Pinaki Biswas

International Retrospective Analysis of 73 Cases of Invasive Fusariosis Treated with Voriconazole

ABSTRACT The outcomes for 73 invasive fusariosis patients treated with voriconazole were investigated. Patients with proven (n = 67) or probable (n = 6) infections were identified from the voriconazole clinical database (n = 39) and the French National Reference Center for Mycoses and Antifungals database (n = 34). Investigator-determined success was a complete or partial response. Survival was determined from day 1 of voriconazole therapy to the last day known alive. Patients were 2 to 79 years old (median, 43 years), and 66% were male. Identified Fusarium species (62%) were F. solani, F. moniliforme, F. proliferatum, and F. oxysporum. Underlying conditions analyzed included hematopoietic stem cell transplant (HSCT; 18%), hematologic malignancy (HM; 60%), chronic immunosuppression (CI; 12%), or other condition (OC; 10%). Infection sites were brain (5%), disseminated excluding brain (67%), lungs/sinus (15%), and other (12%). Most patients (64%) were or had recently been neutropenic (<500 cells/mm3). Therapy duration was 1 to 480 days (median, 57 days), with a 47% success rate. Baseline neutropenia impacted success adversely (P ≤ 0.03). Success varied by underlying condition (HSCT, 38%; HM, 45%; CI, 44%; OC, 71%) and infection site (brain, 0%; disseminated, 45%; other, 56%; lung/sinus, 64%) (P > 0.05). Combination therapy (13 patients) was no better than treatment with voriconazole alone. Overall, 59% of the patients died (49% died of fusariosis), and 90-day survival was 42%. Site of infection influenced survival (P = 0.02). Median survival (in days) by species was as follows: F. solani, 213; F. oxysporum, 112; Fusarium spp., 101; F. proliferatum, 84; F. moniliforme, 76. We conclude that voriconazole is a therapeutic option for invasive fusariosis.

A risk-adjusted CUSUM in continuous time based on the Cox model

In clinical practice, it is often important to monitor the outcomes associated with participating facilities. In organ transplantation, for example, it is important to monitor and assess the outcomes of the transplants performed at the participating centers and send a signal if a significant upward trend in the failure rates is detected. In manufacturing and process control contexts, the cumulative summation (CUSUM) technique has been used as a sequential monitoring scheme for some time. More recently, the CUSUM has also been suggested for use in medical contexts. In this article, we outline a risk-adjusted CUSUM procedure based on the Cox model for a failure time outcome. Theoretical approximations to the average run length are obtained for this new proposal and for some discrete time procedures suggested in the literature. The proposed scheme and approximations are evaluated in simulations and illustrated on transplant facility data from the Scientific Registry of Transplant Recipients.

A Genotypic Test for HIV-1 Tropism Combining Sanger Sequencing with Ultradeep Sequencing Predicts Virologic Response in Treatment-Experienced Patients

A tropism test is required prior to initiation of CCR5 antagonist therapy in HIV-1 infected individuals, as these agents are not effective in patients harboring CXCR4 (X4) coreceptor-using viral variants. We developed a clinical laboratory-based genotypic tropism test for detection of CCR5-using (R5) or X4 variants that utilizes triplicate population sequencing (TPS) followed by ultradeep sequencing (UDS) for samples classified as R5. Tropism was inferred using the bioinformatic algorithms geno2pheno[coreceptor] and PSSMx4r5. Virologic response as a function of tropism readout was retrospectively assessed using blinded samples from treatment-experienced subjects who received maraviroc (N = 327) in the MOTIVATE and A4001029 clinical trials. MOTIVATE patients were classified as R5 and A4001029 patients were classified as non-R5 by the original Trofile test. Virologic response was compared between the R5 and non-R5 groups determined by TPS, UDS alone, the reflex strategy and the Trofile Enhanced Sensitivity (TF-ES) test. UDS had greater sensitivity than TPS to detect minority non-R5 variants. The median log10 viral load change at week 8 was −2.4 for R5 subjects, regardless of the method used for classification; for subjects with non-R5 virus, median changes were −1.2 for TF-ES or the Reflex Test and −1.0 for UDS. The differences between R5 and non-R5 groups were highly significant in all 3 cases (p<0.0001). At week 8, the positive predictive value was 66% for TF-ES and 65% for both the Reflex test and UDS. Negative predictive values were 59% for TF-ES, 58% for the Reflex Test and 61% for UDS. In conclusion, genotypic tropism testing using UDS alone or a reflex strategy separated maraviroc responders and non-responders as well as a sensitive phenotypic test, and both assays showed improved performance compared to TPS alone. Genotypic tropism tests may provide an alternative to phenotypic testing with similar discriminating ability.

Anidulafungin compared with fluconazole for treatment of candidemia and other forms of invasive candidiasis caused by Candida albicans: a multivariate analysis of factors associated with improved outcome

BackgroundCandida albicans is the most common cause of candidemia and other forms of invasive candidiasis. Systemic infections due to C. albicans exhibit good susceptibility to fluconazole and echinocandins. However, the echinocandin anidulafungin was recently demonstrated to be more effective than fluconazole for systemic Candida infections in a randomized, double-blind trial among 245 patients. In that trial, most infections were caused by C. albicans, and all respective isolates were susceptible to randomized study drug. We sought to better understand the factors associated with the enhanced efficacy of anidulafungin and hypothesized that intrinsic properties of the antifungal agents contributed to the treatment differences.MethodsGlobal responses at end of intravenous study treatment in patients with C. albicans infection were compared post-hoc. Multivariate logistic regression analyses were performed to predict response and to adjust for differences in independent baseline characteristics. Analyses focused on time to negative blood cultures, persistent infection at end of intravenous study treatment, and 6-week survival.ResultsIn total, 135 patients with C. albicans infections were identified. Among these, baseline APACHE II scores were similar between treatment arms. In these patients, global response was significantly better for anidulafungin than fluconazole (81.1% vs 62.3%; 95% confidence interval [CI] for difference, 3.7-33.9). After adjusting for baseline characteristics, the odds ratio for global response was 2.36 (95% CI, 1.06-5.25). Study treatment and APACHE II score were significant predictors of outcome. The most predictive logistic regression model found that the odds ratio for study treatment was 2.60 (95% CI, 1.14-5.91) in favor of anidulafungin, and the odds ratio for APACHE II score was 0.935 (95% CI, 0.885-0.987), with poorer responses associated with higher baseline APACHE II scores. Anidulafungin was associated with significantly faster clearance of blood cultures (log-rank p < 0.05) and significantly fewer persistent infections (2.7% vs 13.1%; p < 0.05). Survival through 6 weeks did not differ between treatment groups.ConclusionsIn patients with C. albicans infection, anidulafungin was more effective than fluconazole, with more rapid clearance of positive blood cultures. This suggests that the fungicidal activity of echinocandins may have important clinical implications.Trial registrationClinicalTrials.gov: NCT00058682

All-cause mortality imbalance in the tigecycline phase 3 and 4 clinical trials

In 12 of 13 phase 3 and 4 comparative clinical trials, all-cause mortality was higher in the tigecycline group versus the comparator group. Study-level mortality risk differences were pooled using a random-effects meta-analysis. Statistical models evaluated the association between patient-level all-cause mortality and baseline factors using logistic regression, recursive partitioning [classification and regression tree (CART) analysis] and survival techniques. The estimated risk difference (tigecycline minus comparator) in all-cause mortality from the meta-analysis was 0.6% (95% confidence interval 0.1-1.2%). Statistical modelling identified baseline bacteraemia associated with mortality only in the tigecycline group. In patients with ventilator-associated pneumonia (VAP) and baseline bacteraemia, mortality was 50.0% (9/18) for tigecycline versus 7.7% (1/13) for the comparator group. Study-level and patient-level analyses have identified that patients in the hospital-acquired pneumonia trial, particularly those with VAP with baseline bacteraemia, were at a higher risk of clinical failure and mortality.

Clinical efficacy of oral linezolid compared with intravenous vancomycin for the treatment of methicillin-resistant Staphylococcus aureus-complicated skin and soft tissue infections: a retrospective, propensity score-matched, case-control analysis.

BACKGROUND Linezolid is 100% bioavailable in oral and intravenous formulations. In a recent prospective, randomized, open-label, comparator-controlled, multicenter, phase 4 clinical trial in adults with complicated skin and soft tissue infections (cSSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA), linezolid achieved clinical and microbiologic success comparable to appropriately dosed intravenous vancomycin. Although patients were randomly assigned to receive linezolid or vancomycin, the protocol allowed patients to start therapy using oral or intravenous linezolid on the basis of investigator discretion and patient ability to tolerate oral medication. OBJECTIVE The objective of this study was to assess the efficacy and tolerability of linezolid when administered orally in adults with cSSTI caused by MRSA. In this retrospective analysis, we examined data collected from the aforementioned trial to compare outcomes in patients who received either oral linezolid or intravenous vancomycin therapy. METHODS This study analyzed outcomes in patients who received treatment for 7 to 14 days with either oral linezolid (600 mg q12h; n = 95) or intravenous vancomycin (15 mg/kg q12h, adjusted for creatinine clearance and trough concentration; n = 210). By design, these groups were not randomized. Propensity score matching on baseline variables was used to balance these groups by identifying a comparable group of patients who received vancomycin therapy and comparing them with patients who received oral linezolid therapy. Clinical and microbiologic success rates at the end of treatment and the end of the study (EOS) were then directly compared between the groups using matched-pair logistic regression. The tolerability of the 2 treatments (within this matched group) was also described. RESULTS Ninety-two patients with well-matched baseline characteristics were included in each treatment group. At EOS, the odds ratio for clinical success of oral linezolid therapy vs intravenous vancomycin therapy was 4.0 (95% CI, 1.3-12.0; P = 0.01), and the odds ratio for microbiologic success at EOS was 2.7 (95% CI, 1.2-5.7; P = 0.01). Overall rates of adverse events in each group were consistent with reported safety profiles for each drug. CONCLUSION A favorable clinical cure rate was achieved with oral linezolid therapy when compared with intravenous vancomycin therapy in propensity score-matched patients with cSSTI proved to be caused by MRSA. ClinicalTrials.gov Identifier: NCT00087490.

The Safety and Immunogenicity of Live Zoster Vaccination in Patients With Rheumatoid Arthritis Before Starting Tofacitinib: A Randomized Phase II Trial

Patients with rheumatoid arthritis (RA) are at increased risk of herpes zoster, and vaccination is recommended for patients ages 50 years and older, prior to starting treatment with biologic agents or tofacitinib. Tofacitinib is an oral JAK inhibitor for the treatment of RA. We evaluated its effect on the immune response and safety of live zoster vaccine (LZV).

Influence of CYP2C19 polymorphism on the pharmacokinetics of nelfinavir and its active metabolite.

AIMS This study reports the pharmacokinetics of nelfinavir, its active metabolite, M8, and active moiety (nelfinavir + M8) in volunteers genotyped for CYP2C19 as extensive metabolizer (*1*1; n = 38), heterozygous poor metabolizer (PM) (*1*2; n = 22) and homozygous PM (*2*2; n = 6). METHODS Subjects received nelfinavir at normal dose (3.5 days of 1250 mg q12h) or high dose (1250 mg q12h for 3 days and single dose of 3125 mg on day 4). Steady-state plasma samples were analysed by high-performance liquid chromatography/ultraviolet assay to determine pharmacokinetics. RESULTS At steady state, the mean C(max) was 42% [95% confidence interval (CI) 19, 69] and 63% (95% CI 20, 122) higher, and mean AUC was 51% (95% CI 24, 83) and 85% (95% CI 32, 159) higher for *1*2 and *2*2 compared with *1*1 subjects, respectively. For M8, the mean C(max) and AUC were 35% (95% CI 6, 55) and 33% (95% CI -3, 56), respectively, lower for *1*2 compared with *1*1 subjects. M8 was not detectable in *2*2 subjects. The mean C(max) and AUC values for the active moiety were higher by 30-35% for the *1*2 and *2*2 compared with *1*1 subjects. CONCLUSIONS Mutation in CYP2C19 increased the systemic exposure of nelfinavir and reduced the exposure of M8. No significant differences were noted among the heterozygous (*1*2) and homozygous (*2*2) PMs. These changes are not considered to be clinically relevant and hence the use of nelfinavir does not require prior assessment of CYP2C19 genotype.

Impact of patient characteristics and infection type on clinical outcomes of patients who received linezolid or vancomycin for complicated skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus: a pooled data analysis

Phase III randomized, clinical trials are primarily designed to evaluate overall treatment-outcome comparisons. Although valuable data are gained from such comparisons, it is difficult to draw meaningful inferences about potential outcomes differences in specific patient groups and infection types. It is well established that clinical outcomes are dependent on host, treatment- and pathogen-related factors and understanding which groups benefit from one treatment relative to another is of great importance. This study sought to determine if clinical success in the treatment of complicated skin and skin structure infections (cSSSI) caused by methicillin resistant Staphylocccus aureus (MRSA) with linezolid or vancomycin varied across subpopulations and infection type. Data from 3 prospective, randomized trials evaluating linezolid and vancomycin for the treatment of MRSA cSSSI were pooled. Treatment related differences in outcomes were found, on both the absolute and relative scales, for most subpopulations and infection types. Identifying treatment differences in outcome by patient subpopulation can enhance clinical decision making.

The Safety and Immunogenicity of Live Zoster Vaccination in Rheumatoid Arthritis Patients Before Starting Tofacitinib: A Randomized Phase II Trial

Patients with rheumatoid arthritis (RA) are at increased risk of herpes zoster, and vaccination is recommended for patients ages 50 years and older, prior to starting treatment with biologic agents or tofacitinib. Tofacitinib is an oral JAK inhibitor for the treatment of RA. We evaluated its effect on the immune response and safety of live zoster vaccine (LZV).