David C. M. Kong

Antifungal Prophylaxis in Lung Transplantation— A World-wide Survey

While variations in antifungal prophylaxis have been previously reported in lung transplant (LTx) recipients, recent clinical practice is unknown. Our aim was to determine current antifungal prophylactic practice in LTx centers world‐wide. One nominated LTx clinician from each active center was invited by e‐mail to participate in a web‐based survey between September 2009 and January 2010. Fifty‐seven percent (58/102) responded. The majority of responses were from medical directors of LTx centers (72.4%), and from the United States (44.8%). Within the first 6 months post‐LTx, most centers (58.6%) employed universal prophylaxis, with 97.1% targeting Aspergillus species. Voriconazole alone, and in combination with inhaled amphotericin B (AmB), were the preferred first‐line agents. Intolerance to side effects of voriconazole (69.2%) was the main reason for switching to alternatives. Beyond 6 months post‐LTx, most (51.8%) did not employ antifungal prophylaxis. Fifteen centers (26.0%) conducted routine antifungal therapeutic drug monitoring during prophylactic period. There are differences in strategies employed between U.S. and European centers. Most respondents indicated a need for antifungal prophylactic guidelines. In comparison to earlier findings, there was a major shift toward prophylaxis with voriconazole and an increased use of echinocandins, posaconazole and inhaled lipid formulation AmB.

Randomized trial of an adherence programme for clients with HIV

Our aim was to determine if a comprehensive adherence package improved self reported adherence to antiretroviral therapy. The adherence package included an education programme, individualized planning of regimens, and the opportunity for a patient to choose from a number of adherence aids and reminder devices. A randomized step wedge design was used. Forty-three individuals were randomized to begin the intervention over a five-month period. There was a substantial fall in the number of missed doses reported for the last four days (0.76 to 0.38, P =0.03) and last seven days (1.5 to 0.74, P =0.005) but not for the last 28 days (2.5 to 2.5, P =0.63). There was no statistical difference in the viral load or CD4 lymphocyte count in the period before or after the intervention. The Morisky score during the pre and post intervention periods was significantly different (P =0.006), 2.9 (SD 0.9) and 3.3 (SD 0.8) respectively. This adherence package improved self reported adherence during the last four and seven days.

Prevalence of multidrug-resistant organisms and risk factors for carriage in long-term care facilities: a nested case–control study

BACKGROUND Long-term care facilities (LTCFs) are a potentially important reservoir of multidrug-resistant (MDR) organisms; however, limited data exist. METHODS A point-prevalence study was conducted in four co-located LTCFs in Australia. Nasal and rectal swabs were cultured for methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and MDR Gram-negative bacilli (GNB). Molecular typing and resistance detection were performed. Risk factors for colonization with an MDR organism were determined using a nested case-control study. RESULTS Consent was obtained from 115 (85%) of 136 eligible participants. Forty-one (36%) residents carried at least one type of MDR organism. The prevalence was 16% MRSA (n = 18), 6% VRE (n = 7) and 21% MDR GNB [n = 24; including extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (n = 12) and Acinetobacter baumannii (n = 6)]. The majority of ESBL-producing E. coli and A. baumannii were clonal. Current wound management [adjusted OR (AOR) 8.81 (95% CI 2.78-27.94), P < 0.001], medical device in situ [AOR 5.58 (95% CI 1.34-23.32), P = 0.018] and pressure ulcer [AOR 3.69 (95% CI 1.06-12.86), P = 0.04] were independent risk factors for MDR organism colonization. Advanced dementia [AOR 3.54 (95% CI 1.23-10.23), P = 0.02] and prolonged antibiotic use [AOR 2.95 (95% CI 1.01-8.60), P = 0.047] were independently associated with MRSA colonization, whilst current wound management [AOR 15.59 (95% CI 4.85-50.10), P < 0.001] and fluoroquinolone use [AOR 4.27 (95% CI 1.20-15.25), P = 0.025] were risk factors for MDR GNB colonization. CONCLUSIONS LTCFs are an important reservoir of MDR organisms, with person-to-person transmissions being a potential issue. We have identified several predictors of colonization with MDR organisms, allowing a more targeted management of high-risk residents.

Utility of bronchoalveolar lavage fluid galactomannan alone or in combination with PCR for the diagnosis of invasive aspergillosis in adult hematology patients: A systematic review and meta-analysis

Abstract Background: The clinical utility of bronchoalveolar lavage (BAL) fluid galactomannan (GM) for the early diagnosis of invasive aspergillosis (IA) varies widely across studies mainly due to heterogeneity of the studied populations. Methods: We conducted a systematic review and meta-analysis of 16 studies involving 783 adults with hematological malignancies to derive summary estimates of the overall accuracy of BAL-GM for diagnosing IA. Findings: Summary estimates of BAL-GM using an optical density (OD) index cutoff value of 1.5 for proven and probable IA were: sensitivity 0.92 (95% CI = 0.48–0.99), specificity 0.98 (95% CI = 0.78–1.00), positive likelihood ratio 53.7 (95% CI = 3.7–771.8), and negative likelihood ratio 0.08 (95% CI = 0.01–0.83). Comparing serum GM and Aspergillus PCR testing on BAL fluid, BAL-GM conferred greater sensitivity, but lower specificity than the serum GM test, and similar specificity as the PCR assay. The use of BAL-GM with serum GM or BAL-PCR tests increased the sensitivity moderately when a positive result was defined by either assay. Interpretation: GM quantification in BAL fluid at an OD index cutoff value of 1.5 has excellent sensitivity and specificity to assist clinical decision-making in confirming or excluding a diagnosis of IA when results are interpreted with clinical findings. Additional research investigating the effects of antifungal agents, optimal timing and processing of BAL sampling are needed to improve the diagnostic accuracy of BAL-GM testing.

Clinical utility of voriconazole eye drops in ophthalmic fungal keratitis

Fungal keratitis is one of the major causes of ophthalmic mycosis and is difficult to treat. The range of common antifungal agents available for fungal keratitis remains inadequate and is generally associated with poor clinical outcomes. Voriconazole is a new generation triazole antifungal agent. Only marketed in systemic formulation and, with broad-spectrum activity and high intraocular penetration, voriconazole has demonstrated effectiveness against fungal keratitis. Systemic voriconazole, however, is not without side effects and is costly. Voriconazole eye drops have been prepared extemporaneously and used for the treatment of ophthalmic fungal keratitis. The current article sought to review the literature for evidence related to the effectiveness and safety of topical voriconazole and its corneal penetration into the aqueous humor of the eye. The voriconazole eye drops used are typically of 1% concentration, well tolerated by the eye, and are stable. Despite existing evidence to suggest that the eye drops are effective in the treatment of fungal keratitis, more studies are needed, especially in relation to using the eye drops as first-line and stand-alone treatment, preparation of higher concentrations, and optimal dosing frequency.

Enterococcal bacteraemia: Factors influencing mortality, length of stay and costs of hospitalization

Enterococci are a major cause of nosocomial bacteraemia. The impacts of vanB vancomycin resistance and antibiotic therapy on outcomes in enterococcal bacteraemia are unclear. Factors that affect length of stay (LOS) and costs of managing patients with enterococcal bacteraemia are also unknown. This study aimed to identify factors associated with mortality, LOS and hospitalization costs in patients with enterococcal bacteraemia and the impact of vancomycin resistance and antibiotic therapy on these outcomes. Data from 116 patients with vancomycin-resistant Enterococci (VRE), matched 1:1 with patients with vancomycin-susceptible Enterococcus (VSE), from two Australian hospitals were reviewed for clinical and economic outcomes. Univariable and multivariable logistic and quantile regression analyses identified factors associated with mortality, LOS and costs. Intensive care unit admission (OR, 8.57; 95% CI, 3.99-18.38), a higher burden of co-morbidities (OR, 4.55; 95% CI, 1.83-11.33) and longer time to appropriate antibiotics (OR, 1.02; 95% CI, 1.01-1.03) were significantly associated with mortality in enterococcal bacteraemia. VanB vancomycin resistance increased LOS (4.89 days; 95% CI, 0.56-11.52) and hospitalization costs (AU

Penetration of Voriconazole, 1%, Eyedrops Into Human Aqueous Humor : A Prospective Open-Label Study

28 872; 95% CI, 734-70 667), after adjustment for confounders. Notably, linezolid definitive therapy was associated with lower mortality (OR, 0.13; 95% CI, 0.03-0.58) in vanB VRE bacteraemia patients. In patients with VSE bacteraemia, time to appropriate antibiotics independently influenced mortality, LOS and hospitalization costs, and underlying co-morbidities were associated with mortality. The study findings highlight the importance of preventing VRE bacteraemia and the significance of time to appropriate antibiotics in the management of enterococcal bacteraemia.

Differential Bidirectional Transfer of Indinavir in the Isolated Perfused Human Placenta

OBJECTIVE To determine the therapeutic efficacy of adjuvant use of voriconazole, 1%, eyedrops in the treatment of refractory fungal keratitis. METHODS A prospective open-label trial was conducted to determine voriconazole levels obtained in human aqueous humor after administration of a 1% solution, preserved with 0.01% benzalkonium chloride, every 6 hours for 3 days, or hourly for 4 doses. Ten participants were selected among patients scheduled to undergo elective anterior segment surgery, and samples were tested using validated high-performance liquid chromatography. RESULTS The mean (SD) voriconazole concentrations after hourly dosing (n = 5) was 1.90 (1.12) microg/mL and after a single dosing every 6 hours (n = 5) was 0.94 (1.21) microg/mL, respectively. The mean (SD) sampling times after the last administration of eyedrops were 1.1 (0.5) hours after hourly dosing and 2.1 (0.6) hours after a single dosing every 6 hours. CONCLUSIONS Voriconazole, 1%, eyedrops are well tolerated and penetrate into human aqueous humor when administered at hourly or 6-hourly intervals. They are effective in treating Candida and Aspergillus keratitis, are substantially more affordable than oral therapy, and have less potential to cause systemic adverse effects.

Generic medicines: Perceptions of general practitioners in Melbourne, Australia

ABSTRACT The protease inhibitor (PI) indinavir may be used in the management of human immunodeficiency virus (HIV) infection during pregnancy. Poor maternal-to-fetal transfer of indinavir has been reported previously, but the mechanisms of transfer remain unknown. The bidirectional transfer of indinavir was assessed in dually perfused, isolated human placentae. Term placentae (n = 5) were obtained from non-HIV-infected pregnant women. To investigate transport mechanisms, the steady-state transfer of indinavir was compared to those of antipyrine (a marker of passive diffusion) and [3H]vinblastine (a marker of P-glycoprotein [P-gp] transport) in the maternal-to-fetal and fetal-to-maternal directions in each placenta. Indinavir and antipyrine perfusate concentrations were determined by using reverse-phase, high-performance liquid chromatography; [3H]vinblastine concentrations were measured by liquid scintillation. The antipyrine transfer clearance in each direction did not differ (P = 0.76), a finding consistent with passive diffusion. However, the maternal-to-fetal transfer clearance of vinblastine, normalized to that of antipyrine (clearance index) (0.31 ± 0.05), was significantly lower than the fetal-to-maternal clearance index of vinblastine (0.67 ± 0.17; P = 0.017), suggesting the involvement of placental P-gp. Similarly, the maternal-to-fetal clearance index of indinavir (0.39 ± 0.09) was significantly lower than its fetal-to-maternal clearance index (0.97 ± 0.12; P < 0.001). These results represent the first evidence for differential transfer of a xenobiotic in the intact human placenta. The use of transport modulators to increase the maternal-to-fetal transfer of PIs as a possible strategy to reduce mother-to-child transmission of HIV warrants investigation.

Community pharmacy in the United Arab Emirates: Characteristics and workforce issues

The aims of this study were to investigate factors affecting generic medicine prescribing among general practitioners (GPs) in Melbourne, Australia. A qualitative approach was used. A convenience sample of GPs practising in Melbourne was interviewed using a semi-structured interview guide. Thematic content analysis of the interviews identified seven major themes: medicine prescribing patterns, knowledge and confidence with generic medicines, patient acceptance of generic medicines, issues related to ‘pseudo-generics’ and medicine labelling, drug advertising and marketing, brand substitution by community pharmacists and, finally, strategies to increase generics prescribing. Informants suggested some methods that could be used to increase the current rate of generics prescribing, including financial reward for GPs, patient education on generic medicines, convincing GPs of the safety and efficacy of generic medicines and educating senior medical students on issues involving generic medicines and generics prescribing. This study suggested that GPs in Melbourne have mixed attitudes to generics prescribing. The findings also show that misconceptions about safety and efficacy of generic medicines still persist among some GPs. Unless they are sufficiently educated by interested parties, such as the government and the generic medicines industry, this will have a negative impact on utilisation of generic medicines in future.