Mario Cruciani

Nosocomial epidemic of active tuberculosis among HIV-infected patients.

In an investigation of a nosocomial outbreak of tuberculosis, 18 HIV-infected inpatients were found to have been exposed to Mycobacterium tuberculosis; active tuberculosis developed in 8, 7 within 60 days of diagnosis of the index case. The patients with lower total lymphocyte and CD4 lymphocyte counts were more likely to get the disease than were those with higher counts. A low score on multiple antigen skin testing was also associated with the development of active tuberculosis. 4 of the 18 patients had a positive tuberculin skin test before exposure to M tuberculosis; none of them subsequently got the disease.

Use of PCR for diagnosis of invasive aspergillosis: Systematic review and meta-analysis

A systematic review and meta-analysis was done on the use of PCR tests for the diagnosis of invasive aspergillosis. Data from more than 10000 blood, serum, or plasma samples obtained from 1618 patients at risk for invasive aspergillosis were retrieved from 16 studies. Overall, the mean diagnostic odds ratios (DORs) of PCR for proven and probable cases were similar whether two consecutive positive samples were required to define positivity (DOR 15.97 [95% CI 6.83-37.34]) or a single positive PCR test was required (DOR 16.41 [95% CI 6.43-41.88]). Sensitivity and specificity of PCR for two consecutive positive samples were 0.75 (95% CI 0.54-0.88) and 0.87 (95% CI 0.78-0.93), respectively, and if only a single positive sample was required, these values were 0.88 (95% CI 0.75-0.94) and 0.75 (95% CI 0.63-0.84), respectively. Whereas specificity based on a single positive test was significantly lower (p=0.027) than two positive tests, the sensitivity and DOR did not differ significantly. A single PCR-negative result is thus sufficient to exclude a diagnosis of proven or probable invasive aspergillosis. However, two positive tests are required to confirm the diagnosis because the specificity is higher than that attained from a single positive test. Populations at risk varied and there was a lack of homogeneity of the PCR methods used. Efforts are underway to devise a standard for Aspergillus sp PCR for screening, which will help enable formal validation of PCR and estimate its use in patients most likely to benefit.

β-Glucan antigenemia assay for the diagnosis of invasive fungal infections in patients with hematological malignancies: a systematic review and meta-analysis of cohort studies from the Third European Conference on Infections in Leukemia (ECIL-3).

BACKGROUND Invasive fungal infections (IFIs) are life-threatening complications in patients with hemato-oncological malignancies, and early diagnosis is crucial for outcome. The compound 1,3-β-D-glucan (BG), a cell wall component of most fungal species, can be detected in blood during IFI. Four commercial BG antigenemia assays are available (Fungitell, Fungitec-G, Wako, and Maruha). This meta-analysis from the Third European Conference on Infections in Leukemia (ECIL-3) assessed the performance of BG assays for the diagnosis of IFI in hemato-oncological patients. METHODS Studies reporting the performance of BG antigenemia assays for the diagnosis of IFI (European Organization for Research and Treatment of Cancer and Mycoses Study Group criteria) in hemato-oncological patients were identified. The analysis was focused on high-quality cohort studies with exclusion of case-control studies. Meta-analysis was performed by conventional meta-analytical pooling and bivariate analysis. RESULTS Six cohort studies were included (1771 adult patients with 414 IFIs of which 215 were proven or probable). Similar performance was observed among the different BG assays. For the cutoff recommended by the manufacturer, the diagnostic performance of the BG assay in proven or probable IFI was better with 2 consecutive positive test results (diagnostic odds ratio for 2 consecutive vs one single positive results, 111.8 [95% confidence interval {CI}, 38.6-324.1] vs 16.3 [95% CI, 6.5-40.8], respectively; heterogeneity index for 2 consecutive vs one single positive results, 0% vs 72.6%, respectively). For 2 consecutive tests, sensitivity and specificity were 49.6% (95% CI, 34.0%-65.3%) and 98.9% (95% CI, 97.4%-99.5%), respectively. Estimated positive and negative predictive values for an IFI prevalence of 10% were 83.5% and 94.6%, respectively. CONCLUSIONS Different BG assays have similar accuracy for the diagnosis of IFI in hemato-oncological patients. Two consecutive positive antigenemia assays have very high specificity, positive predictive value, and negative predictive value. Because sensitivity is low, the test needs to be combined with clinical, radiological, and microbiological findings.

Meta-Analysis of BACTEC MGIT 960 and BACTEC 460 TB, with or without Solid Media, for Detection of Mycobacteria

ABSTRACT In a meta-analysis of 10 studies, the BACTEC 960/MGIT and BACTEC 460 systems showed a sensitivity and specificity in detecting mycobacteria (1,381 strains from 14,745 clinical specimens) of 81.5 and 99.6% and 85.8 and 99.9%, respectively. Combined with solid media, the sensitivity of the two systems increased to 87.7 and 89.7%, respectively.

The relationship between ritonavir plasma levels and side-effects: implications for therapeutic drug monitoring

OBJECTIVES To assess whether the neurological or gastrointestinal adverse effects of ritonavir correlate with parameters of ritonavir systemic exposure. METHODS Peak (Cmax) and trough (Cmin) ritonavir plasma levels were compared in 11 patients experiencing side-effects (group A) versus 10 patients without side-effects (group B). Ritonavir was administered with the following escalation dosing scheme: 300, 400, 500 mg twice a day for 3, 4, and 5 days, respectively, then the full dose of 600 mg twice a day. Blood sampling was done in group A within 24 h of the occurrence of side-effects and in group B after at least 3 days of the full dosage regimen. RESULTS Both Cmax and Cmax were significantly higher (Mann-Whitney U test) in patients with side-effects. Cmax was [median (interquartile range)] 26.7 (22.7-33.3) mg/l versus 16.2 (13.4-17.0) mg/l (P = 0.001) and Cmin was 12.6 (9.1-13.9) versus 7.5 (4.9-8.6) mg/l (P = 0.002). CONCLUSION Patients with higher ritonavir concentrations are at a higher risk of experiencing neurological or gastrointestinal side-effects. Individualization of the dosage regimen, e.g. a downward titration of the ritonavir dose in patients with side-effects, guided by plasma level monitoring, may result in a substantial increase in the percentage of patients tolerating ritonavir without increasing the risk of treatment failure as a result of suboptimal systemic exposure.

Antifungal prophylaxis in liver transplant patients: A systematic review and meta-analysis†

We performed a meta‐analysis to determine whether antifungal prophylaxis decreases infectious morbidity and mortality in liver transplant patients. We searched for randomized trials dealing with prophylaxis with systemic antifungal agents. We used a fixed effect model, with risk ratio (RR) and 95% confidence interval (CI); we assessed study quality for heterogeneity and publication bias. Six studies (5 double‐blind), for a total of 698 patients, compared fluconazole, itraconazole, or liposomal amphotericin to placebo (5 studies) or oral nystatin. Prophylaxis reduced colonization (RR, 0.45; CI, 0.37‐0.55), total proven fungal infections (RR, 0.31; CI, 0.21‐0.46), which included both superficial (RR, 0.27; CI, 0.16‐0.45) and invasive (RR, 0.33; CI, 0.18‐0.59) infections, and mortality attributable to fungal infection (RR, 0.30; CI, 0.12‐0.75). Prophylaxis did not affect overall mortality (RR, 1.06; CI, 0.69‐1.64) or empiric treatment for suspected fungal infection (RR, 0.80; CI, 0.39‐1.67). The beneficial effect of antifungal prophylaxis was predominantly associated with the reduction of Candida albicans infection and mortality attributable to C. albicans. Compared to controls, however, patients receiving prophylaxis experienced a higher proportion of episodes of non–albicans Candida, and in particular of C. glabrata. No beneficial effect on invasive Aspergillus infection was observed. In conclusion, our analysis shows a clear, though limited, beneficial effect of antifungal prophylaxis in liver transplant patients. Concerns about the selection of triazole‐resistant Candida strains, however, are realistic, and the potential disadvantages of prophylaxis should be weighed against the established benefits. Liver Transpl 12:850–858, 2006.

Prophylaxis of Candida infections in adult trauma and surgical intensive care patients: a systematic review and meta-analysis

ObjectiveTo determine whether systemic antifungal prophylaxis decreases infectious morbidity and mortality in nonneutropenic, critically ill, trauma and surgical intensive care unit (ICU) adult patients.DesignSystematic review and meta-analysis of randomized clinical trials. We used a fixed effect model, with risk ratio (RR) and 95% confidence intervals (CI).ParticipantsPatients admitted to ICU after surgery or trauma, with multiple risk factors for fungal infections.InterventionsNine studies (seven double blind) with a total of 1,226 patients compared ketoconazole (three) or fluconazole (six) to placebo (eight) or no treatment (one).ResultsProphylaxis with azole was associated with reduced rates of candidemia (RR 0.30, 95% CI 0.10–0.82), mortality attributable to Candida infection (RR 0.25, 95% CI 0.08–0.80), and overall mortality (RR 0.60, 95% CI 0.45–0.81). Time to event analysis showed a significantly lower probability of fungal infections in treated patients. There was no evidence of statistical heterogeneity between studies, and publication bias assessment gave a negative results. There was, however, wide variability in the definition and reporting of some relevant clinical outcomes (e.g., confirmed or suspected infections, colonization) and pooling of these outcome measures was not feasible.ConclusionsProphylaxis of candidal infection among critically ill ICU patients has beneficial effect on certain outcome measures, but additional data from well designed clinical trials and long-term epidemiological observations are needed to provide firm recommendations for the selection of subgroups of patients who would most benefit from prophylaxis and to determine the effect of prophylaxis on fungal resistance patterns.

Abacavir use and cardiovascular disease events: a meta-analysis of published and unpublished data

Background:The use of abacavir (ABC) has been associated with an increased risk of cardiovascular disease in some cohort studies. However, no excess risk of myocardial infarction (MI) with ABC therapy has been observed in individual randomized clinical trials (RCTs) and in the aggregated clinical trials database maintained by the manufacturer of ABC. Objective:To combine all the evidence from RCTs by means of meta-analysis to estimate the effect of combined antiretroviral therapy (cART) containing ABC on MI and overall major cardiovascular events (CVEs). Methods:Primary outcomes included MI, CVE, adverse events requiring discontinuation of treatment, and overall mortality. We used a conventional Mantel–Haenszel method, with risk ratio and 95% confidence intervals (CIs) or, in the presence of heterogeneity, a random-effect model. Results:Data were from 28 primary RCTs (9233 participants) comparing ABC-containing cART (4376 participants) to other regimens not containing ABC (4857 controls). MI data were available from 18 trials (31 episodes in 7054 patients) and CVE data from 20 trials (79 episodes in 7899 patients). Compared to the controls, ABC use did not increase significantly the occurrence of MI (risk ratio 0.73, 95% CI 0.39–1.35; P = 0.31), CVE (risk ratio 0.95, 95% CI 0.62–1.44; P = 0.80), overall mortality (risk ratio 1.20, 95% CI 0.63–2.27; P = 0.58), and adverse events requiring discontinuation of treatment (risk ratio 0.82, 95% CI 0.67–1.00; P = 0.05). Conclusion:This meta-analysis of RCTs does not support the hypothesis that ABC-containing cART regimens carry a greater risk of MI or major cardiovascular events relative to comparator cART.

Anal and oral human papillomavirus (HPV) infection in HIV-infected subjects in northern Italy: a longitudinal cohort study among men who have sex with men

BackgroundA study including 166 subjects was performed to investigate the frequency and persistence over a 6-month interval of concurrent oral and anal Human Papillomavirus (HPV) infections in Human Immunodeficiency Virus (HIV)-infected men who have sex with men (MSM).MethodsPatients with no previously documented HPV-related anogenital lesion/disease were recruited to participate in a longitudinal study. Polymerase chain reaction (PCR) was performed to detect HPV from oral and anal swabs and to detect Human Herpes Virus 8 (HHV-8) DNA in saliva on 2 separate specimen series, one collected at baseline and the other collected 6 months later. A multivariate logistic analysis was performed using anal HPV infection as the dependent variable versus a set of covariates: age, HIV plasma viral load, CD4+ count, hepatitis B virus (HBV) serology, hepatitis C virus (HCV) serology, syphilis serology and HHV-8 viral shedding. A stepwise elimination of covariates with a p-value > 0.1 was performed.ResultsThe overall prevalence of HPV did not vary significantly between the baseline and the follow-up, either in the oral (20.1 and 21.3%, respectively) or the anal specimens (88.6 and 86.3%). The prevalence of high-risk (HR) genotypes among the HPV-positive specimens was similar in the oral and anal infections (mean values 24.3% and 20.9%). Among 68 patients with either a HR, low-risk (LR) or undetermined genotype at baseline, 75% had persistent HPV and the persistence rates were 71.4% in HR infections and 76.7% in LR infections. There was a lack of genotype concordance between oral and anal HPV samples. The prevalence of HR HPV in anus appeared to be higher in the younger patients, peaking (> 25%) in the 43-50 years age group. A decrease of the high level of anal prevalence of all genotypes of HPV in the patients > 50 years was evident. HHV-8 oral shedding was positively related to HPV anal infection (p = 0.0046). A significant correlation was found between the persistence of HHV-8 shedding and HIV viral load by logistic bivariate analysis (Odds Ratio of HHV-8 persistence for 1-log increase of HIV viral load = 1.725 ± 0.397, p = 0.018).ConclusionsA high prevalence of HPV infection was found in our cohort of HIV-infected MSM, with a negative correlation between anal HPV infection and CD4 cell count.

Reappraisal With Meta-Analysis of the Addition of Gram-Positive Prophylaxis to Fluoroquinolone in Neutropenic Patients

PURPOSE Past reports and meta-analyses indicate that fluoroquinolones are highly effective in preventing Gram-negative infections in neutropenic cancer patients, but offer inadequate coverage for Gram-positive infections. We evaluated by meta-analysis the efficacy of the addition of antimicrobial agents with enhanced Gram-positive activity to prophylaxis with quinolones. MATERIALS AND METHODS Randomized trials comparing fluoroquinolones alone (ciprofloxacin, ofloxacin, pefloxacin, or norfloxacin) with fluoroquinolone in combination with Gram-positive prophylaxis (rifampin, vancomycin, amoxicillin, roxithromycin, or penicillin) were retrieved. We pooled relative risks (RRs) using a fixed-effects model. RESULTS Nine trials (1,202 patients) published between 1993 and 2000 meet inclusion criteria. Compared with fluoroquinolone alone, Gram-positive prophylaxis reduced total bacteremic episodes (RR, 1.54; 95% CI, 1.26 to 1.88), streptococcal infections (RR, 2.20; 95% CI, 1.44 to 3.37), coagulase-negative staphylococcal infections (RR, 1.46; 95% CI, 1.04 to 2.04), and rate of febrile patients (RR 1.08; 95% CI, 1.00 to 1.16). Occurrence of clinically documented infections, unexplained fever, and infectious mortality was similar in the two groups. The addition of Gram-positive prophylaxis, however, significantly increased side effects (RR, 0.46; 95% CI, 0.28 to 0.76). Rifampin use resulted in a higher incidence of undesirable effects. CONCLUSION Considering the lack of cut-clear benefit on some parameters of morbidity and mortality, routine use of Gram-positive prophylaxis is not advisable. This strategy, however, should be particularly valuable in subgroups of patients at high risk of streptococcal infection (eg, those with severe and prolonged neutropenia or mucositis, and those receiving cytarabine). Problems of tolerability and the potential for the emergence of resistant microorganisms should be considered when prescribing prophylaxis with enhanced Gram-positive activity to neutropenic patients.