Urinary tract infections caused by multi-drug resistant Proteus mirabilis: Risk factors and clinical outcomes.

BACKGROUND: Proteus mirabilis (PM) as well as other members of the Enterobacteriaceae family are a leading cause of infectious diseases in both the community and acute care settings. The prevalence of multi-drug resistant (MDR) bacterial isolates have increased in the last few years, affecting the prognosis and survival of hospitalized patients. The aim of our study was to determine the risk factors and clinical outcomes of urinary tract infections (UTIs) caused by MDR PM in patients hospitalized in our institution. METHODS: This was a retrospective matched case-control study. Records of patients with PM-positive urine culture were reviewed, and data were included for analysis. RESULTS: Univariate analysis revealed that the variables significantly associated with acquisition of MDR PM vs non-MDR PM UTI were younger age ([in years] median 77.5, range 20-94 vs median 78, range 40-94, p = 0.04), other concomitant infectious diseases (57.1 vs 35.7%, p = 0.037),number of prior infectious diseases (mean 0.95 +/- 0.99 vs 0.57 +/- 0.85, p = 0.035), diagnosis of infection at hospital admission (67.9 vs 42.9%, p = 0.008), and prior therapy with antipseudomonal penicillin (17.9 vs 1.8%, p = 0.004),respectively. Mean length of hospitalization was 29.95 days for the MDR group and 30.04 days for the non-MDR group(p = non-significant [NS]). The crude mortality rate following hospital admission was 19/56 (33.9%) vs 14 (25%)in the MDR PM and non-MDR PM groups, respectively(p = 0.300, odds ratio [OR] 1.54, 95% confidence interval[CI] 0.63-3.82). The production of extended-spectrum beta lactamases(ESBL) was found in 100% of MDR-PM vs 31.5%of non-MDR-PM urine isolates (p < 0.001). All variables found to be significantly associated with MDR-PM UTI were included in a logistic regression model. Independent risk factors for MDR-PM UTI were empiric cephalosporin therapy(OR 4.694, 95% CI 1.76-12.516, p = 0.002) and prior antipseudomonal penicillin (piperacillin/tazobactam) therapy during the last year (OR 11.175, 95% CI 1.09-114.2,p = 0.04). CONCLUSIONS: Prior piperacillin/tazobactam and empiric cephalosporin use were the independent risk factors of MDR-PM strains. All MDR-PM urinary isolates at our institution were ESBL producers. Therefore, carbapenem use remains the only available treatment option for MDR-PM isolates in our institution.

Impact of 4% chlorhexidine whole-body washing on multidrug-resistant Acinetobacter baumannii skin colonisation among patients in a medical intensive care unit.

The prevalence of skin colonisation with Acinetobacter baumannii (ACBA) on admission to the medical intensive care unit (MICU) was studied in an institution endemic for ACBA bloodstream infections (BSIs). The impact of 4% chlorhexidine gluconate (4% CG) whole-body washing on the patients' ACBA skin colonisation was also determined. A prospective cohort trial in a MICU during March 2002 to December 2003 was performed, with a comparison between the prevalence and incidence of ACBA-BSIs obtained after intervention and retrospectively. During the intervention period, ACBA skin-screening swabs were taken from all patients on admission and periodically until discharge. Patients underwent whole-body disinfection with 4% CG immediately after obtaining the initial cultures. Disinfection was carried out on a daily basis until discharge, regardless of colonisation status. Of the 320 patients at ward admission, 55 (17%) yielded ACBA. The prevalence of ACBA colonisation among the remaining MICU patients was 5.5% at 24h and 1% at 48h following the disinfection regimen (P=0.002, OR: 2.4). Following a second screen, 80% of colonised patients were decolonised. Prevalence of ACBA-BSIs decreased from 4.6 to 0.6 per 100 patients (P < or = 0.001; OR: 7.6) and incidence decreased from 7.8 to 1.25 (85% reduction). We conclude that daily whole-body disinfection with 4% CG significantly reduced ACBA skin colonisation. This regimen may be considered in addition to well-known infection control measures, particularly in institutions with endemic rates of multidrug-resistant ACBA-BSIs.

Characteristics of low-risk patients hospitalized with community-acquired pneumonia.

BACKGROUND: Despite the wide distribution of different severity scoring systems for community-acquired pneumonia (CAP) patients, low-risk patients are frequently hospitalized, contrary to current recommendations. The aim of our study was to determine the rate, clinical characteristics, and outcome of low-risk patients with CAP admitted to our institution. METHODS: During an 18-month period, we prospectively screened all patients admitted to the Division of Internal Medicine with a presumptive diagnosis of CAP. Pneumonia Outcome Research Team (PORT) score and pneumonia severity index (PSI) were calculated for all patients during the first 24 h. RESULTS: A total of 591 patients had a diagnosis of CAP. Some 196 patients (33.1%) were low-risk (PSI class I, II), 98 (16.6%) intermediate (PSI III), and 297 (50.3%) high-risk patients (PSI IV, V). Patients in low-risk classes were younger (45.5+/-15.8 vs. 65.0+/-12.5 and 74.9+/-11.8 years, respectively, p<0.001) and had fewer background diseases. They had shorter hospitalizations than intermediate- and high-risk groups (4.4+/-3.2, 5.3+/-3.4, and 6.8+/-6.4 days, respectively, p<0.001). There was a significant difference in 30-day mortality between the different risk groups: 0% in the low-risk, 2.0% in the intermediate-risk, and 9.4% in the high-risk group (p<0.001). CONCLUSION: The considerable proportion of low-risk patients hospitalized due to CAP was found to be comparable to the stable 30% rate reported in the literature. We conclude that physicians tend to opt for a wide safety range when considering a CAP patient hospitalization, rather than make a decision based only on severity score calculation.

Conservative management of implantable cardioverter defibrillator-related endocarditis due to Bacillus spp.

Endocarditis is a devastating complication of implantable cardioverter-defibrillator (ICD) therapy. Partial or complete device removal has been advocated for the treatment of this condition although controlled data are lacking. We present a case of ICD-related endocarditis caused by Bacillus spp. that occurred following coronary angiography. To the best of our knowledge, Bacillus spp. has not been previously described in such context. Moreover, conservative treatment with device retention was successful (no recurrence during a 6-year follow-up). Conservative management may be attempted in selected cases of ICD-related endocarditis, especially, those involving low-virulence organisms and rapid response to antibiotic therapy. This case also suggests that coronary angiography may be associated with transient bacteremia and subsequent infection of indwelling cardiac devices.

Regional community-acquired urinary tract infections in Israel: diagnosis, pathogens, and antibiotic guidelines adherence: a prospective study.

INTRODUCTION: The identification and treatment of hospitalized patients with community-acquired urinary tract infections (CAUTI) may be a challenge. The pathogens causing the infection and their relative proportions vary geographically and with time. This observational prospective study had three primary goals: (1) to estimate the likelihood of diagnosis of CAUTI upon admission; (2) to evaluate adherence to the institutional recommendations; (3) to assess the compatibility of the current local antibiotic recommendations with a pathogen's distribution and with its drug sensitivities. METHODS AND RESULTS: Two hundred and twenty-three patients with positive urinary cultures fulfilling criteria for CAUTI were studied. Only 54 (24.2%) were diagnosed as having a urinary tract infection upon admission. Approximately 90% of the patients, who were correctly diagnosed, received the institutional recommended antibiotic therapy (ofloxacin or cefuroxime). Gram-negative intestinal flora comprised 86.1% (192 patients) of the causative microorganisms. Of these, 20.3% of the pathogens demonstrated resistance to ofloxacin and 19.8% to cefuroxime. The prevalence of Escherichia coli, the most common pathogen of UTI, significantly declined in the current study, from 70.5% in 1991 to 56% in 2000. CONCLUSIONS: We observed a low sensitivity in diagnosing community-acquired urinary tract infections upon admission. In patients correctly diagnosed, the use of recommended antibiotics was high. A substantial percentage of the pathogens were resistant to the recommended antibiotics. This study stresses the need for frequent re-evaluation of the prevalence of pathogens involved in regional community-acquired urinary tract infections and the adjustment of the empirical first-line treatment accordingly.

Reduction of blood culture contamination rate by an educational intervention.

The efficacy of an educational intervention to prevent blood culture contamination (BCC) in internal medicine was studied in two medical wards in a busy tertiary-care hospital in which blood cultures were obtained by physicians rather than dedicated phlebotomists. Baseline BCC rates were 5.7% and 7.1% in intervention and control wards, respectively (p 0.6), compared with 1.95% and 6.7%, respectively, post-intervention (p < 0.001). Following multivariate analysis, only an absence of intervention was an independent variable associated with BCC. Thus simple educational intervention reduced BCC in internal medicine and was considered to be cost-effective.

Clonal variability of group B Streptococcus among different groups of carriers in southern Israel.

A high prevalence of maternal group B Streptococcus (GBS) carriage and an extremely low incidence of invasive neonatal disease have been reported from southern Israel. In order to obtain insight into this discrepancy, this study was performed to determine the population structure of GBS from asymptomatic pregnant women living in this area. Seventy-two strains from maternal GBS carriers were characterized using multilocus sequence typing (MLST). Epidemiologic characteristics of the carriers and their newborns, including demographic variables, obstetric status, and general health parameters, were collected by means of a postpartum interview and a review of the relevant medical records. The MLST analysis grouped the bacteria into six different lineages (clonal complexes). Lineage ST-2 was prevalent among Bedouin-Arabs (p=0.01) and lineage ST-22 among Jews (p=0.001). Lineage ST-17 was prevalent among carriers who emigrated after 1997 from western nations of the former USSR (p<0.001). Lineage ST-22 was associated with carriage of surface-protein C (p=0.01) and lineage ST-17 with surface-protein R (p<0.01). Lineage ST-2 was prevalent among consumers of antibiotics (p=0.02) and was associated with erythromycin-resistant strains (p<0.001). Each subgroup of the southern Israeli maternal population has a different distribution of GBS clones. The clones prevalent among the Bedouin-Arabs and the Jews are known to be of low virulence. Lineage ST-17, which is associated with invasive disease, is prevalent among women who emigrated from western Soviet nations. Therefore, a different policy of GBS prophylaxis, resembling the one executed in endemic areas, should be considered in this population.

Prevalence and clinical significance of pleural microbubbles in computed tomography of thoracic empyema.

AIM: To determine the prevalence and clinical significance of pleural microbubbles in thoracic empyema. MATERIALS AND METHODS: The charts of 71 consecutive patients with empyema were retrospectively reviewed for relevant demographic, laboratory, microbiological, therapeutic and outcome data. Computed tomography (CT) images were reviewed for various signs of empyema as well as pleural microbubbles. Two patient groups, with and without microbubbles were compared. RESULTS: Mean patient age was 49 years and 72% were males. Microbubbles were detected in 58% of patients. There were no significant differences between patients with and without microbubbles in regard to pleural fluid chemistry. A causative organism was identified in about 75% of cases in both. There was no difference in the rates of pleural thickening and enhancement, increased extra-pleural fat attenuation, air-fluid levels or loculations. Microbubbles were diagnosed after a mean of 7.8 days from admission. Thoracentesis before CT was performed in 90 and 57% of patients with and without microbubbles (p=0.0015), respectively. Patients with microbubbles were more likely to require repeated drainage (65.9 versus 36.7%, p=0.015) and surgical decortication (31.7 versus 6.7%, p=0.011). Mortalities were 9.8 and 6.6% respectively (p=0.53). CONCLUSION: Pleural microbubbles are commonly encountered in CT imaging of empyema but have not been systematically studied to date. Microbubbles may be associated with adverse outcome such as repeated drainage or surgical decortication. The sensitivity and specificity of this finding and its prognostic implications need further assessment.

Surveillance of chronic haemodialysis-associated infections in southern Israel.

During a 12-month surveillance period, haemodialysis (HD) patients in southern Israel were categorised according to the type of vascular access site (VAS), i.e., arteriovenous (AV) fistula, synthetic AV graft, and cuffed or non-cuffed vascular catheters. Endpoints, expressed as cases/100 patient-months, were: incidence of hospital admission; antibiotic therapy; bloodstream infection (BSI); and VAS infection. These were compared to Centers for Disease Control (CDC) surveillance data, overall and by VAS type. In total, 2568 patient-months were analysed. The VAS distribution differed significantly from CDC data for fistulas (72% vs. 31%), grafts (12% vs. 41%), cuffed catheters (11% vs. 25%) and non-cuffed catheters (5% vs. 3%) (p < 0.0001 in all cases). Of 151 admissions, 32% resulted from infection, for which 112 antibiotic courses (22% vancomycin) were given. There were 16 BSIs, three involving resistant strains. The incidences of admission, antibiotic therapy, BSI and VAS infection were significantly lower overall, compared to CDC rates, as were most VAS-specific endpoints. These differences may be explained by VAS type distribution, although other factors may also be involved. Reporting regional or national surveillance data may allow a standardised comparison of the incidence of HD-associated infections.

Drug-resistant HIV infection among drug-naive patients in Israel.

BACKGROUND: In Israel, <0.06% of the general population is infected with human immunodeficiency virus (HIV), with a much higher prevalence among specific groups. These groups are distinguished demographically by risk behavior category and by virus subtype. We investigated transmission of drug resistance within groups to assess the impact of these factors. METHODS: Plasma samples from >15% of all patients with new diagnoses of HIV infection were randomly collected between June 1999 and June 2003. Sequences from 176 drug-naive patients included 20 of subtype A, 20 of subtype AE, 2 of subtype AC, 29 of subtype B, 100 of subtype C, and 5 of subtype F. RESULTS: Major drug resistance mutations (protease: L90M; reverse transcriptase: M41L, K103N, V106M, M184V, Y181S, G190A, L210W, T215Y/F, and K219R) were detected in 1 subject with A subtype, 3 with subtype B, and 9 with subtype C. In addition, 1 subject with A subtypes, 2 with subtype B, and 10 with subtype C had secondary mutations (protease: M46I; reverse transcriptase: A98G, K101Q, and V108I). Only 1 patient had mutations associated with >1 class of drugs. Among subjects who contracted HIV infection in Israel, 16 of 56 (1 of 7 with subtypes A or AE, 4 of 17 with subtype B, and 11 of 32 with subtype C; P=.7-1.0) carried resistant virus--a significantly higher proportion (P<.001) than in subjects infected in other countries (10 of 120 infected). CONCLUSIONS: Drug-resistant virus was detected in 14.8% of patients with new diagnoses of HIV infection but in 28.6% of patients known to have been infected in Israel. The implications include a need for pretreatment resistance testing and for better programs aimed at prevention of transmission, directed particularly at patients. We did not find significant differences in transmission of resistant virus between those infected with subtypes B and C, despite the different demographic background. A conclusive analysis and interpretation should await a more extensive study.

Impact of regular attendance by infectious disease specialists on the management of hospitalised adults with community-acquired febrile syndromes.

The impact of attendance by infectious disease specialists (IDS) on hospitalised adults with community-acquired infection was assessed by studying 402 consecutive febrile adults who were admitted randomly to either of two internal medicine wards over a 4-month period and given intravenous antibiotics. In ward 1, patients were attended by IDS, whereas those in ward 2 were attended by physicians from other specialties. In total, 160 patients were treated in ward 1 and 242 in ward 2 (median age 66 years; 49% male). The case-mix was comparable. Only 39% of ward 2 patients underwent minimal fever diagnostic tests compared to 82% in ward 1 (p < 0.001). Ward 1 and 2 patients received 188 and 315 antibiotic courses, respectively, of which 32% and 20% required approval from IDS (p 0.003). Patients in ward 1 were more likely to receive ceftriaxone (7.5% vs. 2%; p 0.002), erythromycin (7% vs. 1.5%; p 0.002) and cefuroxime (48% vs. 26%; p < 0.0001), but were less likely to receive amoxycillin-clavulanate (8% vs. 28%; p < 0.0001). The mean durations of therapy were 3.6 and 3.2 days (not significant), and therapy was deemed to be completely appropriate in 55.5% and 43% of cases, respectively (p 0.012). The crude mortality rates were 6.3% and 7.9%, respectively (not significant), while the medication costs were US dollars 27.4 and US dollars 26.4/patient/antibiotic day, respectively. Regular attendance by IDS resulted in significantly higher rates of accurate diagnosis and appropriate therapy. IDS prescribed more restricted (and expensive) agents, but preferred less expensive agents among unrestricted drugs, thereby offsetting the overall medication costs.

Cytosolic phospholipase A2 is responsible for prostaglandin E2 and leukotriene B4 formation in phagocyte-like PLB-985 cells: studies of differentiated cPLA2-deficient PLB-985 cells.

Our previously established model of cytosolic phospholipase A(2) (cPLA(2))-deficient, differentiated PLB-985 cells (PLB-D cells) was used to determine the physiological role of cPLA(2) in eicosanoid production. Parent PLB-985 (PLB) cells and PLB-D cells were differentiated toward the monocyte or granulocyte lineages using 5 x 10(-)(8) M 1,25 dihydroxyvitamin D(3) or 1.25% dimethyl sulfoxide, respectively. Parent monocyte- or granulocyte-like PLB cells released prostaglandin E(2) (PGE(2)) when stimulated by ionomycin, A23187, opsonized zymosan, phorbol 12-myristate 13-acetate, or formyl-Met-Leu-Phe (fMLP), and monocyte- or granulocyte-like PLB-D cells did not release PGE(2) with any of the agonists. The kinetics of cPLA(2) translocation to nuclear fractions in monocyte-like PLB cells stimulated with fMLP or ionomycin was in correlation with the kinetics of PGE(2) production. Granulocyte-like PLB cells, but not granulocyte-like PLB-D cells, secreted leukotriene B(4) (LTB(4)) after stimulation with ionomycin or A23187. Preincubation of monocyte-like parent PLB cells with 100 ng/ml lipopolysaccharide (LPS) for 16 h enhanced stimulated PGE(2) production, which is in correlation with the increased levels of cPLA(2) detected in these cells. LPS preincubation was less potent in increasing PGE(2) and LTB(4) secretion and did not affect cPLA(2) expression in granulocyte-like PLB cells, which may be a result of their lower levels of surface LPS receptor expression. LPS had no effect on monocyte- or granulocyte-like PLB-D cells. The lack of eicosanoid formation in stimulated, differentiated cPLA(2)-deficient PLB cells indicates that cPLA(2) contributes to stimulated eicosanoid formation in monocyte- and granulocyte-like PLB cells.

Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-zeta.

AIMS/HYPOTHESIS: Chronic exposure of 3T3-L1 adipocytes to the HIV protease inhibitor nelfinavir induces insulin resistance, recapitulating key metabolic alterations of adipose tissue in the lipodystrophy syndrome induced by these agents. Our goal was to identify the defect in the insulin signal transduction cascade leading to nelfinavir-induced insulin resistance. METHODS: Fully differentiated 3T3-L1 adipocytes were exposed to 30 micro mol/l nelfinavir for 18 h, after which the amount, the phosphorylation and the localisation of key proteins in the insulin signalling cascade were evaluated. RESULTS: Insulin-induced interaction of phosphatidylinositol 3'-kinase (PI 3-kinase) with IRS proteins was normal in cells treated with nelfinavir, as was IRS-1-associated PI 3-kinase activity. Yet insulin-induced phosphorylation of Akt/protein kinase B (PKB), p70S6 kinase and extracellular signal-regulated kinase 1/2 was significantly impaired. This could not be attributed to increased protein phosphatase 2A activity or to increased expression of phosphoinositide phosphatases (SHIP2 or PTEN). However, insulin failed to induce translocation of the PI 3-kinase effectors Akt/PKB and protein kinase C-zeta (PKC-zeta) to plasma membrane fractions of nelfinavir-treated adipocytes. CONCLUSIONS/INTERPRETATION: We therefore conclude that nelfinavir induces a defect in the insulin signalling cascade downstream of the activation of PI 3-kinase. This defect manifests itself by impaired insulin-mediated recruitment of Akt/PKB and PKC-zeta to the plasma membrane.

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.

Zoonotic infections as causes of hospitalization among febrile Bedouin patients in southern Israel.

A prospective 12-month study was conducted throughout 1998 to determine the frequency of selected bacterial zoonoses as causes of fever among hospitalized Bedouins in southern Israel. One or more zoonoses were diagnosed in 30 (27%) of 110 patients admitted with fever. Brucellosis was diagnosed in 9 (8%), rickettsial infections in 20 (18%), and ehrlichiosis in 2 (2%), one of whom had also evidence of rickettsial spotted fever infection. None of the patients was diagnosed with Q fever. Compared with patients without zoonoses, patients with zoonoses were younger (P = 0.01), fewer of them had underlying conditions (P < 0.02), they had a longer febrile period prior to hospitalization (P = 0.04), a significantly higher proportion had arthralgia (P = 0.02), rash (P = 0.03), and splenomegaly (P = 0.04) and a lower proportion had pathological findings on chest auscultation (P < 0.01). Patients with zoonoses were found to have more commonly anaemia (P = 0.03) and leucopenia (P = 0.02) compared to the rest of the study population. Of the 30 patients with zoonoses 60% were misdiagnosed and only 57% received adequate antibiotic treatment. Zoonotic infections are a common cause of fever in adult Bedouins living in southern Israel. Because of the non-specific features of these diseases they are often misdiagnosed. Blood cultures and multiple serological tests should be used in the investigation of fever in such patients and tetracycline should be considered for initial empirical treatment.

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.

Polymicrobial polyarticular septic arthritis: a rare clinical entity.

Polymicrobial polyarticular septic arthritis is a rare clinical entity, with only a few cases having been reported to date. We report a case due to Streptococcus pyogenes and Staphylococcus aureus in an IVDU, complicated by fatal streptococcal toxic-shock syndrome, and review the current literature. We conclude that whenever polymicrobial polyarticular septic arthritis is diagnosed, a high index of suspicion should be maintained for the detection of locally destructive infectious processes as well as systemic complications, and that a high mortality rate should be expected.

The HIV protease inhibitor nelfinavir induces insulin resistance and increases basal lipolysis in 3T3-L1 adipocytes.

HIV protease inhibitors (HPIs) are potent antiretroviral agents clinically used in the management of HIV infection. Recently, HPI therapy has been linked to the development of a metabolic syndrome in which adipocyte insulin resistance appears to play a major role. In this study, we assessed the effect of nelfinavir on glucose uptake and lipolysis in differentiated 3T3-L1 adipocytes. An 18-h exposure to nelfinavir resulted in an impaired insulin-stimulated glucose uptake and activation of basal lipolysis. Impaired insulin stimulation of glucose up take occurred at nelfinavir concentrations >10 micromol/l (EC(50) = 20 micromol/l) and could be attributed to impaired GLUT4 translocation. Basal glycerol and free fatty acid (FFA) release were significantly enhanced with as low as 5 micromol/l nelfinavir, displaying fivefold stimulation of FFA release at 10 micromol/l. Yet, the antilipolytic action of insulin was preserved at this concentration. Potential underlying mechanisms for these metabolic effects included both impaired insulin stimulation of protein kinase B Ser 473 phosphorylation with preserved insulin receptor substrate tyrosine phosphorylation and decreased expression of the lipolysis regulator perilipin. Troglitazone pre- and cotreatment with nelfinavir partly protected the cells from the increase in basal lipolysis, but it had no effect on the impairment in insulin-stimulated glucose uptake induced by this HPI. This study demonstrates that nelfinavir induces insulin resistance and activates basal lipolysis in differentiated 3T3-L1 adipocytes, providing potential cellular mechanisms that may contribute to altered adipocyte metabolism in treated HIV patients.