Utility of voriconazole therapeutic drug monitoring: a meta-analysis.

BACKGROUND: Voriconazole therapeutic drug monitoring (TDM) is increasingly used in clinical practice. However, the utility of voriconazole TDM to guide therapy remains uncertain and controversial. We conducted a meta-analysis of studies assessing the relationship between voriconazole serum concentration and clinical outcomes of success and toxicity. METHODS: We searched bibliographic databases for studies on voriconazole serum concentrations and clinical outcomes. We compared success outcomes between patients with therapeutic and subtherapeutic voriconazole serum concentrations, and toxicity outcomes between patients with and without supratherapeutic serum concentrations. RESULTS: Twenty-four studies were analysed. Pooled analysis for efficacy endpoint demonstrated that patients with therapeutic voriconazole serum concentrations (1.0-2.2 mg/L) were more likely to have successful outcomes compared with those with subtherapeutic voriconazole serum concentrations (OR 2.30; 95% CI 1.39-3.81). A therapeutic threshold of 1.0 mg/L was most predictive of successful outcome (OR 1.94; 95% CI 1.04-3.62). Patients with therapeutic concentrations did not have better survival rates. Pooled analysis for toxicity endpoint demonstrated that patients with supratherapeutic voriconazole serum concentrations (4.0-6.0 mg/L) were at increased risk of toxicity (OR 4.17; 95% CI 2.08-8.36). A supratherapeutic threshold of 6.0 mg/L was most predictive of toxicity (OR 4.60; 95% CI 1.49-14.16). CONCLUSIONS: Patients with therapeutic voriconazole serum concentrations were twice as likely to achieve successful outcomes. The likelihood of toxicity associated with supratherapeutic voriconazole serum concentrations was 4-fold that of therapeutic concentrations. Our findings suggest that the use of voriconazole TDM to aim for serum concentrations between 1.0 and 6.0 mg/L during therapy may be warranted to optimize clinical success and minimize toxicity.

Ganciclovir-resistant cytomegalovirus infections among lung transplant recipients are associated with poor outcomes despite treatment with foscarnet-containing regimens.

Ganciclovir-resistant cytomegalovirus (CMV) infections are reported infrequently among lung transplant recipients receiving extended valganciclovir prophylaxis. We performed a single-center, retrospective review of ganciclovir-resistant CMV infections in a program that employed valganciclovir prophylaxis for ≥6 months after lung transplant. CMV infections were diagnosed in 28% (170/607) of patients. UL97 mutations were detected in 9.4% (16/170) of CMV-infected patients at a median of 8.5 months posttransplant (range, 5 to 21) and despite prophylaxis for a median of 7 months (range, 4 to 21). UL97 mutations were canonical; 25% (4/16) of strains carried concurrent UL54 mutations. Ganciclovir-resistant CMV was more likely with breakthrough infections (75% [12/16] versus 19% [30/154]; P = 0.00001) and donor positive/recipient negative (D+/R-) serostatus (75% versus 45% [69/154]; P = 0.03). The median whole-blood CMV load was 4.13 log10 copies/cm(3) (range, 2.54 to 5.53), and 93% (14/15) of patients had low-moderate immune responses (Cylex Immunoknow). Antiviral therapy was successful, failed, or eradicated viremia followed by relapse in 12% (2/16), 31% (5/16), and 56% (9/16) of patients, respectively. Eighty-seven percent (14/16) of patients were treated with foscarnet-containing regimens; toxicity developed in 78% (11/14) of these. Median viral load half-life and time to viremia eradication among foscarnet-treated patients were 2.6 and 23 days, respectively, and did not correlate with protection from relapse. Sixty-nine percent (11/16) of patients developed CMV pneumonitis, and 25% (4/16) died of it. Serum viral load was independently associated with death among foscarnet-treated patients (P = 0.04). In conclusion, ganciclovir-resistant CMV infections remained a major cause of morbidity and mortality following lung transplantation. Foscarnet-based regimens often eradicated viremia rapidly but were ineffective in the long term and limited by toxicity.

Performance of Candida real-time polymerase chain reaction, ß-D-glucan assay, and blood cultures in the diagnosis of invasive candidiasis.

BACKGROUND: The sensitivity of blood cultures for diagnosing invasive candidiasis (IC) is poor. METHODS: We performed a validated Candida real-time polymerase chain reaction (PCR) and the Fungitell 1,3-ß-D-glucan (BDG) assay on blood samples collected from prospectively identified patients with IC (n = 55) and hospitalized controls (n = 73). Patients with IC had candidemia (n = 17), deep-seated candidiasis (n = 33), or both (n = 5). Controls had mucosal candidiasis (n = 5), Candida colonization (n = 48), or no known Candida colonization (n = 20). RESULTS: PCR using plasma or sera was more sensitive than whole blood for diagnosing IC (P = .008). Plasma or sera PCR was more sensitive than BDG in diagnosing IC (80% vs 56%; P = .03), with comparable specificity (70% vs 73%; P = .31). The tests were similar in diagnosing candidemia (59% vs 68%; P = .77), but PCR was more sensitive for deep-seated candidiasis (89% vs 53%; P = .004). PCR and BDG were more sensitive than blood cultures among patients with deep-seated candidiasis (88% and 62% vs 17%; P = .0005 and .003, respectively). PCR and culture identified the same Candida species in 82% of patients. The sensitivity of blood cultures combined with PCR or BDG among patients with IC was 98% and 79%, respectively. CONCLUSIONS: Candida PCR and, to a lesser extent, BDG testing significantly enhanced the ability of blood cultures to diagnose IC.

Prospective, observational study of voriconazole therapeutic drug monitoring among lung transplant recipients receiving prophylaxis: factors impacting levels of and associations between serum troughs, efficacy, and toxicity.

Voriconazole prophylaxis is common following lung transplantation, but the value of therapeutic drug monitoring is unknown. A prospective, observational study of lung transplant recipients (n = 93) receiving voriconazole prophylaxis was performed. Serum voriconazole troughs (n = 331) were measured by high-pressure liquid chromatography. The median initial and subsequent troughs were 1.91 and 1.46 µg/ml, respectively. The age of the patient directly correlated with initial troughs (P = 0.005). Patients that were ≥ 60 years old and cystic fibrosis patients were significantly more likely to have higher and lower initial troughs, respectively. In 95% (88/93) of patients, ≥ 2 troughs were measured. In 28% (25/88) and 32% (28/88) of these patients, all troughs were ≤ 1.5 µg/ml or >1.5 µg/ml, respectively. Ten percent (10/93) and 27% (25/93) of the patients developed invasive fungal infection (tracheobronchitis) and fungal colonization, respectively. The median troughs at the times of positive and negative fungal cultures were 0.92 and 1.72 µg/ml (P = 0.07). Invasive fungal infections or colonization were more likely with troughs of ≤ 1.5 µg/ml (P = 0.01) and among patients with no trough of >1.5 µg/ml (P = 0.007). Other cutoff troughs correlated less strongly with microbiologic outcomes. Troughs correlated directly with aspartate transferase levels (P = 0.003), but not with other liver enzymes. Voriconazole was discontinued due to suspected toxicity in 27% (25/93) of the patients. The troughs did not differ at the times of suspected drug-induced hepatotoxicity, central nervous system (CNS) toxicity, or nausea/vomiting and in the absence of toxicity. Voriconazole prophylaxis was most effective at troughs of >1.5 µg/ml. A cutoff for toxicity was not identified, but troughs of >4 µg/ml were rare. The data support a target range of >1.5 to 4 µg/ml.

Cryptococcus infection in a non-HIV patient: a case report.

Cryptococcal infections are fungal infections most commonly seen in immunocompromised patients. Chronic high-dose steroid may precipitate such an immunocompromised state and thus create susceptibility to fungal infections. Cryptococcus neoformans is a saprophyte usually found in soil contaminated with pigeon droppings. Suspicion to diagnose begins with clinical symptoms that can be non-specific such as fevers, cough, and headaches. We present a case of steroid-induced cryptococcal infection in a non-HIV-infected person.

Sporadic urban leptospirosis.

Severe leptospirosis (Weil Syndrome) was diagnosed in an otherwise healthy environmental worker in Baltimore alleys in late November 2010. He developed multiple organ failure but responded to antibiotic therapy and experienced a full recovery within 4 weeks. His diagnosis was confirmed by a rise in indirect hemagglutinin titer (acute 0, convalescent 400). The subject had close contact with Baltimore alley rats; a similar epidemiologic exposure and location reported in an outbreak 15 years ago.

Fatal meningococcemia.

Within the past six years, a case of bothWaterhouse-Freidrichsen Syndrome and fulminant meningococcemia have presented to Union Memorial Hospital. Both cases presented in markedly different fashions, differed in microbiologic serogrouping, showed minimal histopathologic similarities; however achieved ultimately the same outcome through two different pathological pathways. The following case reports illustrate two mechanisms through which N. Meningitis may pathogenize a host, both leading to complete cardiovascular collapse in less than 12 hours.

Age-specific complications among lung transplant recipients 60 years and older.

BACKGROUND: An age limit of 65 years has been suggested for lung transplantation (LTx). METHODS: We conducted a retrospective study of LTx recipients at our institution and compared survival rates among patients aged <60, 60 to 65, and >65 years. We identified common complications and risk factors for death among patients aged ≥ 60 years. RESULTS: Between January 2006 and May 2008, 126 of 268 (47%) of LTx recipients were aged >60 years, among whom 36% were 60 to 65 and 64% were >65 years. There were no differences in survival among patients aged <60, 60 to 65, and >65 years. Among older patients, the major complications were infections (78%), rejection (36%), thromboembolism (21%), bone fractures (12%), malignancies (10%), and drug toxicity (10%). Rejection was more common among patients who were aged 60 to 65, and malignancies and drug toxicity were more common among patients >65 years. Other complications did not differ by age group. Infections accounted for 69% of deaths within 12 months, and infection-related deaths did not differ among the groups. Major infections were the strongest independent risk factors for death (hazard ratio, 4.37), followed by cytomegalovirus mismatch (hazard ratio, 3.69) and pre-transplant coronary artery disease (hazard ratio, 2.43). CONCLUSIONS: Survival rates among LTx recipients were similar regardless of age, but specific complications among older patients differed by age. Selection for LTx should not be based strictly on an age cutoff, but rather individualized according to general health status and other risk factors. Further research on risk factors affecting outcomes, pharmacokinetics and dynamics, quality of life, and mechanisms of untoward events is needed among older LTx recipients.

A polymorphism linked to elevated levels of interferon-γ is associated with an increased risk of cytomegalovirus disease among Caucasian lung transplant recipients at a single center.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) associated with active cytomegalovirus (CMV) infections after lung transplantation have not been identified. METHODS: SNPs associated with varying levels of interferon (IFN)-γ (+874T/A), tumor necrosis factor-α (-308G/A), interleukin-10 (-1082G/A, -819C/T, -592C/A) and interleukin-6 (-174G/C) were characterized for 170 Caucasian lung transplant recipients who received alemtuzumab induction and valganciclovir prophylaxis against CMV. RESULTS: Patients were followed for a median of 34 months post-transplant, and 66% (113 of 170), 24% (40 of 170) and 10% (17 of 170) had no CMV infection, CMV viremia and CMV disease, respectively. Median times to CMV viremia and disease were 7 and 10 months, respectively. For each gene, there was no significant deviation from Hardy-Weinberg equilibrium. Independent risk factors for the development of CMV disease were IFN-γ +874 T/T genotype (associated with high levels of IFN-γ production), CMV donor-positive/recipient-negative (D(+)/R(-)) serostatus and acute cellular rejection requiring augmented immunosuppression (p = 0.001, 0.003 and 0.049, respectively). The association between IFN-γ +874 T/T genotype and CMV disease was most striking among R(+) patients (p = 0.02). D(+)/R(-) serostatus was also a significant risk factor for CMV viremia (p = 0.0005). IFN-γ +874 T/T genotype was associated with significantly lower peak CMV viral loads (p = 0.03). There were no associations between tumor necrosis factor-α, interleukin-10 or interleukin-6 SNPs and CMV infections. CONCLUSION: A genetic predisposition to elevated IFN-γ levels may play a dual role in controlling active CMV infection among lung transplant recipients receiving alemtuzumab induction and valganciclovir prophylaxis, limiting the extent of viral replication in serum but increasing the risk of CMV disease.

Cytomegalovirus disease among donor-positive/recipient-negative lung transplant recipients in the era of valganciclovir prophylaxis.

BACKGROUND: Valganciclovir prophylaxis is advocated for lung transplant recipients, but its efficacy is unknown. METHODS: Retrospective review was done of 109 donor-positive/recipient-negative lung transplant patients who received alemtuzumab induction and valganciclovir for cytomegalovirus prophylaxis. RESULTS: Median duration of follow-up after transplant was 27 months. Valganciclovir dose reductions (< 900 mg/day or renal-equivalent) were required for 18 patients (17%) due to toxicity, most commonly for neutropenia (n = 15) or gastrointestinal symptoms (n = 2). Of the 109 patients, 34 (31%) had no CMV infections, 45 (41%) had asymptomatic viremia, and 30 (27%) had CMV disease. CMV disease developed off prophylaxis in 10 patients (18%) at a median of 8.7 months after transplant and 2 months after valganciclovir discontinuation. Breakthrough disease occurred during prophylaxis in 10 patients (9%) at a median of 6.7 months. Patients with asymptomatic viremia or no CMV infection received prophylaxis for median 8.6 and 8.7 months, respectively. Risk factors for CMV disease by univariate analysis were increased age (p = 0.01), single-lung transplant (p = 0.03), chronic obstructive pulmonary disease (p = 0.05), reduced-dose valganciclovir (p = 0.001), and less than 6 months of prophylaxis (p = 0.005). By multivariate analysis, advanced age (p = 0.01) and reduced-dose valganciclovir (p = 0.0006) were independent risk factors for CMV disease. CMV disease developed in 4 patients (4%) due to ganciclovir-resistant viruses. CMV-attributable mortality was 5% (5 of 109), including 100% (4 of 4) with ganciclovir-resistant disease. CONCLUSIONS: Valganciclovir prophylaxis among donor-positive/recipient-negative lung transplant recipients delayed but did not eliminate CMV disease or CMV-related deaths and was limited by toxicity and ganciclovir-resistance. Our experience suggests that valganciclovir at reduced-doses or for less than 6 months is sub-optimal in preventing CMV disease.

Voriconazole exposure and geographic location are independent risk factors for squamous cell carcinoma of the skin among lung transplant recipients.

BACKGROUND: Skin cancer, in particular squamous cell carcinoma (SCC), is the most common malignancy after solid-organ transplantation. SCC has been reported in immunosuppressed patients receiving voriconazole, but the agent has not been shown to be a risk factor. Universal voriconazole prophylaxis and alemtuzumab induction are standard in our lung transplant program. METHODS: We performed a retrospective, case-control study (matched 1:3) among lung transplant recipients at our center from 2003 to 2008. RESULTS: SCC was diagnosed in 3.1% (17 of 543) of patients at a median follow-up of 36 months. Median time to development of SCC was 19 months post-transplant. Risk factors for SCC by univariate analysis included older age (p = 0.02), residence in locations with high levels of sun exposure (p = 0.0001), single-lung transplant (p = 0.02) and duration (p = 0.03) and cumulative dose (p = 0.03) of voriconazole. Duration of voriconazole (hazard ratio [HR] = 2.1; p = 0.04) and residence in locations with high sun exposure (HR = 3.8; p = 0.0004) were independent risk factors by multivariate analysis. SCC lesions were located on the head and neck in 94% of cases, and 53% had multiple lesions. All patients were treated with surgery. At least one independent lesion developed subsequently in 47% of patients. Local spread and distant metastases each occurred in 7% of cases. There were no deaths among the cases. CONCLUSIONS: Voriconazole exposure is a risk factor for SCC after lung transplantation, particularly among older patients living in areas with high sun exposure. Voriconazole should be used cautiously in these patients.

Impact of mold infections in explanted lungs on outcomes of lung transplantation.

INTRODUCTION: Little is known about the incidence or significance of mold infections in the explanted lungs of lung transplant recipients. METHOD: We reviewed the histopathology of the explanted lungs from 304 patients who underwent lung transplantation at our institution from 2005 to 2007 and received alemtuzumab induction therapy and posttransplant voriconazole prophylaxis. RESULTS: Invasive mold infections were present in the explanted lungs of 5% (14 of 304) of patients, including chronic necrotizing pneumonias (n=7), mycetomas (n=4), and invasive fungal pneumonias (n=3). Only 21% (3 of 14) received immunosuppressive therapy within 1 year before lung transplantation, suggesting that lung damage itself predisposed patients to mold infections. The risk of mold infection was higher in patients with cystic fibrosis (11%, 4 of 35) than other underlying lung diseases (4%, 10 of 269). Pulmonary mold infections were not diagnosed or suspected in 57% (8 of 14) of patients. Despite secondary voriconazole prophylaxis, fungal infections developed in 43% (6 of 14) of patients with mold infections of the explanted lungs compared with 14% (42 of 290) of patients without mold infections (P=0.01). Three patients developed invasive fungal infections while on voriconazole prophylaxis and three developed fungal infections more than 8 months after the discontinuation of voriconazole. The mortality attributable to invasive fungal infections among patients with mold infections of the explanted lungs was 29% (4 of 14). CONCLUSION: Invasive mold infections in the explanted lungs are often not recognized before lung transplantation and are associated with poor outcomes.

Use of smear-positive samples to assess the PCR-based genotype MTBDR assay for rapid, direct detection of the Mycobacterium tuberculosis complex as well as its resistance to isoniazid and rifampin.

Isoniazid (INH) and rifampin (RIF) are two of the most important antituberculosis drugs, and resistance to both of these drugs can often result in treatment failure and fatal clinical outcome. Resistance to these two first-line drugs is most often attributed to mutations in the katG, inhA, and rpoB genes. Historically, the identification and testing of the susceptibility of Mycobacterium tuberculosis complex (MTBC) strains takes weeks to complete. Rapid detection of resistance using the PCR-based Genotype MTBDR assay (Hain Lifescience GmbH, Nehren, Germany) has the potential to significantly shorten the turnaround time from specimen receipt to reporting of results of susceptibility testing. Therefore, the aim of the present study was to determine (i) the sensitivity and accuracy of the Genotype MTBDR assay for the detection of MTBC strains and (ii) the ability of the assay to detect the presence of INH and RIF resistance-associated mutations in katG and rpoB from samples taken directly from smear-positive clinical specimens. The results were compared with those obtained with the reference BACTEC 460TB system combined with standard DNA sequencing analysis methods for katG, inhA, and rpoB. A total of 92 drug-resistant and 51 pansusceptible smear-positive specimens were included in the study. The Genotype MTBDR assay accurately and rapidly detected MTBC strains in 94.4% of the 143 specimens and showed a sensitivity of 94.4% for katG and 90.9% for rpoB when used directly on smear-positive specimens. The assay correctly identified INH resistance in 48 (84.2%) of the 57 specimens containing strains with resistance to high levels of INH (0.4 microg/ml) and RIF resistance in 25 (96.2%) of the 26 specimens containing RIF-resistant strains.