[Show abstract][Hide abstract] ABSTRACT: Treating infections caused by multidrug-resistant Gram-negative pathogens is challenging, and there is concern regarding the toxicity of the most effective antimicrobials for Gram-negative pathogens. We hypothesized that conjugating a fatty acid moiety onto a peptide dimer could maximize the interaction with lipopolysaccharide (LPS) and facilitate the permeabilization of the LPS barrier, thereby improving potency against Gram-negative pathogens. We systematically designed a series of N-lipidated peptide dimers that are active against Gram-negative bacteria, including carbapenem-resistant Enterobacteriaceae (CRE). The optimized lipid length was 6-10 carbons. At these lipid lengths, the N-lipidated peptide dimers exhibited strong LPS permeabilization. Compound 23 exhibited synergy with select antibiotics in most of the combinations tested. 23 and 32 also displayed rapid bactericidal activity. Importantly, 23 and 32 were non-hemolytic at 10 mg/mL, with no cellular or in vivo toxicity. These characteristics suggest that these compounds can overcome the limitations of current Gram-negative-targeted antimicrobials such as polymyxin B.
[Show abstract][Hide abstract] ABSTRACT: An infective aetiology, including fungal infection, should be considered in the differential diagnosis of immunocompromised patients presenting with skin lesions. Dematiaceous fungi are recognised as pathogens in organ transplant recipients. Herein, we describe a rare case of a chronic necrotising granulomatous skin lesion caused by Pyrenochaeta romeroiin a renal transplant recipient, and review the existing literature on the topic. To the best of our knowledge, this is the first report of such a case in Singapore. Recognition of infections caused by dematiaceous fungi is important because some strains are difficult to identify and require special molecular diagnostic techniques. Treatment involves surgical excision and long-term antifungal therapy. Data on the optimal antifungal regimen in such a diagnosis is limited.
Singapore medical journal 04/2014; 55(4):e64-6. DOI:10.11622/smedj.2014063 · 0.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study examined the efficacy of photocatalytic titanium dioxide (TiO2) coating in reducing environmental
MRSA contamination via a cross-sectional observational study in a tertiary hospital. This involved using
environmental samplings of TiO2 treated and TiO2 untreated surfaces from single rooms in intensive care unit,
open-planned intermediate care area and general ward. Planned scheduled sampling occurred up to 24 months
post TiO2 treatment. Ad hoc sampling of MRSA exposed environment occurred whenever MRSA infected or
colonized patient was admitted for >48 hours. Efficacy of TiO2 in preventing environmental contamination was
computed. Culture positive rates were compared between treated and untreated surfaces, and planned and ad
hoc sampling. 698 samples were obtained. Samples from untreated surfaces and ad hoc samples were more
likely to be culture positive (for MRSA and other bacteria) [untreated versus treated surfaces: odds ratio (OR)
2.95, 95% confidence interval (CI) 1.25 – 6.94, p=0.01; ad hoc sampling post MRSA exposure versus planned
sampling: OR 4.52, 95% CI 2.131 – 9.615, p< 0.001)] . Multivariate analysis suggests only MRSA exposure
influenced positive cultures. TiO2 did not influence positive culture results. More research is needed to evaluate
the relative lack of TiO2 efficacy in preventing contamination.
International Journal of Infection Control 09/2013; 9(3). DOI:10.3396/IJIC.v9i3.022.13
[Show abstract][Hide abstract] ABSTRACT: We investigated an outbreak of 47 probable and 6 confirmed cases of microsporidial keratoconjunctivitis involving participants of an international rugby tournament in Singapore in April 2012.The mode of transmission was eye contact with soil. Vittaforma corneae was identified in 4 of 6 corneal scrapings and in 1 of 12 soil water samples.
[Show abstract][Hide abstract] ABSTRACT: This work describes how to tune the amphiphilic conformation of α-mangostin, a natural compound that contains a hydrophobic xanthone scaffold, to improve its antimicrobial activity and selectivity for Gram-positive bacteria. A series of xanthone derivatives was obtained by cationic modification of the free C3 and C6 hydroxyl groups of α-mangostin with amine groups of different pKa values. Modified structures using moieties with high pKa values, such as AM-0016 (3b), exhibited potent antimicrobial properties against Gram-positive bacteria. Compound 3b also killed bacteria rapidly without inducing drug resistance and was nontoxic when applied topically. Biophysical studies and molecular dynamics simulations revealed that 3b targets the bacterial inner membrane, forming an amphiphilic conformation at the hydrophobic–water interface. In contrast, moieties with low pKa values reduced the antimicrobial activity of the parent compound when conjugated to the xanthone scaffold. This strategy provides a new way to improve “hits” for the development of membrane-active antibiotics that target drug-resistant pathogens.
[Show abstract][Hide abstract] ABSTRACT: This work described how to tune the amphiphilic conformation of α-mangostin, a natural compound with a hydrophobic xanthone scaffold to improve the antimicrobial activity and selectivity for Gram-positive bacteria. A series of xanthone derivatives were obtained by cationic modification of free hydroxyl groups of α-mangostin at C3 and C6 positions with amines groups of different pKa values. Modified structures using high pKa moieties such as AM-0016 (3b) showed potent antimicrobial properties against Gram-positive bacteria. 3b also killed bacteria rapidly, did not induce drug resistance and was non-toxic when applied topically. Biophysical studies and molecular dynamic simulations revealed that 3b targeted the bacterial inner membrane, forming an amphiphilic conformation at the hydrophobic-water interface. In contrast, moieties conjugated to the xanthone scaffold with low pKa values diminished the antimicrobial activities. This strategy provides a new insight to improve "hits" in the development of new membrane-active antibiotics for drug-resistant pathogens.
[Show abstract][Hide abstract] ABSTRACT: The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has created the need for better therapeutic options. In this study, five natural xanthones were extracted and purified from the fruit hull of Garcinia mangostana and their antimicrobial properties were investigated. α-Mangostin was identified as the most potent among them against Gram-positive pathogens (MIC=0.78-1.56μg/mL) which included two MRSA isolates. α-Mangostin also exhibited rapid in vitro bactericidal activity (3-log reduction within 5min). In a multistep (20 passage) resistance selection study using a MRSA isolated from the eye, no resistance against α-mangostin in the strains tested was observed. Biophysical studies using fluorescence probes for membrane potential and permeability, calcein encapsulated large unilamellar vesicles and scanning electron microscopy showed that α-mangostin rapidly disrupted the integrity of the cytoplasmic membrane leading to loss of intracellular components in a concentration-dependent manner. Molecular dynamic simulations revealed that isoprenyl groups were important to reduce the free energy for the burial of the hydrophobic phenyl ring of α-mangostin into the lipid bilayer of the membrane resulting in membrane breakdown and increased permeability. Thus, we suggest that direct interactions of α-mangostin with the bacterial membrane are responsible for the rapid concentration-dependent membrane disruption and bactericidal action.
[Show abstract][Hide abstract] ABSTRACT: To determine trends and clinical and epidemiologic features of legionellosis in Singapore, we studied cases reported during 2000-2009. During this period, 238 indigenous and 33 imported cases of legionellosis were reported. Cases were reported individually and sporadically throughout each year. Although the annual incidence of indigenous cases had decreased from 0.46 cases per 100,000 population in 2003 to 0.16 cases per 100,000 in 2009, the proportion of imported cases increased correspondingly from 6.2% during 2000-2004 to 27.3% during 2005-2009 (p<0.0005). The prevalence of Legionella bacteria in cooling towers and water fountains was stable (range 12.1%-15.3%) during 2004-August 2008.
[Show abstract][Hide abstract] ABSTRACT: Because invasive fungal infections cause significant morbidity and mortality in liver transplant recipients, the use of antifungal prophylaxis, and the early empirical use of antifungal agents, is widespread on liver transplant units. The new-generation azoles such as voriconazole and the echinocandins have been welcome additions to the antifungal armamentarium. These agents have become the leading options for prophylaxis in liver transplant units, despite the absence of strong data for their efficacy in this setting.
We report two recipients of living-donor liver transplants who became infected/colonised with fungi resistant to an echinocandin and the azoles after exposure to these agents. One patient developed trichosporonosis while on caspofungin and the other became infected/ colonised with Candida glabrata that was resistant to voriconazole and posaconazole.
We report these to highlight some of the consequences of using the newer antifungal agents.
Annals of the Academy of Medicine, Singapore 06/2011; 40(6):287-90. · 1.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The incidence of Clostridium (C.) difficile infection (CDI) was on the rise from 2001 to 2006 in Singapore. Recent unpublished data suggests that its incidence had remained stable or decreased in most local public hospitals between 2006 and 2010. It is, however, not known if the polymerase chain reaction (PCR) ribotype 027 strains have been circulating, although reports suggest that this strain is emerging in Asia, with the first cases reported from Japan in 2007, as well as in Hong Kong and Australia in 2009. We initiated a culture-based surveillance to detect this epidemic strain in Singapore.
From September 2008 to December 2009, all non-duplicate toxin-positive stool samples from the three largest public hospitals in Singapore were collected for culture and further analysis.
Out of the 366 samples collected, 272 viable isolates were cultured. Of these, 240 tested toxin-positive and ten tested positive for the binary toxin gene; 35 different PCR ribotypes were found. Three isolates that tested positive for binary toxin contained the same PCR ribotyping pattern as the C. difficile 027 control strain. All three had the 18-bp deletion and single nucleotide tcdC deletion at position 117. Susceptibility testing was performed, demonstrating susceptibility to erythromycin and moxifloxacin.
We report the first three isolates of C. difficile 027 from Singapore. However, their susceptibility patterns are more consistent with the historical 027 strains. Rising CDI incidence may not be associated with the emergence of the epidemic 027 strain at this time.
Singapore medical journal 05/2011; 52(5):361-4. · 0.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The rapid identification of C. albicans solely based on the presence of a pseudohyphal fringe ('spiking' colony morphology) has been descibed to give excellent sensitivity (even surpassing that of the well-established germ tube test) and specificity. We therefore evaluated the performance of this method using our standard Trypticase Soy Agar with 5% sheep blood (TSA BAP), and following overnight (18-24 hours) of incubation in a CO2 incubator, using our standard germ tube method with horse serum as the reference standard. A lower sensitivity (78.6%) than previously described was found, but the method appears to be feasible for the presumptive identification of yeasts for semi-critical and non-sterile sites. Another caveat is the possibility of Trichosporon spp. giving spiking colonial morphology, and therefore being mistaken for C. albicans.
Journal of Medical Microbiology 04/2011; 60(Pt 5):687-8. DOI:10.1099/jmm.0.028431-0 · 2.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This paper describes the epidemiological, microbiological and environmental investigations conducted during an outbreak of Salmonella gastroenteritis in Singapore.
A case-control study was undertaken to identify the vehicle of transmission. Microbiological testing was performed on faecal, food and environmental samples. Isolates of Salmonella were further characterized by phage typing and ribotyping.
There were 216 gastroenteritis cases reported from 20 November to 4 December 2007. The causative agent was identified as Salmonella enterica subspecies enterica serotype Enteritidis for 14 out of 20 cases tested. The vehicle of transmission was traced to cream cakes produced by a bakery and sold at its retail outlets (P < 0.001, OR = 143.00, 95% Cl = 27.23-759.10). More than two-thirds of the 40 Salmonella strains isolated from hospitalized cases, food samples and asymptomatic food handlers were of phage type 1; the others reacted but did not conform to any phage type. The phage types correlated well with their unique antibiograms. The ribotype patterns of 22 selected isolates tested were highly similar, indicating genetic relatedness. The dendrogram of the strains from the outbreak showed distinct clustering and correlation compared to the non-outbreak strains, confirming a common source of infection.
The cream cakes were likely contaminated by one of the ingredients used in the icing. Cross-contamination down the production line and subsequent storage of cakes at ambient temperatures for a prolonged period before consumption could have contributed to the outbreak.
[Show abstract][Hide abstract] ABSTRACT: Various studies have documented a shift in species distribution in Candida bloodstream infections (BSI), but there are little data from Southeast Asia. This study was performed to determine the species epidemiology and antifungal susceptibilities of Candida species BSI in Singapore. Candida spp. from BSI were collected from a tertiary and secondary referral hospital, and an obstetrics/paediatric hospital over a 3-year period. The most common isolates were Candida albicans (36%), Candida tropicalis (27%), Candida glabrata (16%) and Candida parapsilosis (16%). Candida parapsilosis and C. albicans were predominant in the paediatric hospital, and C. albicans and C. tropicalis predominant in the other two institutions. Candida tropicalis temporarily replaced C. albicans as the predominant strain from BSI in 2006. Overall, 87.3% of Candida isolates were susceptible to fluconazole, and 10.4% classified as susceptible-dose-dependent. Fluconazole resistance was detected in C. tropicalis (3.6%), C. parapsilosis (2.1%) and C. glabrata (4.0%). Candida albicans is the predominant species isolated from BSI in Singapore. However, non-albicans species accounted for nearly two-thirds of all cases of candidaemia and the relative increase in C. tropicalis infections deserves further investigation. Resistance to fluconazole was uncommon.
[Show abstract][Hide abstract] ABSTRACT: The antimicrobial susceptibility of Burkholderia pseudomallei isolates identified by the bacteriology laboratory at Singapore General Hospital was reviewed. Laboratory data were found to be available since 1987 and showed that ceftazidime, amoxicillin-clavulanate, chloramphenicol and tetracycline had remained effective through the years. Imipenem was added to the list of antimicrobials tested after 1989, and the isolates showed high susceptibility rates. Co-trimoxazole was found to be useful based on Etest results, but the isolates had low susceptibility rates when tested using disk diffusion.
Transactions of the Royal Society of Tropical Medicine and Hygiene 01/2009; 102 Suppl 1:S101-2. DOI:10.1016/S0035-9203(08)70024-5 · 1.84 Impact Factor