double-blind trial comparing 300 mg with 600 mg administered once monthly. The clinical relevance of the adverse pulmonary effects is unclear and requires further investigation.

Evaluation of new anti-infective drugs for surgical prophylaxis. Infectious Diseases Society of America and the Food and Drug Administration.

It has been established by substantial research that antimicrobial prophylaxis for various surgical procedures can reduce the risk of postoperative morbidity and mortality. When the incidence of infectious complications is high, the reduction with prophylaxis is most dramatic. However, even for many "clean" procedures (vascular procedures, total joint replacement), the small reduction in potentially calamitous complications justifies the use of prophylaxis. Many issues of detail remain unanswered: timing and duration of administration of antimicrobial drug; type of drug; use of topical anti-infective agents as ancillary measures; and choices for high-risk individuals and others ordinarily excluded from clinical trials. An approach to the conduct of clinical trials of anti-infective drugs for surgical prophylaxis is provided. Both general guidelines and specific recommendations for total hip replacement, colorectal operations, appendectomy, and transurethral resection of the prostate are included.

Pharmacokinetics of intravenous pentamidine in patients with normal renal function or receiving hemodialysis.

The pharmacokinetics of intravenous pentamidine were studied in 10 patients with normal renal function (group 1), 9 volunteer subjects without Pneumocystis carinii pneumonia who were receiving maintenance hemodialysis (group 2), and 5 patients with normal or mildly abnormal renal function (group 3) after the last dose of therapy. The concentration-time data were best represented by a three-compartment model. The peak plasma concentration, plasma clearance, and elimination half-life ranged from 249 +/- 80 to 227 +/- 110 ng/ml, 268 +/- 70 to 329 +/- 58 l/h, and 29 +/- 25 to 118 +/- 119 h, respectively, in groups 1 and 2. In group 1, trough concentration increased progressively (linear regression: y = 4.4x; r = .91, P = .001) without achieving steady state, and the renal clearance-to-plasma clearance ratio was 2.1% +/- 0.01%. In group 3, the elimination half-life after the last dose was 12.0 +/- 2.3 days. The elimination half-life of pentamidine was long and accumulation occurred with daily dosing even in patients with normal renal function. Dose adjustment is not recommended for renal impairment as renal clearance accounts for a small fraction (2.1%) of plasma clearance.

Intravenous or inhaled pentamidine for treating Pneumocystis carinii pneumonia in AIDS. A randomized trial.

OBJECTIVE: To evaluate the efficacy and toxicity of aerosolized pentamidine and of reduced-dose intravenous pentamidine for the treatment of mild to moderate Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN: Randomized open study with serial pulmonary function testing and measurement of pentamidine concentrations in plasma and bronchoalveolar lavage fluid. PATIENTS: Of 44 men and 1 woman with a mild to moderate first episode of P. carinii pneumonia (Pao2 greater than or equal to 7.3 kPa [55 mm Hg]), 23 received aerosolized pentamidine and 22, intravenous pentamidine. INTERVENTIONS: Pentamidine isethionate, 600 mg by inhalation using a Respirgard II nebulizer (Marquest Medical Products, Inc., Englewood, Colorado) or 3 mg/kg body weight intravenously, administered once daily for 2 to 3 weeks. MEASUREMENTS AND MAIN RESULTS: The planned 60-patient study was stopped after 45 patients had been enrolled. The rates (aerosolized compared with intravenous pentamidine) of initial failure, early recrudescence of symptoms, and relapse were 12% and 19% (difference, 7%; 99% confidence interval [CI], - 23% to 37%; P = 0.67), 35% and 0% (difference, 35%; CI, 13% to 58%; P = 0.02), and 24% and 0% (difference, 24%; CI, 4% to 49%; P = 0.03). The rates (aerosolized compared with intravenous pentamidine) of major toxicity were 0% (0 of 17 patients) and 10% (2 of 21 patients) (difference 10%; CI, -1% to 29%; P = 0.24). The mean (+/- SD) pentamidine concentration in bronchoalveolar lavage fluid for patients receiving aerosolized pentamidine was 96.6 +/- 65.1 ng/mL compared with 14.4 +/- 17.7 ng/mL for patients receiving intravenous treatment. Trough concentrations of pentamidine in plasma increased from 0 to 25.4 +/- 16.4, 56.5 +/- 26.1, and 61.1 +/- 56.0 ng/mL at the end of weeks 1, 2, and 3 of intravenous therapy, respectively. CONCLUSIONS: The data suggest that reduced-dose intravenous pentamidine was more effective than aerosolized pentamidine for treating mild to moderate P. carinii pneumonia. Systemic absorption during aerosolized therapy was minimal; daily doses of intravenous pentamidine resulted in increased accumulation of pentamidine in plasma.