Fluoroquinolone-Related Neuropsychiatric Events in Hospitalized Veterans.

OBJECTIVE: To measure the incidence and risk factors for fluoroquinolone (ciprofloxacin, moxifloxacin, and levofloxacin)-associated psychosis or delirium in a veteran population. METHODS: A retrospective study was conducted in the Western New York Veterans Affairs Health System (2005-2013). Participants were hospitalized veterans receiving a fluoroquinolone for at least 48 hours (n = 631). Cases of delirium or psychosis were defined by the Diagnostic and Statistical Manual of Mental Disorders-IV criteria, and the Naranjo scale (score ≥ 1) was used to determine the probability of the adverse drug reaction being related to fluoroquinolones. A bivariate analysis of covariates followed by a multivariate logistic regression was used to determine predisposing factors to the development of delirium/psychosis. RESULTS: The mean age of the population was 71.5 years (range: 22-95). Fluoroquinolone-associated delirium/psychosis occurred in 3.7% of the inpatients studied (n = 23). The median Naranjo score was 3 indicating a possible association. Psychosis/delirium occurred in 3.6% of ciprofloxacin-treated patients (n = 14/391), 4.5% of patients-treated with moxifloxacin (n = 9/200), and 0% of those receiving levofloxacin (n = 0/40); p = 0.4. Significant risk factors for development of delirium/psychosis in patients receiving a fluoroquinolone in the multivariate logistical regression included typical antipsychotic use (OR, 5.4; 95% CI: 1.4-16.7) and age. A 10-year increase in age was associated with a 1.8-fold greater odds of a neuropsychiatric event. CONCLUSIONS: Fluoroquinolones may be more commonly associated with delirium/psychosis than originally reported in this veteran population. Caution should be used when prescribing a fluoroquinolone for patients on typical antipsychotics and those of advanced age.

Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors.

In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr-Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr-Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr-Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr-Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.

Corticosteroid use is associated with a reduced incidence of Clostridium difficile-associated diarrhea: a retrospective cohort study.

The impact of corticosteroid use on the incidence of Clostridium difficile-associated diarrhea (CDAD) was examined retrospectively in 532 patients receiving antibiotic treatment for respiratory infections. As determined by logistic regression, corticosteroids were associated with a decreased incidence of CDAD (Odds Ratio 0.12, 95% Confidence Interval 0.006-0.95).

Discovery and structural analysis of Eph receptor tyrosine kinase inhibitors.

The Eph family of receptor tyrosine kinases has drawn growing attention due to their role in regulating diverse biological phenomena. However, pharmacological interrogation of Eph kinase function has been hampered by a lack of potent and selective Eph kinase inhibitors. Here we report the discovery of compounds 6 and 9 using a rationally designed kinase-directed library which potently inhibit Eph receptor tyrosine kinases, particularly EphB2 with cellular EC(50)s of 40nM. Crystallographic data of EphA3 and EphA7 in complex with the inhibitors show that they bind to the 'DFG-out' inactive kinase conformation and provide valuable information for structure-based design of second generation inhibitors.

Pulmonary infection with Mycobacterium szulgai: A case report.

Mycobacterium szulgai is a non-tuberculous mycobacterium that is an uncommon cause of infection in humans. Risk factors for infection include immunosuppression and pre-existing lung pathology. Herein, we present a case of a 42-year-old male with chronic obstructive pulmonary disease with pulmonary infection caused by M. szulgai that was successfully treated with a regimen of rifampin, isoniazid, pyrazinamide and ethambutol for 2 months, followed by rifampin, isoniazid and azithromycin for an additional 8 months. Symptomatic and radiographic resolutions were achieved.

Cutaneous alternariosis in a renal transplant patient successfully treated with posaconazole: Case report and literature review.

Cutaneous alternariosis is an uncommon fungal infection that most commonly presents in organ transplant patients on immunosuppressive therapy. There are no clinical trials or guidelines to guide treatment of this condition, however itraconazole is the most commonly used antifungal in published cases. Here we report on a case of cutaneous alternariosis in a renal transplant recipient treated with a newer antifungal, posaconazole. A review of published reports of cutaneous alternariosis since 2008 is also discussed.

Mesenteric venous thrombosis precipitated by foodborne gastrointestinal illness.

Foodborne illnesses are common and are usually considered as part of the differential diagnosis when a patient presents with gastrointestinal symptoms including nausea, vomiting, abdominal pain, diarrhea and fever. The majority of foodborne illness is transient and self-limited, while life threatening complications are rare. Here, we describe a case of a patient presenting with inflammatory diarrhea after consumption of undercooked seafood. She developed mesenteric and portal venous thrombosis and small bowel infarction requiring surgical intervention and resection of gangrenous small bowel. This is a rare presentation and outcome of common food poisoning. The case report is followed by a brief discussion of common foodborne illnesses and mesenteric venous thrombosis.

Efficacy of Prompt Initiation of Antiretroviral Therapy in the Treatment of Hemophagocytic Lymphohistiocytosis Triggered by Uncontrolled Human Immunodeficiency Virus.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, rapidly progressive hematologic disorder involving uncontrolled immune system activation. HLH has been associated with viral infections, including human immunodeficiency virus (HIV) infections. We report a case of a critically ill 30-year-old female who was hospitalized with HIV-associated HLH, with a CD4 count of 4 cells/mL and HIV viral load of 1,842,730 copies/mL. After ruling out other potential infectious causes of HLH, antiretroviral therapy (ART) was initiated with darunavir, ritonavir, tenofovir, and emtricitabine. Within one week of initiation of ART, the patient began to improve clinically and hematologically and was stable enough for discharge from the hospital three weeks after starting therapy. This case suggests that treatment with ART in patients with HIV-associated HLH should be considered even in critically ill patients with low CD4 counts.

Urinary tract infection with Pasteurella multocida in a patient with cat exposure and abnormal urinary tract physiology: Case report and literature review.

Pasteurella multocida is a gram-negative organism that commonly colonizes the mouth of cats and dogs, and is known to cause infection in humans associated with animal bites or scratches. Sites of infection other than skin and soft tissue are rare, but have been reported in patients with specific risk factors including anatomical abnormalities or immunosuppression. Herein, we report a case of a symptomatic urinary tract infection caused by P. multocida in a 59 year old female who presented to the hospital with complaints of systemic symptoms including malaise, rigors, and chills, as well as thick, malodorous urine. The patient self-catheterized multiple times daily due to urostomy with Kock pouch. Treatment with piperacillin/tazobactam followed by amoxicillin resulted in resolution of the infection.

GNF-2 Inhibits Dengue Virus by Targeting Abl Kinases and the Viral E Protein.

Dengue virus infects more than 300 million people annually, yet there is no widely protective vaccine or drugs against the virus. Efforts to develop antivirals against classical targets such as the viral protease and polymerase have not yielded drugs that have advanced to the clinic. Here, we show that the allosteric Abl kinase inhibitor GNF-2 interferes with dengue virus replication via activity mediated by cellular Abl kinases but additionally blocks viral entry via an Abl-independent mechanism. To characterize this newly discovered antiviral activity, we developed disubstituted pyrimidines that block dengue virus entry with structure-activity relationships distinct from those driving kinase inhibition. We demonstrate that biotin- and fluorophore-conjugated derivatives of GNF-2 interact with the dengue glycoprotein, E, in the pre-fusion conformation that exists on the virion surface, and that this interaction inhibits viral entry. This study establishes GNF-2 as an antiviral compound with polypharmacological activity and provides "lead" compounds for further optimization efforts.

Outcomes and Pharmacoeconomic Analysis of a Home Intravenous Antibiotic Infusion Program in Veterans.

PURPOSE: The use of outpatient parenteral antibiotic therapy (OPAT) programs has become more frequent because of benefits in costs with equivalent clinical outcomes compared with inpatient care. The purpose of this study was to evaluate the outcomes of our program. A modified pharmacoeconomic analysis was performed to compare costs of our program with hospital or rehabilitation facility care. METHODS: This was a retrospective chart review of 96 courses of OPAT between April 1, 2011, and July 31, 2013. Clinical failures were defined as readmission or death due to worsening infection or readmission secondary to adverse drug event (ADE) to antibiotic therapy. This does not include those patients readmitted for reasons not associated with OPAT therapy, including comorbidities or elective procedures. Baseline characteristics and program-specific data were analyzed. Statistically significant variables were built into a multivariate logistic regression model to determine predictors of failure. A pharmacoeconomic analysis was performed with the use of billing records. FINDINGS: Of the total episodes evaluated, 17 (17.71%) clinically failed therapy, and 79 (82.29%) were considered a success. In the multivariate analysis, number of laboratory draws (P = 0.02) and occurrence of drug reaction were significant in the final model, P = 0.02 and P = 0.001, respectively. The presence an adverse drug reaction increases the odds of failure (OR = 10.10; 95% CI, 2.69-44.90). Compared with inpatient or rehabilitation care, the cost savings was $6,932,552.03 or $2,649,870.68, respectively. IMPLICATIONS: In our study, patients tolerated OPAT well, with a low number of failures due to ADE. The clinical outcomes and cost savings of our program indicate that OPAT can be a viable alternative to long-term inpatient antimicrobial therapy.

Effectiveness and safety of nitrofurantoin in outpatient male veterans.

OBJECTIVES: The aim of the study was to assess both the safety and the effectiveness of nitrofurantoin in male veterans treated for urinary tract infections (UTIs) with varying degrees of renal impairment in the outpatient setting. Nitrofurantoin is an important oral option for treating UTIs given increasing resistance to commonly used agents. Nitrofurantoin is currently contraindicated in patients with a creatinine clearance (CrCl) of < 60 ml/min, but the reason for this threshold has not been well documented. METHODS: Data were collected through a retrospective chart review from January 2004 to July 2013 of men who had received nitrofurantoin. Bivariate analyses followed by multivariate analyses were performed between patients experiencing clinical cure and those who did not, to determine factors significantly impacting effectiveness. RESULTS: The Gram stain of the organism causing the UTI and CrCl were significant factors impacting effectiveness. For every 1 ml/min increase in CrCl, the odds of clinical cure increased by 1.3%. Patients with Gram-negative UTIs predictably had 80% cure rates with CrCl around 60 ml/min. Patients with Gram-positive UTIs required higher CrCl, nearing 100 ml/min, to establish an 80% cure rate. Adverse effects did not vary with CrCl. CONCLUSIONS: The odds of clinical cure varied with CrCl and with the type of organism causing the UTI, while adverse events did not differ based on renal function. A minimum CrCl of 60 ml/min is suggested for men to achieve an 80% cure rate for UTIs with the most common urinary pathogens.

A review of the economics of treating Clostridium difficile infection.

Clostridium difficile infection (CDI) is a costly result of antibiotic use, responsible for an estimated 14,000 deaths annually in the USA according to the Centers for Disease Control and Prevention. Annual costs attributable to CDI are in excess of $US 1 billion. This review summarizes appropriate utilization of prevention and treatment methods for CDI that have the potential to reduce the economic and humanistic costs of the disease. Some cost-effective strategies to prevent CDI include screening and isolation of hospital admissions based on C. difficile carriage to reduce transmission in the inpatient setting, and probiotics, which are potentially efficacious in preventing CDI in the appropriate patient population. The most extensively studied agents for treatment of CDI are metronidazole, vancomycin, and fidaxomicin. Most economic comparisons between metronidazole and vancomycin favor vancomycin, especially with the emergence of metronidazole-resistant C. difficile strains. Metronidazole can only be recommended for mild disease. Moderate to severe CDI should be treated with vancomycin, preferably the compounded oral solution, which provides the most cost-effective therapeutic option. Fidaxomicin offers a clinically effective and potentially cost-effective alternative for treating moderate CDI in patients who do not have the NAP1/BI/027 strain of C. difficile. Probiotics and fecal microbiota transplant have variable efficacy and the US FDA does not currently regulate the content; the potential economic advantages of these treatment modalities are currently unknown.

Expanding the diversity of allosteric bcr-abl inhibitors.

Inhibition of Bcr-Abl kinase activity by imatinib for the treatment of chronic myeloid leukemia (CML) currently serves as the paradigm for targeting dominant oncogenes with small molecules. We recently reported the discovery of GNF-2 (1) and GNF-5 (2) as selective non-ATP competitive inhibitors of cellular Bcr-Abl kinase activity that target the myristate binding site. Here, we used cell-based structure-activity relationships to guide the optimization and diversification of ligands that are capable of binding to the myristate binding site and rationalize the findings based upon an Abl-compound 1 cocrystal. We elucidate the structure-activity relationships required to obtain potent antiproliferative activity against Bcr-Abl transformed cells and report the discovery of new compounds (5g, 5h, 6a, 14d, and 21j-I) that display improved potency or pharmacological properties. This work demonstrates that a variety of structures can effectively target the Bcr-Abl myristate binding site and provides new leads for developing drugs that can target this binding site.