Carla J. Walraven

Antifungal Lock Therapy

ABSTRACT The widespread use of intravascular devices, such as central venous and hemodialysis catheters, in the past 2 decades has paralleled the increasing incidence of catheter-related bloodstream infections (CR-BSIs). Candida albicans is the fourth leading cause of hospital-associated BSIs. The propensity of C. albicans to form biofilms on these catheters has made these infections difficult to treat due to multiple factors, including increased resistance to antifungal agents. Thus, curing CR-BSIs caused by Candida species usually requires catheter removal in addition to systemic antifungal therapy. Alternatively, antimicrobial lock therapy has received significant interest and shown promise as a strategy to treat CR-BSIs due to Candida species. The existing in vitro, animal, and patient data for treatment of Candida-related CR-BSIs are reviewed. The most promising antifungal lock therapy (AfLT) strategies include use of amphotericin, ethanol, or echinocandins. Clinical trials are needed to further define the safety and efficacy of AfLT.

Site of infection rather than vancomycin MIC predicts vancomycin treatment failure in methicillin-resistant Staphylococcus aureus bacteraemia

BACKGROUND Therapeutic use of vancomycin is characterized by decreased susceptibilities and increasing reports of clinical failures. Few studies have examined the clinical outcomes of patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia treated with vancomycin. The primary objective was to compare clinical outcomes of patients with MRSA bacteraemia treated according to standard of care practices. METHODS Patients were included if: (i) admitted to University of New Mexico Hospital between 2002 and 2009; (ii) ≥18 years of age; (iii) had one blood culture positive for MRSA; and (iv) received vancomycin. Clinical outcomes were defined as cure, failure (relapse of infection 30 days after completion of therapy, death or change in therapy) or unevaluable. Patient demographics, source of bacteraemia, treatment regimen, and microbiological characteristics were determined. RESULTS Two hundred patients with MRSA bacteraemia were included. Sixty-one patients were unevaluable, leaving 139 patients for the final analysis. Seventy-two (51.8%) patients were cured and 67 (48.2%) experienced vancomycin failure. Vancomycin MIC(90) was 2 mg/L for both groups by Etest. Patients with endocarditis (P = 0.02) or pneumonia (P = 0.02) were more likely to fail therapy. Panton-Valentine leucocidin, loss of agr functionality and strain type were not predictors of outcomes in this study. CONCLUSIONS High failure rates were observed in patients with MRSA bacteraemia treated with vancomycin, despite high vancomycin troughs and low rates of nephrotoxicity. Predictors of vancomycin failure included endocarditis and pneumonia. In these situations, vancomycin provides suboptimal therapy.

Fatal Disseminated Cryptococcus gattii Infection in New Mexico

We report a case of fatal disseminated infection with Cryptococcus gattii in a patient from New Mexico. The patient had no history of recent travel to known C. gattii-endemic areas. Multilocus sequence typing revealed that the isolate belonged to the major molecular type VGIII. Virulence studies in a mouse pulmonary model of infection demonstrated that the strain was less virulent than other C. gattii strains. This represents the first documented case of C. gattii likely acquired in New Mexico.

In vitro analyses of ethanol activity against Candida albicans biofilms.

ABSTRACT Candida albicans is a common cause of catheter-related bloodstream infections (CR-BSI). Ethanol (EtOH) lock therapy has been attempted despite limited data on optimal dose and duration. Concentrations of 35% EtOH or higher for a minimum of 4 h demonstrated a >99% reduction in mature C. albicans biofilm metabolic activity and prevented regrowth. Concentrations of 10% EtOH or higher reduced C. albicans biofilm formation by >99%. Further investigation of EtOH lock therapy for treatment and prevention of C. albicans CR-BSI is warranted.

In vitro analyses of the effects of heparin and parabens on Candida albicans biofilms and planktonic cells

ABSTRACT Infections and thromboses are the most common complications associated with central venous catheters. Suggested strategies for prevention and management of these complications include the use of heparin-coated catheters, heparin locks, and antimicrobial lock therapy. However, the effects of heparin on Candida albicans biofilms and planktonic cells have not been previously studied. Therefore, we sought to determine the in vitro effect of a heparin sodium preparation (HP) on biofilms and planktonic cells of C. albicans. Because HP contains two preservatives, methyl paraben (MP) and propyl paraben (PP), these compounds and heparin sodium without preservatives (Pure-H) were also tested individually. The metabolic activity of the mature biofilm after treatment was assessed using XTT [2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide] reduction and microscopy. Pure-H, MP, and PP caused up to 75, 85, and 60% reductions of metabolic activity of the mature preformed C. albicans biofilms, respectively. Maximal efficacy against the mature biofilm was observed with HP (up to 90%) compared to the individual compounds (P < 0.0001). Pure-H, MP, and PP each inhibited C. albicans biofilm formation up to 90%. A complete inhibition of biofilm formation was observed with HP at 5,000 U/ml and higher. When tested against planktonic cells, each compound inhibited growth in a dose-dependent manner. These data indicated that HP, MP, PP, and Pure-H have in vitro antifungal activity against C. albicans mature biofilms, formation of biofilms, and planktonic cells. Investigation of high-dose heparin-based strategies (e.g., heparin locks) in combination with traditional antifungal agents for the treatment and/or prevention of C. albicans biofilms is warranted.

In Vitro Analysis of Finasteride Activity against Candida albicans Urinary Biofilm Formation and Filamentation

ABSTRACT Candida albicans is the 3rd most common cause of catheter-associated urinary tract infections, with a strong propensity to form drug-resistant catheter-related biofilms. Due to the limited efficacy of available antifungals against biofilms, drug repurposing has been investigated in order to identify novel agents with activities against fungal biofilms. Finasteride is a 5-α-reductase inhibitor commonly used for the treatment of benign prostatic hyperplasia, with activity against human type II and III isoenzymes. We analyzed the Candida Genome Database and identified a C. albicans homolog of type III 5-α-reductase, Dfg10p, which shares 27% sequence identity and 41% similarity to the human type III 5-α-reductase. Thus, we investigated finasteride for activity against C. albicans urinary biofilms, alone and in combination with amphotericin B or fluconazole. Finasteride alone was highly effective in the prevention of C. albicans biofilm formation at doses of ≥16 mg/liter and the treatment of preformed biofilms at doses of ≥128 mg/liter. In biofilm checkerboard analyses, finasteride exhibited synergistic activity in the prevention of biofilm formation in a combination of 4 mg/liter finasteride with 2 mg/liter fluconazole. Finasteride inhibited filamentation, thus suggesting a potential mechanism of action. These results indicate that finasteride alone is highly active in the prevention of C. albicans urinary biofilms in vitro and has synergistic activity in combination with fluconazole. Further investigation of the clinical utility of finasteride in the prevention of urinary candidiasis is warranted.

An Optimized Lock Solution Containing Micafungin, Ethanol and Doxycycline Inhibits Candida albicans and Mixed C. albicans - Staphyloccoccus aureus Biofilms.

Candida albicans is a major cause of catheter-related bloodstream infections and is associated with high morbidity and mortality. Due to the propensity of C. albicans to form drug-resistant biofilms, the current standard of care includes catheter removal; however, reinsertion may be technically challenging or risky. Prolonged exposure of an antifungal lock solution within the catheter in conjunction with systemic therapy has been experimentally attempted for catheter salvage. Previously, we demonstrated excellent in vitro activity of micafungin, ethanol, and high-dose doxycycline as single agents for prevention and treatment of C. albicans biofilms. Thus, we sought to investigate optimal combinations of micafungin, ethanol, and/or doxycycline as a lock solution. We performed two- and three-drug checkerboard assays to determine the in vitro activity of pairwise or three agents in combination for prevention or treatment of C. albicans biofilms. Optimal lock solutions were tested for activity against C. albicans clinical isolates, reference strains and polymicrobial C. albicans-S. aureus biofilms. A solution containing 20% (v/v) ethanol, 0.01565 μg/mL micafungin, and 800 μg/mL doxycycline demonstrated a reduction of 98% metabolic activity and no fungal regrowth when used to prevent fungal biofilm formation; however there was no advantage over 20% ethanol alone. This solution was also successful in inhibiting the regrowth of C. albicans from mature polymicrobial biofilms, although it was not fully bactericidal. Solutions containing 5% ethanol with low concentrations of micafungin and doxycycline demonstrated synergistic activity when used to prevent monomicrobial C. albicans biofilm formation. A combined solution of micafungin, ethanol and doxycycline is highly effective for the prevention of C. albicans biofilm formation but did not demonstrate an advantage over 20% ethanol alone in these studies.

Candida auris: Disinfectants and Implications for Infection Control

Candida auris is a rapidly emerging pathogen and is able to cause severe infections with high mortality rates. It is frequently misidentified in most clinical laboratories, thus requiring more specialized identification techniques. Furthermore, several clinical isolates have been found to be multidrug resistant and there is evidence of nosocomial transmission in outbreak fashion. Appropriate infection control measures will play a major role in controlling the management and spread of this pathogen. Unfortunately, there are very few data available on the effectiveness of disinfectants against C. auris. Chlorine-based products appear to be the most effective for environmental surface disinfection. Other disinfectants, although less effective than chlorine-based products, may have a role as adjunctive disinfectants. A cleaning protocol will also need to be established as the use of disinfectants alone may not be sufficient for maximal decontamination of patient care areas. Furthermore, there are fewer data on the effectiveness of antiseptics against C. auris for patient decolonization and hand hygiene for healthcare personnel. Chlorhexidine gluconate has shown some efficacy in in vitro studies but there are reports of patients with persistent colonization despite twice daily body washes with this disinfectant. Hand hygiene using soap and water, with or without chlorhexidine gluconate, may require the subsequent use of alcohol-based hand sanitizer for maximal disinfection. Further studies will be needed to validate the currently studied disinfectants for use in real-world settings.

Antimicrobial Stewardship Intervention and Feedback to Infectious Disease Specialists: A Case Study in High-Dose Daptomycin

Infectious Diseases specialists have used high-dose daptomycin (≥6 mg/kg/day) in select patients with difficult to treat methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus (VRE) infections to optimize outcomes. Antimicrobial stewardship programs enforce antimicrobial formulary restrictions; however, interventions specifically aimed at Infectious Disease specialists can be particularly challenging. The purpose of this study was to create a high-dose daptomycin algorithm for Infectious Disease specialists that are consistent with best-practices. Daptomycin prescribing habits pre- and post-daptomycin algorithm implementation were evaluated using a quasi-experimental study design. Patients were included if ≥18 years of age and received daptomycin for ≥48 h. Patients were excluded if daptomycin was initiated on an outpatient setting. During the 12-month pre-intervention phase, 112 patients were included, with 73 patients in the 12-month post-intervention phase. A statistically significant decrease in the mean daptomycin dose from 9.01 mg/kg to 7.51 mg/kg (p < 0.005) was observed, resulting in an annual drug cost-savings of over

The Impact of Cryptococcus gattii with a Focus on the Outbreak in North America

75,000 without adversely affecting readmission rates due to infection. Creation of a daptomycin algorithm with consideration of pathogen, disease state, and prior treatment, is an effective means of influencing prescribing habits of Infectious Disease specialists.