Background
Typhoid is a contagious enteric infection associated with the ingestion of food or drinks contaminated by the bacterium
Salmonella enterica serovar typhi. Typhoid causes global morbidity and mortality and is a significant health burden, particularly in low- and middle-income countries. Global trends of typhoid fever reported by the Institute for Health Metrics have shown a steady decline in the disability-adjusted life years (DALYs) from 280.77 per 100,000 population in 1990 to 110.43 per 100,000 population in 2017 [
1]. However, an estimate from the Global Burden of Disease Study in 2017 using modeling methods reported the incidence is still high as 11 million typhoid cases were reported in 2017 with more than 116,000 deaths attributable to this disease [
2]. Surveillance data from five Asian countries in urban and urban slum areas with the targeted group have shown 81.7 and 493.5 cases per 100,000 population per year in Indonesia and India, respectively, at all age groups, 451.7 cases per 100,000 per year from age 2 to 15 years in Pakistan, 24.2 cases per 100,000 per year in people aged 6 to 18 years in Vietnam and 15.3 cases per 100,000 per year in people aged 5 to 60 years in China [
3]. Heavily populated areas with poor conditions of the house and neighborhood were observed to be risks of typhoid in many urban slum or rural areas.
A recent report on typhoid fever in Malaysia noted a low incidence of 0.59 and a death rate of 0.02 per 100,000 population [
4]. A review on diarrheal diseases also reported a decreased pattern of typhoid cases in Malaysia over the years [
5]. However, typhoid is more prevalent in certain states where it is still endemic in the east coast of Malaysia [
4,
6]. It is more common in rural areas where limited access to clean water and poor sanitation increases the risk of contracting typhoid infection. Infection is also contributed by unhygienic food practices among street hawkers who usually do not comply with the safe and healthy procedural guidelines [
6,
7]. Despite being a rural disease, a recent increase in the incidence of typhoid in urban areas in Malaysia has sparked public health concern. Numerous preventative efforts, including regulations and enforcement of food hygiene and safety have been implemented, but sporadic and clusters of typhoid cases are still being reported in urban areas.
Poor management in the diagnosis and non-compliance of antibiotic use contribute to the spread of typhoid infection that subsequently could increase the cases of drug-resistant typhoid [
2]. Globally, the reported cases of multidrug-resistant (MDR) typhoid are on increasing. The emergence of MDR typhoid is a threat to global public health, and this situation will result in higher antibiotic concentration use, increasing the cost of treatment. The slow development of new antibiotics treatment for typhoid could further exacerbate the threat from drug-resistant typhoid. Hence, this study aimed to investigate the burden and trend of typhoid fever in the urban Klang Valley area over 5 years from 2011 to 2015. We would also like to examine the reporting coverage system of typhoid cases between the government and private practices and the pattern of MDR typhoid cases that could potentially have caused a major prolonged outbreak in the Klang Valley area within the five-year period.
Discussion
Typhoid fever is a common foodborne disease in Malaysia. In Klang Valley, typhoid cases were higher in men (
n = 272) at 55.6% than in women (
n = 217) at 44.4%. The mean age of typhoid fever cases in Klang Valley was 29.80 years (±17.44). Most of the typhoid cases were detected among patients aged 21 to 30 years. Other studies in Malaysia have shown that children (0–4 years) and young adults (25–29 years) were more susceptible to typhoid than the older age population [
7]. The overall trend of typhoid cases in Klang Valley had increased from 2011 (37 cases), 2012 (44 cases) and 2013 (50 cases). There was a sudden spike of cases in 2015 with 98 cases compared with 36 cases in 2014. This sudden increment was associated with an outbreak that involved construction workers where 13.7% (
n = 70) of cases from this study were contributed by foreigners (non-Malaysian) from India, Indonesia, Bangladesh, Myanmar and Nepal. Notably, the increased number cases of typhoid from 2011 to 2015 was contributed by foreigners, where five typhoid cases were reported among foreigners in 2011 and further increased to 27 typhoid cases in 2015. This finding is in contrast to an outbreak that occurred in Kelantan, where typhoid was associated with contaminated ice and ready-to-eat food distributed by street hawkers in the night market [
17]. In Malaysia, particularly in Klang Valley, the water supply is properly monitored and assuredly clean, with good management of the sewer system; however, typhoid infection remains an important public health problem. Most cases in developed countries occur in migrants, travelers and contaminated food chains by food handlers. A study performed in Japan (2015) reported that 54.8% of typhoid cases were reported from people who had traveled to Myanmar; in 2013, the incremental cases were imported cases from Cambodia [
18]. The finding from this study also found that ethnicity contributed to 14.4% (
n = 73) of typhoid cases by foreigners, representing the third-highest rate after Malay (
n = 264, 52.1%) and Chinese (
n = 97, 19.1%).
Typhoid fever is endemic in Malaysia where the country still experiences periodic epidemic outbreaks. In Malaysia, typhoid is more common in Kelantan state where multiple outbreaks were recorded in Kelantan in 2001 until 2007 [
7,
19], with a major outbreak in 2005. The estimated annual incidence rate in Kelantan state (which has 10 districts) was 37 per 100,000 population [
13]. Other studies in Malaysia reported that the incidence rates of typhoid fever in the Federal Territory of Kuala Lumpur for 1996 and 1997 were 3.68 and 3.78 per 100,000 population respectively [
20], but lower incidence rates were observed in our study in Klang Valley with 0.58 and 1.42 per 100,000 population in 2011 and 2015, respectively. The annual incidence rate in Malaysia is between 10.2 and 17.9 per 100,000 population [
21]. In contrast, Singapore, an urban country, showed a steady decline in cases from 5.9 per 100,000 to 1.2 per 100,000 over 10 years [
22]. Similar to Singapore, a study in Thailand reported that the national incidence trend had decreased from 2008 to 2014 with 8.6 per 100,000 population in 2008 and 3 per 100,000 population in 2014 [
23].
Being an urban area in Malaysia, the Klang Valley has 12 public health facilities (government hospital) and an estimated 43 private health facilities (private hospital). Of 507 cases, only 198 patients chose to visit government hospitals for treatment and 309 patients had visited private facilities. Most private companies in Malaysia have their own hospital panel for their employees that is usually a private hospital. Thus, most typhoid patients receive treatment at private hospitals rather than at government hospitals. From the observation, most of the typhoid cases (n = 184) at government hospitals used the culture method test, which is widely recommended by international society, while private facilities were seen more used to the Typhidot and WWF tests, 110 and 118 cases, respectively, likely because this method was easy to perform and quicker results were produced. According to WHO, the isolation of Salmonella typhi from the bone marrow is the current gold standard to confirm typhoid fever cases. However, the equipment, supplies, cost and requirement for personal training render its use limited, particularly in middle- and low-income countries where blood culture is a more practical. However, results from blood culture take up to 3 days, possibly causing delays in treatment. Thus, the rapid test is more widely used in many countries, including Malaysia, to diagnose typhoid fever.
e-Notification, formerly known as Communicable Disease Control Information System (CDCIS), is a web-based application implemented by the Disease Control Division, Ministry of Health Malaysia where only the registered authorized public health officer can access the system. Notifications are received from public health facilities, including health clinics, outpatient departments, and government hospitals, as well as from private hospitals and general medical practitioners [
24]. Notification of any suspected, probable or confirmed cases are mandatory under the Prevention and Control of Infectious Diseases Act 1988 within 7 days from the diagnosis date to the nearest district health office, but only laboratory-confirmed cases should be registered. From this study, 78.9% of confirmed cases were reported, indicating that typhoid cases were under-reported in the system and notification was possibly not performed. However, the reporting coverage rates of unconfirmed cases (79.5%) and PVP (89.3%) were high. This finding was much higher than that in a study in Kelantan, which had a reporting coverage of 69%, with 22% unconfirmed cases and 43% PVP [
13].
Usually, the antimicrobial susceptibility test will be performed to determine the sensitivity of the drug that can be used for patient management or treatment. The mortality in typhoid fever was reduced after the introduction of the antibiotic drug [
3]. This susceptibility test should be conducted following the guidelines from the Clinical and Laboratory Standard Institute (CLSI) or European Committee on Antimicrobial Susceptibility Testing (EUCAST) [
25]. As a recommendation by CLSI and EUCAST,
Salmonella typhi should be tested for its susceptibility to ampicillin, chloramphenicol, co-trimoxazole, ciprofloxacin, ceftriaxone and azithromycin. However, the drug panel can be expanded based on local resistant patterns. Normally, for typhoid fever, patients will be treated using ampicillin, chloramphenicol and co-trimoxazole because these are the first-line antibiotics [
14,
19,
26]. Across our study, among the seven antibiotics that were tested, nalidixic acid reported the highest antimicrobial resistance with 36.0%, followed by ampicillin, co-trimoxazole and chloramphenicol at 11.1, 9.8 and 9.5%, respectively. Additionally, 8.1% of
Salmonella typhi cases were resistant to tetracycline, 6.5% to ciprofloxacin and 1.6% to ceftriaxone. However, the sensitivity to common antibiotics (ampicillin, chloramphenicol and co-trimoxazole) was still high (more than 88%) in Klang Valley. A study conducted in Thailand from 2003 through 2014 showed that most
Salmonella typhi cases were susceptible to cefotaxime and norfloxacin, and resistance to ampicillin, cefotaxime, norfloxacin and co-trimoxazole remained below 40% [
23]. A separate study in Bangladesh reported a prevalence of
Salmonella typhi isolates expressing high-level of resistance to ciprofloxacin of 90.6% [
27], with 43% showing resistance to co-trimoxazole and chloramphenicol, and 40% to ampicillin and nalidixic acid [
19]. After the MDR
Salmonella arose toward first-line antibiotics and became the major problem in several countries worldwide, fluoroquinolones (ciprofloxacin) was chosen for patient treatment and had a high cure rate among the carriers [
28‐
30]. Ceftriaxone, a third-generation cephalosporin, and azithromycin (a macrolide) are now used as other options (second-line antibiotics) to treat typhoid fever when first-line drugs and fluoroquinolone cannot be used [
31,
32]. In our study, azithromycin was not a routine treatment for typhoid fever and ceftriaxone was used when necessary. Only the medical doctor can prescribe the antibiotic, and pharmacies will release the antibiotic according to the prescribed form. A case report by Phoon et al. in 2015 in Singapore reported
Salmonella resistance to azithromycin for the first time to ciprofloxacin and ceftriaxone [
28]. The development of resistance is likely due to misuse, overuse and inappropriate prescribing procedures [
27,
30].
MDR
Salmonella typhi strains emerged in Southeast Asia in the 1990s [
3]. Of 132 typhoid cases in Klang Valley, 10 (7.3%) were MDR
Salmonella typhi. The trend of MDR
Salmonella typhi increased from 10% in 2011 to 30% in 2015. Compared with a study in Egypt (2000), the prevalence of MDR
Salmonella typhi increased from 19% in 1987 to 100% in 1993, but it subsequently decreased to 5% in 2000 [
33]. The increasing pattern of MDR
Salmonella typhi was also observed in Bangladesh [
27], Kenya [
34] and Africa [
24]. The findings from these studies also showed a significant difference between genders regarding MDR
Salmonella typhi (
p = 0.004), but no significant difference was found in age (
p = 0.735). Compared with a study in Islamabad, Pakistan, no significant difference was found between gender and age group regarding MDR
Salmonella typhi [
14]. Several other studies also reported that the frequency of MDR typhoid fever was higher in men than in women but was higher in children than in adults [
30,
32,
35]. This is likely due to young children’s unhygienic habits and their dependence on adults for food, who may be carriers of the MDR strains [
30]. A significant difference was also seen in citizenship (
p = 0.008) and ethnicity (
p = 0.034) in Klang Valley. A study showed that microbial resistance among Asian travelers was the highest. The resistance rate for travelers from India, Pakistan and Bangladesh were 75, 80 and 60%, respectively [
14].
Strengths and limitations
This study provides data on the burden of typhoid fever in Klang Valley, Malaysia that included data from unreported typhoid fever cases. Typically, most reports will utilize data from the national surveillance system, which tends to miss data underreported by private practitioners. This study also described the trends of typhoid cases/incidences in Klang valley and a pattern of antibiotic resistance and provided data on the MDR strain.
However, this study possessed limitations. The source of data from this study came from multiple sources; hence, the data we received were not in the standard variable list required from them. For the laboratory tests, private hospitals and laboratories have their own regulations and laboratory procedures for typhoid fever testing. Various testing methods (Culture, Typhidot and WWF) were performed for typhoid diagnosis or screening. Some health facilities or laboratories only performed the Typhidot and WWF test for typhoid fever without confirmation with the culture test, and no data on additional identification methods were stated for the culture test. We also had very limited information or data on the antibiotics susceptibility results, which were not available in the e-Notifikasi system. Data analysis for antibiotics susceptibility was performed based on the data obtained by several health facilities (n = 132), but not all hospitals and laboratories tested their samples with the full panel of antibiotics suggested and no data on the antibiotic concentration were received.
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