Michael Alkan

Pharmacokinetic dosing of aminoglycosides: a controlled trial

PURPOSE To evaluate whether individualized pharmacokinetic dosing of aminoglycosides can reduce nephrotoxicity and improve the outcome of patients with gram-negative sepsis. METHODS We conducted a prospective controlled trial at a tertiary care university hospital. Eighty-one patients with suspected or documented gram-negative infections were enrolled. All were treated with either gentamicin or amikacin, according to clinical judgement. Patients were allocated to one of two groups based on the last digit (odd/even) of their identification number. In the study group (pharmacokinetic dosing) of 43 patients, plasma aminoglycoside levels were determined 1 hour after initiation of drug infusion and 8 to 16 hours later to estimate the elimination half-life and volume of distribution, from which the subsequent dosage schedule was calculated. Target peak plasma levels were 20 microg/mL for gentamicin and 60 microg/mL for amikacin. Target trough levels were <1 microg/mL for both drugs. The control group (fixed once-daily dosing) consisted of 38 patients who were prescribed single daily doses of gentamicin or amikacin. The primary endpoints were renal toxicity (> or = 25% increase in serum creatinine level or a serum creatinine level > or = 1.4 mg/dL) and 28-day mortality. RESULTS The two study groups were similar in age, sex, indications for therapy, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and clinical assessment at baseline. Although the pharmacokinetic group received significantly greater doses of aminoglycosides than did the once-daily group, the incidence of nephrotoxicity was significantly lower in the pharmacokinetic group (5% [2/43] vs. 21% [8/38], P = 0.03). There was no statistically significant difference in 28-day mortality (27% [12/43] vs. 22% [8/38], P = 0.3). CONCLUSION These results suggest that individualized pharmacokinetic dosing of aminoglycosides reduces the incidence of nephrotoxicity and allows the use of greater doses of aminoglycosides.

Nosocomial multi-drug resistant Acinetobacter baumannii bloodstream infection: risk factors and outcome with ampicillin-sulbactam treatment

The emergence of multidrug-resistant (MDR) Acinetobacter baumannii poses a therapeutic problem. The aim of this study was to assess the risk factors for nosocomial MDR-A. baumannii bloodstream infection (BSI) and the efficacy of ampicillin-sulbactam (A/S) in its treatment. Of 94 nosocomial A. baumannii BSI during the year 2000, 54% involved MDR strains, 81% of which were genetically related. Various risk factors for MDR-A. baumannii were found, of which intensive-care unit admission and prior aminoglycoside therapy were independently associated with MDR-A. baumannii acquisition on multivariate analysis. Of MDR-A. baumannii BSI cases, 65% received A/S and 35% inadequate antibiotic therapy, whereas of 43 non-MDR cases, 86% were treated according to susceptibility and 14% inappropriately with antibiotics to which these organisms were resistant. Crude mortality was comparable in the adequately treated groups. Respective mortalities among patients treated adequately and inadequately were 41.4 and 91.7% (p<0.001). Among severely ill patients, A/S therapy significantly decreased the risk of death (P=0.02 OR=7.64). MDR-A. baumannii has become highly endemic in our institution. A/S appears to be one of the last effective and safe empirical resorts for treatment of MDR A. baumannii BSI.

Genotypic variation of HIV-1 reverse transcriptase and protease: comparative analysis of clade C and clade B.

Objective To compare drug-resistant variants from untreated (naive) and treated patients infected with clade B or C virus. Methods Consecutive samples (165) from patients throughout Israel were analyzed. All those in the treated group were failing highly active antiretroviral therapy. Results There were 78 clade C (20 naive) and 87 clade B (14 naive) with significant differences in the prevalence of known drug-resistance mutations between the clades: in naive patients in the protease region M36I 7% and 95% (P < 0.0001), K20R 0% and 27% (P = 0.063), A71V 18% and 0% (P = 0.063), M46I 0% and 13%, and V77I 18% and 0% (P = 0.063), respectively, and in the reverse transcriptase region A98G/S 0% and 20% (P = 0.12), respectively. Most clade C viruses also showed significant differences from clade B consensus sequence at additional protease sites: R41K 100%, H69K/Q 85%, L89M 95% and I93L 80% (P < 0.0001). There were also significant differences (P < 0.03 to < 0.0001) in treated patients in clades B and C: in the protease region L10I 40% and 12%, M36I 26% and 95%, L63P 67% and 40%, A71I 38% and 7%, G73I and V77I 18% and 0%, I84V 16% and 3%, and L90M 40% and 12%, respectively; in the reverse transcriptase M41L 41% and 17%, D67N 41% and12%, K70R 30% and 7%, T215Y 48% and 29%, K219Q 21% and 7%, and A98G/S 3% and 24%, respectively. Conclusion Significantly differences between clade B and C viruses may be associated with development of differing resistance patterns during therapy and may affect drug utility in patients infected with clade C.

Benign familial leukopenia and neutropenia in different ethnic groups

Benign hereditary leukopenia‐neutropenia has been reported in several ethnic groups, including Yemenite Jews, Blacks of South African extraction, West Indians and Arab Jordanians. The subjects with BFL were shown not to have an increased incidence of infections, and their response to infection did not differ from subjects having normal white blood cell counts. This study entails the report of two additional unrelated ethnic groups with familial neutropenia — Black Beduin and Falashah Jews. The familial nature of the phenomenon was confirmed. The suggested mechanism of this type of neutropenia is a defect in release of mature WBC from the bone marrow to the peripheral circulation. All ethnic groups thus far reported have tanned or dark skin. The significance of this common feature has still to be elucidated.

Musculoskeletal Manifestations of Brucellosis: A Study of 90 Cases in Israel

Rheumatological manifestations are frequently reported in patients with brucellosis. In a retrospective study of 90 patients diagnosed with brucellosis over a period of 18 years, 83 (92%) patients were Bedouins, 55 of whom (61%) reported ingestion of unpasteurized goat milk and goat milk products. The male/female ratio was 1:1, and the adult to child ratio was 3:2. The mean age of the patients was 25 years (range, 1-72 years). Rheumatological manifestations (myalgia, arthralgia, and arthritis) were reported in more than half of the patients. These manifestations started on days 3 and 4 of the disease and were mild to moderate in severity. Myalagia was evident in 49 (54%) patients and was more common in adults than in children (67% versus 37%; P < .01) and in men (67%) than in women (42%; P < .01). Arthralgia was the most common musculoskeletal manifestation, found in 55 (61%) patients, and occurred more often in children than in adults (74% versus 52%; P < .05). Arthritis was detected in 37 (41%) patients. The hip and knee joints were the most common sites of arthritis (31% each) followed by sacroiliac involvement (17%) and shoulder or spine involvement (5% each). Arthritis was also more common in children (63% versus 29%; P < .01). The prevalence of arthritis was similar in men and women. Cure was achieved in all patients after antibiotic therapy.

Burden of Infection in Patients with End-Stage Renal Disease Requiring Long-Term Dialysis

BACKGROUND This study examines the spectrum of infections in a selected population of patients requiring long-term dialysis, enlarging the focus beyond infections associated with the dialysis process. METHODS Infection data were reviewed from complete archived inpatient and outpatient dialysis records of 433 patients who were treated at a single hospital-based dialysis program and its dialysis satellites over a 9-year period, from 1 January 1992 to 31 December 2000. RESULTS The study period included 424,700 days of dialysis experience. A total of 2412 episodes of bacterial or fungal infections were treated in 433 patients. The infection rate was 5.7 episodes per 1000 days of dialysis. Patients received 5111 courses of antibiotics over 42,627 days of treatment, which cumulatively accounted for 10% of the total days of the study. Infections associated with hemodialysis vascular access devices comprised 20.5% of the total episodes. Infections below the knee (19.3% of infection episodes), pneumonia (13%), and other skin and soft-tissue infections (9%) were also important types and sources of infection, accounting for >42% of the total episodes. Eighty-two percent of the infections (1971 episodes) were acquired in the community. Of these, 868 (44%) required hospitalization. An additional 441 episodes were nosocomial. The profile of bacteria isolated from patients with community-acquired infections mirrored that of bacteria recovered from patients with nosocomial infections. CONCLUSION Patients with end-stage renal disease have an enormous burden of infection. The majority of the infections are unrelated to dialysis. Frequent and long-term antibiotic use and cohorting of patients in the dialysis unit have altered the microbiological flora of such individuals, with clinical and epidemiological implications.

Impact of active monitoring of infection control practices on deep sternal infection after open-heart surgery

BACKGROUND Deep-sternal infection is a devastating complication after open-heart surgery. However, the association between infection control practices and deep-sternal infection rates is unclear. METHODS To identify contributors to increased deep-sternal infection rates in our institution, consecutive open-heart surgery patients were prospectively studied during two periods (75 and 40 days), including 66 and 40 patients, respectively. Active monitoring including 149 infection control practices was performed in the operating room and intensive care unit. End-points were deep-sternal infection rates and their relation to infection control practices. RESULTS Mean age was 62+/-11 years and 68% were males. Coronary bypass was performed in 82%. Clinical and surgical features were comparable, except that patients in period 2 were more likely to have heart failure (15% vs 1.5%, p = 0.01) and had a longer mean duration of surgery (277 vs 217 minutes, p < 0.005). Only 57 practices (38%) were adequately performed. The main categories showing inadequate practices were disinfection, traffic, hand-washing, and surgical attire of nonscrubbed personnel, anesthesiologists, and pump technicians. Many categories showed a statistically significant improvement between periods. Deep-sternal infection rates in prestudy and poststudy periods were 10% and 2.8%, respectively (p = 0.007). CONCLUSIONS Active monitoring among personnel involved in open-heart surgery resulted in a significant and sustained decrease in deep-sternal infection rates, through modification of human behavior and improvement of performance standards, probably mediated by the Hawthorne effect. Periodic active monitoring may be a valuable tool to achieve and even sustain such a decrease with tremendous implications on morbidity, costs, and quality of care.

Incidence and Precipitating Factors of Morbidity among Israeli Travelers Abroad

BACKGROUND During recent years international travel, including visits to the developing world, has become increasingly popular. Many of these travelers suffer from some sort of health problem during their trip or after their return. Travelers clinics that give pretravel immunization and counseling have emerged. This study analyzes the incidence and risk factors for health problems among Israelis traveling abroad. METHODS The study surveyed by telephone 200 people who visited the travelers clinic at Soroka Medical Center in Beer-Sheva during the years 1998 to 1999. The travelers were questioned after returning from their journey about the type and duration of the trip, compliance with medical advice given in the travel clinic, and health problems during the trip. RESULTS The mean age was 26.4 +/- 9.4 years, 7% went on an organized tour, 23% traveled alone, and 77% traveled with a friend. The mean duration of the trip was 14.7 +/- 13.4 weeks. Of the travelers, 70% reported some health impairment. Problems reported most frequently were gastrointestinal tract diseases (43%), respiratory tract diseases (25%), and injuries (10%). Only 4% were admitted to a hospital during their trip. After their return, 19.5% consulted a physician. Comparing the group of travelers who were sick with the rest, a correlation between noncompliance with the keeping of food hygiene and illness was found (p =.008). Additional risk factors for illness were long duration (p <.001), solitary trip (p =.04), and young age (p <.001). Of the people who were advised to take antimalaria chemoprophylaxis, 55% reported regular use of these drugs. Compliance with treatment correlated with older age (p <.001), short duration of stay (p =.01), previous experience, and travel to Africa (p <.001). CONCLUSIONS Most of the travelers to developing countries are young, travel for long periods, and live in basic conditions during their stay abroad. For these reasons travelers are at increased risk for morbidity. High risk travelers should be identified and counseled in order to increase their compliance with the medical advice and immunizations. A screening program for returning travelers should be considered.

Prevalence and risk factors for tinea pedis in Israeli soldiers.

Background  Tinea pedis is a common infection in soldiers. However, prevalence and risk factors for tinea pedis in soldiers were investigated in only a few studies.

Massive pumonary haemorrhage caused by leptospirosis successfully treated with nitric oxide inhalation and haemofiltration

A patient with leptospirosis who developed oliguric renal failure, massive pulmonary haemorrhage and respiratory failure is described. The patients clinical condition and arterial oxygenation failed to improve despite vigorous supportive measures. Nitric oxide inhalation and haemofiltration resulted in a marked clinical improvement and subsequent full recovery. We suggest that the addition of haemofiltration and nitric oxide inhalation therapy should be considered in patients with pulmonary haemorrhage and renal failure caused by leptospirosis, in whom conventional therapy fails.