Introduction
Typhoid fever or enteric fever is a clinical syndrome marked by constitutional symptoms (fever, malaise, and headache) as well as gastrointestinal symptoms such as abdominal pain, vomiting, and diarrhea/constipation. If left untreated, the disease may progress into serious complications such as intestinal perforation, acute hepatitis, and ascites [1]. The causative agents for the disease are gram-negative bacteria, Salmonella typhi, and the Paratyphi serotypes [2]. Lack of clean drinking water with a foundering sanitation system proves to be a major cause of transmission [3].
Up to 21 million people contract typhoid fever each year, of which almost 1,61,000 die [3,4]. Enteric fever continues to challenge public health in the developing countries of the world [5]. Among 16 countries in Asia where this infectious disease is prevalent, the populations of Sindh and Punjab (provinces of Pakistan) are at the highest risk of acquiring it [6]. The burden and high prevalence of enteric fever have been recognized in Pakistani children aged 2–15 years [7,8].
Blood culture is the cornerstone of the diagnosis of typhoid fever, which is usually positive in the first week of illness, provided antibiotics have not been initiated [9]. Based on drug susceptibility patterns, blood cultures may yield drug-sensitive, multi-drug resistant (MDR), or extensively drug-resistant (XDR) typhoid cases. XDR Typhi strains are resistant to antibiotics used to treat susceptible strains, including ampicillin, ceftriaxone, chloramphenicol, ciprofloxacin, and trimethoprim-sulfamethoxazole. The relationship between MDR and XDR typhoid has been closely studied and reported, where the former exhibits resistance to Ampicillin, Trimethoprim-Sulfamethoxazole, and Chloramphenicol. Resistance to these eventually initiated injudicious use of the fluoroquinolones, mainly Ciprofloxacin. These further contracted sporadic resistance and an inadequate response to the aforementioned antibiotics, which ultimately led to the use of Ceftriaxone, a third-generation Cephalosporin. Unfortunately, this drug has also acquired resistance, hence labeling the disease as XDR typhoid [7,10,11].
Karachi and Hyderabad, the two major cities of Pakistan, have been inflicted with XDR typhoid, with cases amounting to an alarming figure of 5,274 since 2016, as per World Health Organization (WHO) [7,8]. The causative organism for this menace, the XDR S. typhi, has acquired resistance to almost all antibiotics recommended for typhoid fever, thereby narrowing down the treatment options [7,12]. Karachi is susceptible to immense typhoid resistance by 2020 due to an increment in the annual antibiotic resistance rate of 30% [3]. Latest studies on using artificial intelligence are being used these days to map and predict the spread of infection and awareness of antibiotic resistance [13]. They have used different predictive models and use technology MDR in the future, and it will be the biggest challenge we will face belonging to a poverty-stricken country as it will increase the disease and morbidity burden.
Herein, we report the epidemic of this dangerous outbreak at Jinnah Medical College Hospital (JMCH), Karachi. The study aimed to ascertain the trends in antimicrobial resistance (AMR) of S. typhi throughout February 2019 and September 2019. Furthermore, the study outlined the demographic and clinical aspects of XDR typhoid patients, which can add valuable insights and facilitate the physicians in the diagnosis and management of the patients.
Methods
The XDR-Typhoid outbreak occurred throughout the city but was predominant in the Korangi district, as we are reporting from February 1 to September 30, 2019.
Karachi is the largest city in the province of Sindh, Pakistan, where this study is conducted. It is divided into six districts. Our field of study encompassed areas adjacent to Jinnah Medical College Hospital (Korangi district) namely: Mehran town, Landhi Town, Shah Faisal Town, and Bilal Colony.
The research approach employed a descriptive, cross-sectional study to measure the XDR cases. A cross-sectional study was planned so as to probe into the current situation at this particular time only. Patients who presented with fever for more than five days in the absence of any identifiable source of infection underwent blood culture and sensitivity which we took data from our hospital pathology laboratory. Of 175 blood culture specimens, only 65 XDR-Typhoid patients were isolated, whereas patients showing negative growth on culture and growth of organisms other than S. typhi and MDR-S. typhi were excluded from the study. These patients who were excluded presented in the same way as high-grade fever for more than five days and of the same demographics as age and gender. After obtaining consent, a face-to-face interview was also conducted using a structured questionnaire to evaluate the demographics (gender and age) and clinical symptoms (fever, vomiting, headache, abdominal pain, and diarrhea) of the patients. Some cases were excluded from the study (organisms other than S. typhi). Complications, such as intestinal perforation, acute hepatitis, and free peritoneal fluid, were confirmed by abdominal ultrasound were mentioned in the data.
XDR-typhoid patients were treated as inpatients with a combination of Imipenem and Azithromycin. Doses were adjusted for patients according to age. Patients below 18 years of age received Imipenem 500 mg intravenously thrice daily and Azithromycin 500 mg per oral once daily. While those above 18 years of age were prescribed Imipenem 1 g intravenously thrice daily and Azithromycin 500 mg per oral once daily.
Data Analysis
The Statistical Package for the Social Sciences (SPSS, IBM Corp., Armonk, New York) software version 25.0 was used for data analysis. Descriptive statistics were generated based on frequencies and percentages for blood culture findings, age, gender, clinical features, complications, and monthly distribution of XDR-S. typhi cases.
Results
A total of 65 cases of XDR-Typhoid were detected from February 1 to September 30, 2019 from a clinical laboratory at JMCH [Table 1]. All isolates were resistant to Ampicillin, Chloramphenicol, Co-Trimoxazole, Ciprofloxacin, and Ceftriaxone.
Table 2 outlines the demographics and clinical parameters of XDR S. typhi cases. More than half the cases were reported in females (36[55.4%]). A maximum number of cases were seen in young adults from 20 to 29 years of age (24[37%]). The striking clinical features were fever (100%), headache (80%), and vomiting (75.4%). A few patients developed complications, including intestinal perforation (1.5%), requiring surgical intervention, acute hepatitis (10.8%), and free peritoneal fluid (4.6%). All cases were successfully treated with Azithromycin and Imipenem. No mortality was reported.
Table 1.
Results of total blood C/S performed (N=175).
| Blood C/S | N (%) |
|---|---|
| Negative growth | 38 (21.7) |
| Staphylococcus aureus | 18 (10.3) |
| Enterococci | 08 (4.6) |
| MDR-S. typhi | 46 (26.3) |
| XDR-S. typhi | 65 (37.1) |
Table 2.
Demographic and clinical characteristics of XDR S. typhi cases (N=65).
| Characteristic | N (%) |
|---|---|
| Gender | |
| Male | 29 (44.6) |
| Female | 36 (55.4) |
| Age group, y | |
| 1–9 | 09 (13.8) |
| 10–19 | 14 (21.5) |
| 20–29 | 24 (37) |
| >30 | 18 (27.7) |
| Clinical features | |
| Fever | 65 (100) |
| Vomiting | 49 (75.4) |
| Headache | 52 (80) |
| Abdominal pain | 18 (27.8) |
| Diarrhea | 27 (41.5) |
| Complications | |
| Intestinal perforation | 01 (1.5) |
| Acute Hepatitis | 07 (10.8) |
| Free peritoneal fluid | 03 (4.6) |
The number of cases reported monthly varied from as low as 2 (3.1%) at the beginning of the epidemic (February) to as high as 11 (16.9%) in August, as illustrated in Figure 1.
Discussion
Low-income and middle-income countries continue to harbor the deadly bacteria S. typhi due to emerging extensively drug-resistant variants. Our study identified 65 (37.1%) XDR cases, and most of them were observed in children aged 20–29 years and among the female population. This disproportionate data might point toward young adults consuming food from local vendors. As shown in Table 2, in contrast to our study, Aslam et al. [9] reported a higher incidence of typhoidal cases in males and children ranging from 1 to 10 years [9]. In a prospective surveillance study from five Asian countries, 57% of all the S. typhi isolated from blood cultures were from children between 5 and 15 years of age [14]. This disparity could be due to exposure to various risk factors, including unsafe handling of food, overcrowding, or poor sanitation in the vicinity, which calls for further research. Likely, these patients were subjected to unsafe food either at their workplace or from local food vendors, given their age is young.
Extensively drug-resistant typhoid carries a significant risk of complications. The complications, which is a significant number in our study, show the morbidity to be increased. While acute hepatitis is the usual complication, only 10.8% of our study population developed it, unlike 18% of XDR-typhoid patients reported by Mansoor et al. Besides acute hepatitis, our study reported one case of intestinal perforation and three cases of free peritoneal fluid [15]. History of antibiotic intake for typhoid fever before hospital admission, in Mansoor et al. survey accounted for an overall low rate of complications. Out of a total of 65, 7 patients developed acute hepatitis, which makes 10% of our patients set, which is significant and warrants more research as it is a burden on morbidity.
In our study, maximum cases (16.9%) were reported in August. A similar upsurge in XDR cases was also observed by Aslam et al. in their study, which reported 22% of cases in August 2019 [9]. As shown in Table 1, a similar trend was also observed in a study that reported maximum typhoid cases from June to September [16]. Such a pattern is indicative of poor sanitary conditions post-monsoon season, which plays a major role in the spread of typhoid in Karachi. Likely, the surge is because of the monsoon and heat, the use of unhygienic food vendors from carts, and the use of unboiled water frequently.
Figure 1.
Monthly distribution of XDR S. typhi cases (N=65) from February 1 to September 30, 2019.
The continuing problem of the development of resistance to existing antimicrobial agents and the dearth of new antibiotics has led to the evolvement of XDR-typhoid. Corroborating with the published literature, most of the studies implicated azithromycin as the last oral resort for outpatient management and parenteral administration of Carbapenems for complicated typhoidal illness [17–19]. The XDR cases from Punjab also underscore the emergence of cephalosporin-resistant S. typhi strains, which entails the implication of urgent measures before such strains acquire resistance to the available antimicrobial agents [20]. Another cross-sectional study conducted by Laghari G, et al. [21] evaluated the antimicrobial susceptibility patterns of Salmonella Species in Southern Pakistan. Drugs, namely Imipenem and Meropenem, showed higher sensitivity of 87.8% and 91%, respectively [21]. Our patients were also successfully treated with Imipenem and Azithromycin.
The fact that this superbug is gaining resistance rapidly, it is plausible that the XDR strain of S. typhi may acquire resistance against azithromycin and carbapenem as well, as to preclude effective deployment of antibiotics. Therefore, irrational use of antibiotics should be discouraged to prevent rising morbidity and mortality.
Conclusion
The frightening rise in the number of XDR typhoid cases adds a sense of urgency and calls for effective strategy implementation in controlling the disease. Typhoid preventive measures, including community awareness and education about personal hygiene, proper sanitation, and vaccination, should be implemented efficiently. In light of emerging antibiotic resistance, antibiotic stewardship programs can also aid in reducing the disease burden significantly.
Conflict of interest
None declared by any of the authors.
Limitations
As it usually comes in summer and there is limited data of a single institution, we would want to have multicentered data for the right projection and for coming up with strategies to deal with it in the future.
Ethical consideration
An ethical certificate was taken before proceeding with the data collection.
