Interaction between Antibiotic Resistance, Resistance Genes, and Treatment Response for Urinary Tract Infections in Primary Care.

Given increasing antimicrobial resistance, we aimed to determine antibiotic susceptibility and presence of resistance genes in uropathogens in primary care, factors associated with resistance to commonly prescribed antibiotics, and effect of treatment on early symptom resolution. We conducted a prospective study of primary care patients with urinary tract infection (UTI) symptoms and culture-confirmed UTI in Singapore from 2015 to 2016. Cohort characteristics and antimicrobial susceptibility of cultured isolates were analyzed. Among Enterobacteriaceae isolates, early symptom resolution (within 3 days) according to antibiotic prescribed and isolate susceptibility and factors associated with antibiotic resistance were evaluated. Of 695 symptomatic patients, 299 were urine culture positive; of these 299 patients, 259 (87%) were female. Escherichia coli was the most common uropathogen (76%). Enterobacteriaceae isolates (n = 283) were highly susceptible to amoxicillin-clavulanate (86%), nitrofurantoin (87%), and fosfomycin (98%), but >20% were resistant to ciprofloxacin and co-trimoxazole. Isolates resistant to appropriate indicator antibiotics were further tested to determine proportions positive for blaCTX-M (14/26, 54%), plasmid-mediated ampC (12/24, 50%), qnr (7/69, 10%), and fos (1/6, 17%) resistance genes. A total of 67% of patients given antibiotics with susceptible isolates reported early resolution versus 45% given antibiotics with nonsusceptible isolates (P = 0.001) and 27% not treated (P = 0.018). On multivariable analysis, Indian ethnicity and diabetes mellitus were associated with amoxicillin-clavulanate resistance. Genitourinary abnormalities, UTI in the past 12 months, and hospitalization in the past 6 months were associated with ciprofloxacin and co-trimoxazole resistance. Patients given active empirical antibiotics were most likely to report early symptom resolution, but correlation with in vitro susceptibility was imperfect. Factors associated with resistance may guide the decision to obtain initial urine culture.

Accuracy of urinary symptoms and urine microscopy in diagnosing urinary tract infection in women.

BACKGROUND: Women with urinary tract infections (UTIs) often present with urinary complaints such as frequency of micturition, dysuria, foul-smelling urine and other non-specific symptoms like fever. Physicians may order urine microscopy to guide empirical antibiotic prescription. However, the performance of this approach has not been assessed. OBJECTIVES: This study aimed to determine the accuracy of UTI symptoms and urine microscopy associated with culture-positive UTI in Asian women. METHODS: A cross-sectional study of adult women who presented with UTI-related symptoms was conducted at three public primary care clinics in Singapore. Demographic data and information on their symptoms were collected, followed by urine microscopy and culture to diagnose UTI. The sensitivity, specificity, positive (PPV), negative predictive values (NPV), accuracy (ACC) and area under curve (AUC) of combinations of symptom and urine investigations were analysed in association with culture-positive UTI, which was regarded as a benchmark. RESULTS: Data on 564 women (73.9% Chinese, 11.5% Malay, 8.2% Indian) were analysed, of which 259 (45.9%) had culture-positive UTI. Frequency and foul-smelling urine, pyuria (WBC ≥10/hpf) and semi-quantitative bacterial count (≥2+) were significantly associated with positive urine culture. The ACC and AUC for single or multiple urinary and/or general symptoms were low. Urine pyuria (minimally >10/hpf) alone or in combination with symptoms and/or semi-quantitative bacterial count achieved high sensitivity (>85%) and PPV, NPV, ACC and AUC of >70%. CONCLUSION: Urinary symptoms have limited accuracy in diagnosing culture-positive UTI. Concurrent urine microscopy showing presence of pyuria and/or bacterial count increased the diagnostic accuracy of culture-positive UTI.

Results from a Patient-Based Health Education Intervention in Reducing Antibiotic Use for Acute Upper Respiratory Tract Infections in the Private Sector Primary Care Setting in Singapore.

We investigated the efficacy of patient-targeted education in reducing antibiotic prescriptions for upper respiratory tract infections (URTIs) among adults in the private primary care setting in Singapore. Our randomized controlled trial enrolled patients aged 21 years and above presenting at general practitioner (GP) clinics with URTI symptoms for 7 days or less. Intervention arm patients were verbally educated via pamphlets about the etiology of URTIs, the role of antibiotics in treating URTIs, and the consequences of inappropriate antibiotic use. Control arm patients were educated on influenza vaccinations. Both arms were compared regarding the proportions prescribed antibiotics and the patients' postconsultation views. A total of 914 patients consulting 35 doctors from 24 clinics completed the study (457 in each arm). The demographics of patients in both arms were similar, and 19.1% were prescribed an antibiotic, but this varied from 0% to 70% for individual GPs. The intervention did not significantly reduce antibiotic prescriptions (odds ratio [OR], 1.20; 95% confidence interval [CI], 0.83-1.73) except in patients of Indian ethnicity (OR, 0.28; 95% CI, 0.09-0.93). Positive associations between the intervention and the view that antibiotics were not needed most of the time for URTIs (P = 0.047) and on being worried about the side effects of antibiotics (P = 0.018) were restricted to the Indian subgroup. GPs in limited liability partnerships or clinic chains prescribed less (OR, 0.36; 95% CI, 0.14 to 0.92), while certain inappropriate patient responses were associated with the receipt of antibiotics. Follow-up studies to investigate differences in responses to educational programs between ethnicities and to explore GP-targeted interventions are recommended.

Knowledge, attitudes and practices towards antibiotic use in upper respiratory tract infections among patients seeking primary health care in Singapore.

BACKGROUND: Patients' expectations can influence antibiotic prescription by primary healthcare physicians. We assessed knowledge, attitude and practices towards antibiotic use for upper respiratory tract infections (URTIs), and whether knowledge is associated with increased expectations for antibiotics among patients visiting primary healthcare services in Singapore. METHODS: Data was collected through a cross-sectional interviewer-assisted survey of patients aged ≥21 years waiting to see primary healthcare practitioners for one or more symptoms suggestive of URTI (cough, sore throat, runny nose or blocked nose) for 7 days or less, covering the demographics, presenting symptoms, knowledge, attitudes, beliefs and practices of URTI and associated antibiotic use. Univariate and multivariate logistic regression was used to assess independent factors associated with patients' expectations for antibiotics. RESULTS: Nine hundred fourteen out of 987 eligible patients consulting 35 doctors were recruited from 24 private sector primary care clinics in Singapore. A third (307/907) expected antibiotics, of which a substantial proportion would ask the doctor for antibiotics (121/304, 40 %) and/or see another doctor (31/304, 10 %) if antibiotics were not prescribed. The majority agreed "antibiotics are effective against viruses" (715/914, 78 %) and that "antibiotics cure URTI faster" (594/912, 65 %). Inappropriate antibiotic practices include "keeping antibiotics stock at home" (125/913, 12 %), "taking leftover antibiotics" (114/913, 14 %) and giving antibiotics to family members (62/913, 7 %). On multivariate regression, the following factors were independently associated with wanting antibiotics (odds ratio; 95 % confidence interval): Malay ethnicity (1.67; 1.00-2.79), living in private housing (1.69; 1.13-2.51), presence of sore throat (1.50; 1.07-2.10) or fever (1.46; 1.01-2.12), perception that illness is serious (1.70; 1.27-2.27), belief that antibiotics cure URTI faster (5.35; 3.76-7.62) and not knowing URTI resolves on its own (2.18; 1.08-2.06), while post-secondary education (0.67; 0.48-0.94) was inversely associated. Those with lower educational levels were significantly more likely to have multiple misconceptions about antibiotics. CONCLUSION: Majority of patients seeking primary health care in Singapore are misinformed about the role of antibiotics in URTI. Agreeing with the statement that antibiotics cure URTI faster was most strongly associated with wanting antibiotics. Those with higher educational levels were less likely to want antibiotics, while those with lower educational levels more likely to have incorrect knowledge.

Review of a two-year methicillin-resistant Staphylococcus aureus screening program and cost-effectiveness analysis in Singapore.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) poses an increasingly large disease and economic burden worldwide. The effectiveness of screening programs in the tropics is poorly understood. The aims of this study are: (i) to analyze the factors affecting MRSA colonization at admission and acquisition during hospitalization and (ii) to evaluate the cost-effectiveness of a screening program which aims to control MRSA incidence during hospitalization. METHODS: We conducted a retrospective case-control study of patients admitted to the Communicable Disease Centre (CDC) in Singapore between Jan 2009 and Dec 2010 when there was an ongoing selective screening and isolation program. Risk factors contributing to MRSA colonization on admission and acquisition during hospital stay were evaluated using a logistic regression model. In addition, a cost-effectiveness analysis was conducted to determine the cost per disability-adjusted life year (DALY) averted due to implementing the screening and isolation program. RESULTS: The average prevalence rate of screened patients at admission and the average acquisition rate at discharge during the study period were 12.1 and 4.8 % respectively. Logistic regression models showed that older age (adjusted odds ratio (OR) 1.03, 95 % CI 1.02-1.04, p < 0.001) and dermatological conditions (adjusted OR 1.49, 95 % CI 1.11-1.20, p = 0.008) were independently associated with an increased risk of MRSA colonization at admission. Age (adjusted OR 1.02, 95 % CI 1.01-1.03, p = 0.002) and length of stay in hospital (adjusted OR 1.04, 95 % CI 1.03-1.06, p < 0.001) were independent factors associated with MRSA acquisition during hospitalization. The screening and isolation program reduced the acquisition rate by 1.6 % and was found to be cost saving. For the whole study period, the program cost US$129,916, while it offset hospitalization costs of US$103,869 and loss of productivity costs of US$50,453 with -400 $/DALY averted. DISCUSSION: This study is the first to our knowledge that evaluates the cost-effectiveness of screening and isolation of MRSA patients in a tropical country. Another unique feature of the analysis is the evaluation of acquisition rates among specific types of patients (dermatological, HIV and infectious disease patients)and the comparison of the cost-effectiveness of screening and isolation between them. CONCLUSIONS: Overall our results indicate high MRSA prevalence that can be cost effectively reduced by selective screening and isolation programs in Singapore.

Using the Johns Hopkins ACG Case-Mix System for population segmentation in a hospital-based adult patient population in Singapore.

OBJECTIVE: Population health management involves risk characterisation and patient segmentation. Almost all population segmentation tools require comprehensive health information spanning the full care continuum. We assessed the utility of applying the ACG System as a population risk segmentation tool using only hospital data. DESIGN: Retrospective cohort study. SETTING: Tertiary hospital in central Singapore. PARTICIPANTS: 100 000 randomly selected adult patients from 1 January to 31 December 2017. INTERVENTION: Hospital encounters, diagnoses codes and medications prescribed to the participants were used as input data to the ACG System. PRIMARY AND SECONDARY OUTCOME MEASURES: Hospital costs, admission episodes and mortality of these patients in the subsequent year (2018) were used to assess the utility of ACG System outputs such as resource utilisation bands (RUBs) in stratifying patients and identifying high hospital care users. RESULTS: Patients placed in higher RUBs had higher prospective (2018) healthcare costs, and were more likely to have healthcare costs in the top five percentile, to have three or more hospital admissions, and to die in the subsequent year. A combination of RUBs and ACG System generated rank probability of high healthcare costs, age and gender that had good discriminatory ability for all three outcomes, with area under the receiver-operator characteristic curve (AUC) values of 0.827, 0.889 and 0.876, respectively. Application of machine learning methods improved AUCs marginally by about 0.02 in predicting the top five percentile of healthcare costs and death in the subsequent year. CONCLUSION: A population stratification and risk prediction tool can be used to appropriately segment populations in a hospital patient population even with incomplete clinical data.

Validation of the Gail model for predicting individual breast cancer risk in a prospective nationwide study of 28,104 Singapore women.

INTRODUCTION: The Gail model (GM) is a risk-assessment model used in individual estimation of the absolute risk of invasive breast cancer, and has been applied to both clinical counselling and breast cancer prevention studies. Although the GM has been validated in several Western studies, its applicability outside North America and Europe remains uncertain. The Singapore Breast Cancer Screening Project (SBCSP) is a nation-wide prospective trial of screening mammography conducted between Oct 1994 and Feb 1997, and is the only such trial conducted outside North America and Europe to date. With the long-term outcomes from this study, we sought to evaluate the performance of GM in prediction of individual breast cancer risk in a Asian developed country. METHODS: The study population consisted of 28,104 women aged 50 to 64 years who participated in the SBSCP and did not have breast cancer detected during screening. The national cancer registry was used to identify incident cases of breast cancer. To evaluate the performance of the GM, we compared the expected number of invasive breast cancer cases predicted by the model to the actual number of cases observed within 5-year and 10-year follow-up. Pearson's Chi-square test was used to test the goodness of fit between the expected and observed cases of invasive breast cancers. RESULTS: The ratio of expected to observed number of invasive breast cancer cases within 5 years from screening was 2.51 (95% confidence interval 2.14 - 2.96). The GM over-estimated breast cancer risk across all age groups, with the discrepancy being highest among older women aged 60 - 64 years (E/O = 3.53, 95% CI = 2.57-4.85). The model also over-estimated risk for the upper 80% of women with highest predicted risk. The overall E/O ratio for the 10-year predicted breast cancer risk was 1.85 (1.68-2.04). CONCLUSIONS: The GM over-predicts the risk of invasive breast cancer in the setting of a developed Asian country as demonstrated in a large prospective trial, with the largest difference seen in older women aged between 60 and 64 years old. The reason for the discrepancy is likely to be multifactorial, including a truly lower prevalence of breast cancer, as well as lower mammographic screening prevalence locally.

Nephrinuria associates with multiple renal traits in type 2 diabetes.

BACKGROUND: The involvement of nephrin in controlling renal function is unclear with the literature only emphasizing its role in albuminuria. We therefore investigated the potential association between nephrinuria as evidenced by the appearance of urinary immunopositive nephrin fragments, with multiple renal traits. METHODS: Western blot analysis of the urine samples from a cross-sectional study of 381 Chinese type 2 diabetic patients revealed four distinct protein fragments, indicative of nephrinuria. Albuminuria was measured in random spot urine samples using the albumin/creatinine ratio (ACR), while estimated glomerular filtration rate (eGFR) was calculated using the creatinine-based Modification of Diet in Renal Disease formula. RESULTS: Each nephrin fragment was associated with a decline in eGFR (smallest P = 0.001). Even with the inclusion of logarithmic form of ACR (ln ACR) in the multivariate model, nephrinuria still remained significantly associated with lower eGFR (smallest P < 0.05). Nephrinuria was also strongly associated with lnACR and this finding was independent of eGFR (smallest P < 0.001). Thus, nephrinuria was independently associated with both renal traits in the form of lnACR and eGFR. Furthermore, nephrinuria was significantly associated with lower eGFR even among normoalbuminuric patients (ACR ≤ 30 mg/g) (smallest P = 0.002), potentially implicating nephrinuria in the development of normoalbuminuric renal insufficiency. Apart from the renal traits under investigation, the presence of nephrinuria did not associate with other patient clinical characteristics. CONCLUSIONS: Nephrinuria was associated with multiple renal traits in type 2 diabetes even in normoalbuminuric patients who are traditionally perceived as having a low risk of chronic kidney disease.

Twentieth century influenza pandemics in Singapore.

INTRODUCTION: Singapore was substantially affected by three 20th Century pandemics. This study describes the course of the pandemics, and the preventive measures adopted. MATERIALS AND METHODS: We reviewed and researched a wide range of material including peer-reviewed journal articles, Ministry of Health reports, Straits Settlements reports and newspaper articles. Monthly mortality data were obtained from various official sources in Singapore. RESULTS: The 1918 epidemic in Singapore occurred in 2 waves--June to July, and October to November--resulting in up to 3500 deaths. The 1957 epidemic occurred in May, and resulted in widespread morbidity, with 77,000 outpatient attendances in government clinics alone. The 1968 epidemic occurred in August and lasted a few weeks, with outpatient attendances increasing by more than 65%. The preventive measures instituted by the Singapore government during the pandemics included the closure of schools, promulgation of public health messages, setting up of influenza treatment centres, and screening at ports. Students, businessmen and healthcare workers were all severely affected by the pandemics. CONCLUSIONS: Tropical cities should be prepared in case of a future pandemic. Some of the preventive measures used in previous pandemics may be applicable during the next pandemic.

Mammographic density phenotypes and risk of breast cancer: a meta-analysis.

BACKGROUND: Fibroglandular breast tissue appears dense on mammogram, whereas fat appears nondense. It is unclear whether absolute or percentage dense area more strongly predicts breast cancer risk and whether absolute nondense area is independently associated with risk. METHODS: We conducted a meta-analysis of 13 case-control studies providing results from logistic regressions for associations between one standard deviation (SD) increments in mammographic density phenotypes and breast cancer risk. We used random-effects models to calculate pooled odds ratios and 95% confidence intervals (CIs). All tests were two-sided with P less than .05 considered to be statistically significant. RESULTS: Among premenopausal women (n = 1776 case patients; n = 2834 control subjects), summary odds ratios were 1.37 (95% CI = 1.29 to 1.47) for absolute dense area, 0.78 (95% CI = 0.71 to 0.86) for absolute nondense area, and 1.52 (95% CI = 1.39 to 1.66) for percentage dense area when pooling estimates adjusted for age, body mass index, and parity. Corresponding odds ratios among postmenopausal women (n = 6643 case patients; n = 11187 control subjects) were 1.38 (95% CI = 1.31 to 1.44), 0.79 (95% CI = 0.73 to 0.85), and 1.53 (95% CI = 1.44 to 1.64). After additional adjustment for absolute dense area, associations between absolute nondense area and breast cancer became attenuated or null in several studies and summary odds ratios became 0.82 (95% CI = 0.71 to 0.94; P heterogeneity = .02) for premenopausal and 0.85 (95% CI = 0.75 to 0.96; P heterogeneity < .01) for postmenopausal women. CONCLUSIONS: The results suggest that percentage dense area is a stronger breast cancer risk factor than absolute dense area. Absolute nondense area was inversely associated with breast cancer risk, but it is unclear whether the association is independent of absolute dense area.

Short communication: risk factors for methicillin-resistant Staphylococcus aureus colonization among HIV patients at hospital admission.

Methicillin-resistant Staphylococcus aureus (MRSA) is a nosocomial pathogen that has become increasingly prominent in hospitals and the community. HIV-positive patients may be one of the most MRSA-susceptible populations because of their immunocompromised status. At the Communicable Disease Centre, Tan Tock Seng Hospital, Singapore, we implemented a universal MRSA screening program and performed a case-control study to identify risk factors for MRSA colonization among 294 HIV patients at admission from January 2009 to January 2010. Among 54 HIV-positive patients who were MRSA positive at hospital admission, 16 (29.6%) were positive at the nares/axilla/groin (NAG; one combined swab), 14 (25.9%) were NAG and perianal positive, 3 (5.6%) were NAG and throat positive, 10 (18.5%) were NAG, perianal, and throat positive, 6 (11.1%) were throat positive, and 5 (9.3%) were perianal positive. Upon multivariate analysis, we found that age [odds ratio (OR)=1.04, 95% confidence interval (CI): 1.01-1.07, p=0.006] and CD4 count <200/µl within the past 6 months (OR=4.29, 95% CI: 1.83-10.06, p=0.001) were significant risk factors for MRSA colonization. We generated a receiver operating characteristic curve using these two variables and found that the area under the curve was 0.69, indicating that age and CD4 count <200/µl performed moderately well in discriminating between those with MRSA colonization and those without. The results of our study indicate that HIV patients of older age and reduced CD4 count may have increased risk of MRSA colonization. These risk factors may serve as indicators for cohorting or isolating HIV patients at hospital admission.

Epidemiological characteristics of cholera in Singapore, 1992-2007.

INTRODUCTION: We carried out an epidemiological review of cholera in Singapore to determine its trends and the factors contributing to its occurrence. MATERIALS AND METHODS: Epidemiological data of all notified cases of cholera maintained by the Communicable Diseases Division, Ministry of Health, for the period 1992 to 2007 were collated and analysed. Case-control studies were carried out in outbreaks to determine the source of infection and mode of transmission. Linear patterns in age and ethnic distribution of cholera cases were assessed using chi2 test for trend. RESULTS: There were a total of 210 cholera cases reported between 1992 and 2007. The incidence of cholera declined from 17 cases in 1992 to 7 cases in 2007. About a quarter of the cases were imported from endemic countries in the region. Between 76% and 95% of the reported cases were local residents. Four elderly patients with comorbidities and who sought medical treatment late died, giving a case-fatality rate of 1.9%. Vibrio cholerae 01, biotype El Tor, serotype Ogawa, accounted for 83.8% of the cases. The vehicles of transmission identified in outbreaks included raw fi sh, undercooked seafood and iced drinks cross-contaminated with raw seafood. CONCLUSION: With the high standard of environmental hygiene and sanitation, a comprehensive epidemiological surveillance system and licensing and control of food establishments, cholera could not gain a foothold in Singapore despite it being situated in an endemic region. However, health education of the public on the importance of personal and food hygiene is of paramount importance in preventing foodborne outbreaks. Physicians should also maintain a high level of suspicion of cholera in patients presenting with severe gastroenteritis, especially those with a recent travel history to endemic countries.

Trends in long-term cancer survival in Singapore: 1968-2002.

INTRODUCTION: The life expectancy of cancer patients has increased in recent decades due to better diagnostic and screening tools as well as better treatment modalities. Hence, it becomes increasingly important to study trends in long-term cancer patient survival in order to document that medical progress has conveyed benefit at the population level. In this paper, we assessed the long-term survival experience of all incident cancer patients in Singapore. MATERIALS AND METHODS: The study population consisted of patients diagnosed with single primary invasive cancer from 1 January 1968 to 31 December 2002, and passively followed up to 31 December 2005. The data was derived from the Singapore Cancer Registry, which has been in existence since 1968. Relative survival via the period approach was used to provide a more up-to-date estimate by looking at recent cohorts of patients. Sex- and stage-specific survival was compared for each cancer. RESULTS: The overall age-standardised 10-year relative survival ratios for the calendar years of 1998 to 2002 were 30.5% in males and 44.2% in females. A steady improvement in overall long-term cancer survival was observed over the study period. This upward trend in survival was observed in localised tumours and cancers with a favourable prognosis such as breast, cervical and colorectal cancers. In contrast, survival of cancers with poor prognosis such as lung, liver and pancreas remained low. CONCLUSIONS: Although factors such as changes in diagnostic criteria could influence the trend in survival, we believed that the improvement in survival predominantly reflected real progress in cancer control in Singapore.

Gender differences in the trend of colorectal cancer incidence in Singapore, 1968-2002.

BACKGROUND AND AIMS: Over the past decades, incidence trends of colorectal cancer are sharply increased in Singapore. In this population-based study we describe changes in colorectal cancer incidence in Singapore and explore the reasons behind these changes through age-period cohort (APC) modeling. METHODS: We included all 22,609 colorectal cancer cases reported to the Singapore Cancer Registry between 1968 and 2002. Poisson regression, using age-period (AP) and age-cohort (AC) models was used to determine the effects of age at diagnosis, calendar period, and birth cohort. RESULTS: Male colorectal cancer rates between 1968 and 2002 from 20 to 40 per 100,000 person years. The increase was sharpest among older men, for whom there was a significant AC effect. Female colorectal cancer rates increased until 1992 (from 16 to 29 per 100,000 person years) and stabilized afterward. For women under 65 years, we observed a significant AP effect, corresponding to a sudden rise in colorectal cancer incidence around 1978. CONCLUSIONS: This study demonstrates important gender differences in colorectal cancer incidence in Singapore, with increasing rates among men, and stabilized rates in women. The increase in men is mainly attributable to an incidence increase in the oldest age groups, probably due to increased exposure to dietary and lifestyle risk factors earlier in life. The stabilization in female colorectal cancer risk could be due to lower exposure to lifestyle risk factors and prophylactic removal of precancerous lesions.

Influenza pandemics in Singapore, a tropical, globally connected city.

Tropical cities such as Singapore do not have well-defined influenza seasons but have not been spared from influenza pandemics. The 1918 epidemic in Singapore, which was then already a major global trading hub, occurred in 2 waves, June-July, and October-November, and resulted in > or = 2,870 deaths. The excess mortality rate was higher than that for industrialized nations in the Northern Hemisphere but lower than that for less industrialized countries in Asia and Africa. The 1957 epidemic occurred in May and resulted in widespread illness. The 1968 epidemic occurred in August and lasted a few weeks, again with widespread illness. Tropical cities may be affected early in a pandemic and have higher mortality rates. With the increase in travel and trade, a future pandemic may reach a globally connected city early and spread worldwide. Preparedness and surveillance plans must be developed to include the megacities of the tropical world.