XDR Typhoid Fever Research Articles

Morbidity and Mortality Associated with Typhoid Fever Among Hospitalized Patients in Hyderabad District, Pakistan, 2017-2018: Retrospective Record Review.

BackgroundHyderabad, Pakistan, was the first city to witness an outbreak of extensively drug resistant (XDR) typhoid fever. The outbreak strain is resistant to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, fluoroquinolones, and third-generation cephalosporin, thus greatly limiting treatment options. However, despite over 5000 documented cases, information on mortality and morbidity has been limited.ObjectiveTo address the existing knowledge gap, this study aimed to assess the morbidity and mortality associated with XDR and non-XDR Salmonella serovar Typhi infections in Pakistan.MethodsWe reviewed the medical records of culture-confirmed typhoid cases in 5 hospitals in Hyderabad from October 1, 2016, to September 30, 2018. We recorded data on age, gender, onset of fever, physical examination, serological and microbiological test results, treatment before and during hospitalization, duration of hospitalization, complications, and deaths.ResultsA total of 1452 culture-confirmed typhoid cases, including 947 (66%) XDR typhoid cases and 505 (34%) non-XDR typhoid cases, were identified. Overall, ≥1 complications were reported in 360 (38%) patients with XDR typhoid and 89 (18%) patients with non-XDR typhoid (P<.001). Ileal perforation was the most commonly reported complication in both patients with XDR typhoid (n=210, 23%) and patients with non-XDR typhoid (n=71, 14%) (P<.001). Overall, mortality was documented among 17 (1.8%) patients with XDR S Typhi infections and 3 (0.6%) patients with non-XDR S Typhi infections (P=.06).ConclusionsAs this first XDR typhoid outbreak continues to spread, the increased duration of illness before hospitalization and increased rate of complications have important implications for clinical care and medical costs and heighten the importance of prevention and control measures.

Continued Outbreak of Ceftriaxone-Resistant Salmonella enterica Serotype Typhi across Pakistan and Assessment of Knowledge and Practices among Healthcare Workers.

Pakistan is experiencing the first known outbreak of extensively drug-resistant (XDR) Salmonella enterica serotype Typhi (resistant to third-generation cephalosporins). The outbreak originated in Hyderabad in 2016 and spread throughout the Sindh Province. Whereas focus has remained on Sindh, the burden of XDR typhoid in Punjab, the most populous province, and the rest of the country is understudied. Using laboratory data from Shaukat Khanum Memorial Cancer Hospital and Research Centre in Lahore (Punjab Province) and its network of more than 100 collection centers across the country, we determined the frequency of blood culture-confirmed XDR typhoid cases from 2017 to 2019. We observed an increase in XDR typhoid cases in Punjab, with the percent of ceftriaxone resistance among Salmonella Typhi cases increasing from no cases in 2017, to 30% in 2018, and to 50% in 2019, with children bearing the largest burden. We also observed spread of XDR typhoid to the two other provinces in Pakistan. To assess prevailing knowledge and practices on XDR typhoid, we surveyed 321 frontline healthcare workers. Survey results suggested that inappropriate diagnostic tests and antibiotic practices may lead to underdiagnosis of XDR typhoid cases, and potentially drive resistance development and spread. Of those surveyed, only 43.6% had heard of XDR typhoid. Currently, serological tests are more routinely used over blood culture tests even though blood culture is imperative for a definitive diagnosis of typhoid fever. We recommend stronger liaisons between healthcare providers and diagnostic laboratories, and increased promotion of typhoid vaccination among healthcare workers and the general population.

A rare case of an imported typhoid fever caused by extensively drug-resistant salmonella typhi in the UAE

The emergence of extensively drug-resistant (XDR) strains of Salmonella enterica serovar Typhi-resistant to multiple first-line antibiotics started in the Sindh Province in Pakistan is a cause of concern in the management of typhoid fever. Recently, we experienced a case of XDR typhoid fever in a 4-year-old unvaccinated girl who contracted it during her visit to Pakistan in the summer of 2019, improved with meropenem and azithromycin. This is the first reported case of paediatric XDR typhoid diagnosed and treated in the UAE. Awareness of the on-going outbreak of XDR typhoid fever in Pakistan is very important for clinicians in the evaluation and management of febrile illnesses in a child with a history of travel to Pakistan.

Knowledge attitude and practices of doctors on drug resistant Typhoid and extreme drug resistance Typhoid in Karachi Pakistan

Background: Since November 2016, Pakistan has been facing an outbreak of XDR typhoid fever. 7529 Multiple Drug Resistant (MDR) typhoid fever cases were reported from Hyderabad and Karachi and the fever is showing resistance to third generation cephalosporin. Study aims to assess knowledge, attitude and practices of medical doctors on diagnosis and management of typhoid, XDR and MDR typhoid in the tertiary care hospitals of Karachi, Pakistan. Methods and materials: Mix method approach was use to conduct the knowledge attitude and practice survey. For quantitative part 321 doctors interviewed in four tertiary care hospitals between April to June 2019. All medical doctors provided consent and involved in prescribing the medication to doctors were included. In the qualitative part 12 IDIs and 4 focus group were conducted using a semi structured guide- to know doctor's perspective on patients compliance related to antibiotic prescription, DR salmonella and XDR salmonella, routine practices, influencing the decision about prescribing, acceptability and appropriateness of potential interventions. Quantitative data analysis was done on SPSS version 25 and results were presented on ratios and percentages. Qualitative data was analyzed manually based on thematic analysis. Results: Knowledge specific to XDR 85% respondent that infection is common in the country, 65% agreed that they have lack of knowledge on AMR to suspect cases. Antibiotics are overly prescribed by doctors (62%), its available over the counter (58%) and (57%) patient compliance to the treatment option were the most reported reasons to AMR in the survey. Azithromycin is the only drug of choice in both DR and XDR 58% and 48% respectively, very few (3.8%) recommending Carbapenes in XDR and no drug combination is using to treat XDR in all four hospital. In the in-depth discussion majority doctors stated that use of third-generation cephalosporin (in basic fever/flue condition), greatly limiting treatment options and Similar environments and approaches to treatment of typhoid fever, may be the reason of widespread typhoid fever. Conclusion: Considering XDR typhoid is increasing and warranted sense of urgency in the country, there is need to endorse National/Provincial Hospital based AMR prevention guidelines for doctors to reduce the burden of treatable diseases.

Adverse events following mass immunization with typhoid conjugate vaccine (Typbar TCV) at Hyderabad, Pakistan

Background: Hyderabad was facing world largest outbreak of XDR typhoid, more than 5000 cases of ceftriaxone sensitive and ceftriaxone resistant are reported from the district. Aga Khan University vaccinated children with Typbar TCV as control intervention among 6 months to 10 years old children. We aim to ascertain the Adverse Event following immunization AEFI associated with TCV as this is for the first time used in general population and lacks the population level data of AEFI. Only human challenge test and phase 1, 2, 3 trial data is available. Methods and materials: Community mobilizers visited each household to perform line listing and mobilize parents with age-eligible children. Children were brought to temporary vaccination centers and vaccinated. The AEFI ascertainment is by using Brighton collaboration 2005 criteria, trained staff for ascertainment of AEFI. Children were observed for 30 min post-vaccination. A 24/7 hotline number was provided to all parents/caretakers to report an AEFI. A subset of age-stratified 7139 children (6 month to 1 year, 1–2, 2–3, 3–4, 4–5, and 5–10years) was actively followed at days 7 and 14 for the ascertainment of AEFI. Results: Overall, 499 AEFI were observed during the campaign. 433/7139 (6.07%) were ascertained through active follow-ups during 14 days of vaccination and 66 (0.03%) were self-reported through the hotline. Fever was the most common AEFI self-reported through the hotline (38/199,861 = 0.02%) and observed during active follow-ups (206/7139 = 2.89%), followed by local reactogenicity (10/199,861 = 0.01% and 134/7139 = 1.88%, respectively). About half (244/499 = 49%) of total AEFI were fever, followed by local reactogenicity (29%) and diarrhea (7%). AEFI was significantly higher among children aged 6–12 month. and then it slowly decreases with an increase in age (p < 0.001). No serious AEFI was observed. Conclusion: Administration of a single dose of Typbar-TCV among children age 6mo to 10 years old during an outbreak setting of Hyderabad Pakistan was safe. No serious AEFI was observed among the vaccines. Fever is the most common AEFI, especially among young children.

Superficial Thrombophlebitis caused by Extensively Drug-resistant Salmonella Enterica Serovar Typhi

Salmonella enterica serovar typhi causes one of the most common blood stream infections, the typhoid fever. However, it can cause pyogenic infections involving different sites as well. Extensively drug resistant (XDR) strains of Salmonella typhi are resistant to all first line anti-typhoidal drugs (chloramphenicol, ampicillin and trimethoprim-sulfamethoxazole) as well as ciprofloxacin and ceftriaxone. XDR-strains were first reported from Pakistan in 2016, and since then the strains have been spreading. These XDR Salmonella cases not only pose a therapeutic challenge but also predispose to complications as a result of prolonged illness and delayed treatment. Here, we report a case of superficial thrombophlebitis at intravenous cannula site in a 49-year male, who was being treated for XDR-typhoid fever. To the best of our knowledge, thrombophlebitis of a superficial vein is an unusual complication of Salmonella typhi, not previously reported in literature. Key Words: Bacteremia, Thrombophlebitis, Extensively drug-resistant, Typhoid fever, Salmonella typhi.

Gastrointestinal and Hepatobiliary Complications of Extensively Drug-Resistant Typhoid at a Tertiary Care Hospital in Pakistan.

Introduction: Typhoid fever is a major health problem in developing countries. Extensively drug-resistant (XDR) typhoid is an emerging threat to world health. The objectives of this study were to report our blood culture proven patients having XDR typhoid and compare the rate of gastrointestinal (GI) and hepatobiliary manifestations and complications of antimicrobial sensitive and resistant strains.Materials and methods: This prospective observational study was carried out at a tertiary care hospital in Pakistan, from January 2019 till August 2020 on all consecutive blood culture proven patients of Salmonella typhi. A total of 57 cases of Salmonella were identified, of which 10 were nonresistant, seven multi drug-resistant (MDR), 39 extensively drug-resistant (XDR), and one was extended-spectrum beta lactamase (ESBL) positive. Alarmingly, one of the S. typhi isolate in addition to the first line drugs, was also resistant to azithromycin. Patients were treated with antibiotics according to antimicrobial susceptibility of the Salmonella in accordance with the World Health Organization (WHO) and Medical Microbiology and Infectious Diseases Society of Pakistan (MMIDSP) guidelines and GI and hepatobiliary complications were recorded.Results: Overall rate of complications was low. Some 10% (1/10) with nonresistant typhoid, 14% (1/7) with MDR, and 15% (6/39) of our patients with XDR typhoid fever had abdominal tenderness (p=0.95). None of the patients had GI bleeding, abdominal abscess, or peritonitis. Some 20% (2/10) patients with nonresistant typhoid, 29% (2/7) with MDR, and 18% (7/39) with XDR typhoid developed acute hepatitis, with greater than three times elevation of liver transaminases. There was no statistically significant difference in the occurrence of hepatitis between these groups (p=0.98). Interestingly, one of our patients with XDR typhoid also developed cholestatic hepatitis.Conclusion: There is no significant difference in GI and hepatobiliary complications amongst antimicrobial sensitive and resistant strains of typhoid. However, emergence of resistant strains calls for focus on prevention and judicious use of antimicrobials.

Response of extensively drug resistant Salmonella Typhi to treatment with meropenem and azithromycin, in Pakistan.

IntroductionSalmonella Typhi is one of the leading health problems in Pakistan. With the emergence of extensively drug resistant (XDR) Salmonella Typhi, treatment options are limited. Here we report the clinical manifestations and the response to treatment of patients with XDR Typhoid fever. The patients were treated with either Meropenem or Azithromycin or a combination of both.MethodsWe reviewed the records of culture confirmed XDR typhoid who visited Aga Khan University Hospital (AKUH), Karachi and Aga Khan Secondary Care Hospital, Hyderabad from April 2017 to June 2018. Symptoms developed during disease, unplanned treatment extension and complications developed while on antimicrobials was recorded. Means with standard deviation were calculated for duration of treatment, time to defervescence, and cost of treatment.ResultsRecords of 81 culture confirmed XDR typhoid patients admitted at the AKU hospitals were reviewed. Most, (n = 45; 56%) were male. Mean age of the cases was 8.03 years with range (1–40). About three quarter (n = 66) of the patients were treated as inpatient. Fever and vomiting were the most common symptoms at the time of presentation. Oral azithromycin alone (n = 22; 27%), intravenous meropenem alone (n = 20; 25%), or a combination of azithromycin and meropenem (n = 39; 48%) were the options used for treatment. Average (95% confidence interval) time to defervescence was 7.1(5.5–8.6), 6.7(4.7–8.7), and 6.7(5.5–7.9) days for each treatment option respectively whereas there were 1,0 and 3 treatment failures in each treatment option respectively. Average cost of treatment per day for azithromycin was US$5.87 whereas it was US$88.46 for meropenem.ConclusionPatients treated with either Azithromycin, Meropenem alone or in combination showed similar time to defervescence. Because of the lower cost of azithromycin, it is preferable in lower socio-economic areas. Background estimates for power calculation can be made for more robust clinical trials using this observational data.

X-DR (Drug Resistant) typhoid fever in children.

Objectives: To study antibiotic sensitivity pattern of Salmonella typhi in children with enteric fever. Study Design: Prospective, Consecutive sampling. Setting: Children Hospital and Institute of Child Health, Faisalabad. Period: 6 Months June 2019 to November 2019. Material &amp; Methods: All admitted children of age 1-16 years with strong clinical suspicion of typhoid fever and with no comorbidities were included in this study. Blood cultures and other relevant investigations were performed to rule out other causes of fever. After identification of organism as Salmonella typhi, antibiotics susceptibility testing was done by disk diffusion technique and zones of inhibition were interpreted according to clinical and Lab standard (CLSI) guidelines. Results: Out of 60 patients maximum children were &lt; 5 year and &gt;10 year of age. Maximum cases were admitted during July to September. Male to female ratio was 1.6:1. We were able to send blood cultures of 31 cases (51%) only. Out of them 14 cases (45%) were found culture positive. All culture positive (100%) were found sensitive to meropenem. 92.8% were found sensitive to azithromycin and 7.1% were found sensitive to amikacin. Overall 16 cases treated with meropenem, 10 cases (16%) with azithromycin and one with amikacin. However, 33 cases (55%) responded to ceftriaxone alone. Conclusion: Sensitivity pattern of Salmonella typhi revealed significant proportion of multidrug and extensive drug resistant strain. So, continue surveillance is needed in this regard to find actual burden of XDR typhoid fever. We recommend local district administration and health authorities to launch an awareness campaign regarding sanitation, good hygiene, use of safe of water and mass vaccination of children with conjugated vaccine against typhoid. Alongwith above measures antibiotic stewardship should be started.

Trends in antibiotic susceptibility of enteric fever isolates among children attending a tertiary care hospital of Peshawar, KP

Introduction: The rising trend of multi-drug resistance in bacteria has also been documented in the organism Salmonella enterica causing Typhoid or Enteric Fevers, and cases of multidrug and extended drug resistance are on the rise. Determining the trends of antibiotic susceptibility provides an important therapeutic aid to the practicing clinician.Objective: To evaluate the ten-year trends in antibiotic susceptibilities of Salmonella typhi and Salmonella paratyphi isolated from blood cultures in the paediatric patients of a tertiary care hospital of Peshawar, Khyber Pakhtunkhwa, Pakistan.Materials &amp; Methods: A descriptive study was conducted in the department of Paediatrics, Rehman Medical Institute, Peshawar from June 2019 to May 2020 based on ten years retrospective data of children with positive blood culture for Salmonella spp. Data were analyzed using IBM SPSS Statistics for Windows, Version 20.0 (IBM Corp., Armonk, NY). The level of significance was set at p ≤0.05.&#x0D; Results: A total of 168 cases Salmonella enterica spp. were isolated over the 10-year study period, of which 97(64.88%) isolates were identified as Salmonella typhi and 71(42.26%) as Salmonella paratyphi A; 94(55.95%) patients were male and 74(44.04%) were female, with mean age of 4.76 ± 2.65 years (range 2 to 12 years); majority, 69(41.07%) of patients were of ages 5-8 years. S. typhi strains showed the highest sensitivity to Imipenem and Meropenem; the lowest sensitivity seen was to Ampicillin. Bacterial sensitivity to Ceftriaxone was 79.76% and to Ciprofloxacin 58.97%. In the S. typhi group, there were six (2.6%) cases of MDR typhoid and four (2.38%) cases of XDR typhoid which was only sensitive to Imipenem.&#x0D; Conclusion: Increased resistance to Ampicillin, Ciprofloxacin and Ceftriaxone was found, however complete sensitivity was found to Imipenem along with Meropenem.

Frequency and Antimicrobial Resistance Pattern of Extensive-Drug Resistance Salmonella typhi Isolates

Objectives: Extensive drug resistance (XDR) typhoid fever, caused by resistance strain of Salmonella typhi, is an emerging public health concern in Pakistan. XDR typhoid fever severely limits the therapeutic options in outbreak cities of Pakistan. Antimicrobial resistance (AMR) surveillance has been carried out at study hospital in Karachi and here reporting the 15 months surveillance data. Methods: A cross-sectional study was conducted on 969 Salmonella typhi isolates obtained from the blood culture samples of suspected typhoid fever cases at Kharadar General Hospital (KGH) from Jan 2018 to Mar 2019. Isolates were tested against 8 antimicrobial agents by quality controlled disk diffusion technique. Salmonella typhi Isolates resistance to first- line drugs; ampicillin, chloramphenicol, and co-trimoxazole referred as Multi-drug resistant (MDR), Whereas first-line, second-line drug (Ciprofloxacin) and third generation Cephalosporin (Ceftriaxone) resistance were considered as XDR. Results: Of total 969 isolates, 777 (80%) were MDR showed resistance to all three first-line antibiotics and 517 (53%) were XDR resistant to five antibiotics (Ampicillin, Chloramphenicol, Co-trimoxazole, Ciprofloxacin and Ceftriaxone). Azithromycin and Imipenem were seen sensitive to all Salmonella typhi isolates (100%) among tested antibiotics. More than half of study S. typhi isolates 513 (53%) came from children under five years of age, among them 284 (55%) were XDR. Conclusions: A large proportion of S. typhi isolates showed XDR-ST strain. Only Azithromycin and Imipenem were sensitive against XDR-ST strain. Current limited antibiotic option poses a serious threat of complete antibiotic failure in future against rapidly changing strain of S. typhi. J Microbiol Infect Dis 2020; 10(2):68-74.

Update on Extensively Drug-Resistant Salmonella Serotype Typhi Infections Among Travelers to or from Pakistan and Report of Ceftriaxone-Resistant Salmonella Serotype Typhi Infections Among Travelers to Iraq - United States, 2018-2019.

Ceftriaxone-resistant Salmonella enterica serotype Typhi (Typhi), the bacterium that causes typhoid fever, is a growing public health threat. Extensively drug-resistant (XDR) Typhi is resistant to ceftriaxone and other antibiotics used for treatment, including ampicillin, chloramphenicol, ciprofloxacin, and trimethoprim-sulfamethoxazole (1). In March 2018, CDC began enhanced surveillance for ceftriaxone-resistant Typhi in response to an ongoing outbreak of XDR typhoid fever in Pakistan. CDC had previously reported the first five cases of XDR Typhi in the United States among patients who had spent time in Pakistan (2). These illnesses represented the first cases of ceftriaxone-resistant Typhi documented in the United States (3). This report provides an update on U.S. cases of XDR typhoid fever linked to Pakistan and describes a new, unrelated cluster of ceftriaxone-resistant Typhi infections linked to Iraq. Travelers to areas with endemic Typhi should receive typhoid vaccination before traveling and adhere to safe food and water precautions (4). Treatment of patients with typhoid fever should be guided by antimicrobial susceptibility testing whenever possible (5), and clinicians should consider travel history when selecting empiric therapy.

Heading towards threat of resistant super bug…. current pattern of antimicrobial sensitivity to salmonella typhi in Karachi.

Objectives: The present study was aimed to find out the prevalence of MDR and XDR Typhoid and the remaining or alternate treatment options here in Karachi. Study Design: Descriptive retrospective analytical study. Setting: Department of Medicine, at Mamji Hospital Karachi. Period: From Jan 2019 till July 2019. Material &amp; Methods: The medical records of all the patient admitted, were reviewed by the department of Medicine, at Mamjee Hospital Karachi specifically diagnosed to have Typhoid fever during the period between Jan 2019 till July 2019. A total of 72 patients were included in this study. Chart reviews were used to obtain and later collect the data. Typhoid was confirmed over Blood culture yielding Salmonella typhi. Demographic data and pattern of antibiotic sensitivity were collected. Statistical analysis was performed on SPSS version 17. Continuous variables were expressed as mean ± SD. Discrete variables were expressed as percentages and proportions. Results: From January 2019 till July 2019, 72 patients were diagnosed to have Typhoid fever (Salmonella Typhi culture positive) of which 43(60%) were male and majority of the patients were aged between 18 to 40 years 37(51%). Out of 14 antibiotics checked for sensitivity to Salmonella Typhi the Quinolones were the most resistant (85%) antibiotics followed by Ampicillin (83%) and Trimethoprim-sulfamethoxazole (82%). 48(66%) among 72 patients had extended drug resistant typhoid, 14(19%) were multidrug resistant typhoid while 11(15%) were pan sensitive. Conclusion: Majority of the patients had extended drug resistant typhoid, whereas quite a few had multidrug resistant typhoid. Most sensitive drugs were Imipenem, meropenem and Azithromycin whereas Quinolones along with other agents were found to have most resistance against Salmonella Typhi.

Extensively Drug-Resistant (XDR) Typhoid: Evolution, Prevention, and Its Management.

Typhoid fever is the result of a human host-restricted Salmonella enteric serotype typhi infection that causes enteric fever. Around 21 million people contract typhoid annually, with Pakistan's inhabitants at most risk amongst Asian countries where typhoid remains prevalent. Decades of indiscriminate antibiotic usage has driven the evolution of multidrug-resistant strains and more recently, extensively drug-resistant (XDR) strains of Salmonella enteric serotype typhi. Current reports of extensively drug-resistant typhoid fever outbreak in Pakistan are not only a major concern for Pakistan but also for health authorities worldwide: intercontinental transmission, spread, and replacement of native strains in neighboring countries and a major impediment to Pakistani health care management. The WHO records that there are 5274 cases of extensively drug-resistant (XDR) typhoid fever out of a total of 8188 total cases of typhoid fever reported in Pakistan. The last remaining feasible oral antibiotic that XDR typhoid remains susceptible to is azithromycin; this is a cause of major concern. Additionally, several cases of XDR typhoid fever have also been reported in patients travelling from Pakistan to the USA, UK, and Canada. This review article attempts to raise the issue of XDR typhoid with respect to its epidemiology, prevention, management, and future outlook and stresses a better understanding of antimicrobial stewardship and general surveillance of the disease. Although progress is being made to combat XDR typhoid locally, efficient, unified efforts on a national and international scale are required to contain the XDR outbreak before it is no longer manageable and leads us back to the preantibiotic era.

The first imported case of extensively drug-resistant Salmonella enterica serotype Typhi infection in Taiwan and the antimicrobial therapy.

The first imported case of XDR typhoid fever in Taiwan contracted with a bacterial strain, which was most closely related to the blaCTX-M-15-carrying strains linked to Pakistan. Meropenem, in combination with an antimicrobial with intracellular activity against Salmonella, should be used for the treatment of XDR typhoid fever.

Extended drug resistance in children with typhoid fever.

In developing countries, typhoid fever is mostly seen due to poor public health and low socioeconomic indices. Currently Pakistan is going through the largest outbreak of XDR typhoid fever which has resulted in increased morbidity and mortality especially in pediatric population. Objectives: To see the pattern of extended drug resistant typhoid fever in different areas of Karachi. Study Design: Cross sectional study. Setting: Department of pediatrics, Ziauddin Hospital (KDLB, NORTH, CLIFTON campus). Period: 6 months from October 2018 till March 2019. Material &amp; Methods: All patients who presented with history of fever for 3 or more days with signs and symptoms of typhoid fever were recruited. For data collection a self-structured questionnaire was used. Age, gender, socioeconomic status, personal hygiene, water supply and sanitation were taken into account. Blood samples were sent for cultures. Salmonella isolates were tested for antibiotic susceptibility. Tested antimicrobials were ampicillin, TMP/SMX, cefixime, ceftriaxone, aztreonam, ciprofloxacin, azithromycin, meropenem. For data analysis SPSS version 22 was used. Results: Out of 415 patients, 235 had culture proven typhoid fever. Salmonella typhi was isolated in 94.4%of the patients and salmonella paratyphi was isolated in 5.57%. Of the 235, Males were 62% and females were 42.4%. Major determinants associated with acquiring salmonella infection were young age (74%), male sex (62%), middle and low socioeconomic status (83.8%), living in west district of Karachi (54.9%) and drinking line water (79.2%). Extended drug resistance was encountered in 69.5%. Most of the isolates were sensitive to meropenem and azithromycin (96.7 %, and 95.5% respectively). Ceftriaxone resistance was prevelant in all three districts of Karachi (p value &lt;0.001), in different age groups 1-6yrs (98%), 7-12 yrs(91%), 13-18 yrs (100%) and in males(58%) predominantly. Conclusion: Karachi is facing an outbreak of XDR typhoid fever. Risk of acquiring extended drug resistant typhoid fever is increased in younger age group 1-6 yrs, males, west district of Karachi and poor socioeconomic status. Drinking unboiled water is identified as one of the major culprits. Actions should be taken at all health care levels to monitor the judicious use of antibiotics, and preventive strategies like safe water supply, improved sanitation along with typhoid vaccination are suggested to overcome this outbreak.

Antimicrobial Susceptibility Patterns of Salmonella Species in Southern Pakistan.

IntroductionTyphoid fever is a major infectious disease among the pediatric population of Pakistan. With inappropriate use of antibiotics and rising trends of multidrug-resistant (MDR) and extended drug-resistant (XDR) typhoid, it is becoming a public health emergency. This study evaluated the current trends in antibiotic susceptibilities to Salmonella (S) typhi and paratyphi A, B, and C in southern Pakistan.Materials and methodsThis cross-sectional study, conducted in the Pediatrics Department, Civil Hospital, Jamshoro from July to December 2018, included children with S. typhi and S. paratyphi A and B strains isolated from the laboratory-based culture of blood samples.ResultsThere were 223 (81.1%) children with S. typhi and 52 (18.9%) with S. paratyphi isolates. Their mean age was 5 ± 3 years. The most common age group with S. typhi strains was two to five years (n = 102; 37.1%). Previous trials of antibiotics were taken by 162 (58.9%) children; 65 (40.1%) of these were physician-prescribed. Cefixime was most commonly taken (66.6%), followed by ciprofloxacin (33.3%). Cefixime and ceftriaxone showed 60.9% and 65.8% sensitivity, respectively. Ciprofloxacin sensitivity was seen in 50.1% S. typhi isolates. There were six (2.6%) cases of MDR typhoid and two (0.9%) cases of XDR typhoid.ConclusionResistance to second-line antityphoid agents is increasing. Therefore, there is a need to modify prescribing behavior. The outbreak of XDR typhoid among children is an alarming public health concern for Pakistan. Widespread antibiotic stewardship programs must be conducted.

ANTIMICROBIAL RESISTANCE: UNIVERSAL EMERGENCY

Antimicrobial resistance (AMR) is a growing public health threat. Resistant microorganisms (i.e. bacteria, viruses and some parasites) through genetic mutations become too strong that they become resistant to the antimicrobials (i.e. antibiotics, antivirals and antimalarial) over the period.1 These microorganisms are present in our environment, spreading from one person to another and from animals to human beings.2 While a considerable burden of AMR is suspected, it is difficult to quantify mortality, disease load and economic loss related to AMR due to the absence of data in Southeast Asia.3 AMR causes prolonged illness, surplus tests, consumption of expensive drugs, intensive care, compromised surgeries, chemotherapy, disability and death. AMR can jeopardize the achievements of the Sustainable Development Goals (SDGs). Resistance is emerging and spreading globally. Many patients with Klebsiella pneumoniae had developed resistance against Carbapenem (last choice for the treatment of gram-negative bacteria) in all regions of the world. Patients with urinary tract infections caused by Escherichia coli are now resistant to fluoroquinolone. In at least 10 developed countries of the world, third generation Cephalosporins are ineffective against the treatment of gonorrhea. World Health Organization (WHO) does not recommend quinolones for the treatment of gonorrhea anymore and has updated treatment guidelines for chlamydial and syphilis infections. Staphylococcus aureus patients are resistant to first-line drug i.e. methicillin. Resistance to colistin, the last remedy for Enterobacteriaceae, has been detected. Alarmingly, extensively drug-resistant tuberculosis (XDR-TB) and multidrug-resistant tuberculosis (MDR-TB) are types of tuberculosis resistant to no less than four and two of the key anti-tuberculous drugs respectively have emerged. XDR-TB has been identified in 105 countries.4 About 480,000 new cases of MDR-TB have been estimated by WHO during 2014. In 2016, around 490,000 people developed MDR-TB worldwide. Five countries of the Greater Mekong are now resistant to the artemisinin-based combination therapies considered as first-line treatment for Plasmodium falciparum malaria since 2016. All Anti-Malarial treatment options for Plasmodium falciparum are now ineffective along the Cambodia-Thailand border. About 7% of patients in developing countries and 10-20% of patients from developed countries were estimated to have human immunodeficiency virus (HIV) resistant to antiretroviral therapy (ART) in 2010. Antiviral drugs i.e. matrix-2 (M2) inhibitors (Amantadine & Rimantadine) are now ineffective to treat the Influenza A virus. Outbreaks of multidrug resistance Typhoid and sporadic cases of infection with Ceftriaxone-resistant Salmonella typhi have been reported in several countries of the world. Recently Pakistan's first extensively drug-resistant (XDR) Salmonella typhi outbreak (resistant to all antibiotics for Typhoid) has created an emergency in the country. The ongoing outbreak had emerged in the district Hyderabad of Pakistan.5 In May 2018, the official case definitions were agreed by the Regional Disease Surveillance and Response Unit (RDSRU) in Karachi. Out of the 8,188 Typhoid cases, 5,274 cases of XDR were reported till December 2018. Among them 69% of the cases were reported from Karachi, 27% from Hyderabad and 4% from other districts of the Sindh province. Currently, Salmonella typhi in circulation is resistant to first, second as well as third generation Cephalosporins. Currently, azithromycin is the only remaining reliable and cost-effective first-line oral therapy to manage patients with XDR Typhoid in low-resource settings.The risk of XDR Salmonella typhi at the national level is considered high in Pakistan due to insufficient unsafe water supply systems, poor sanitation and hygiene (WASH) practices, poor infection control mechanisms, inappropriate food-handling, low vaccination coverage and limited surveillance of Typhoid fever. At the same time antibiotics are not being prescribed properly to the humans as well as animal sector. Furthermore, AMR confirmatory tests are available only at major laboratories and tertiary care hospitals. All these factors have reduced the ability to track the occurrence, spread and containment of XDR Salmonella typhi in Pakistan. Access to safe water, adequate sanitation, hospital sanitation and cleanliness, hygiene among food handlers, advocacy, social mobilization, sensitization of general practitioners/clinicians, Typhoid conjugate vaccination and development of new antibiotics are the most important recommendations for prevention of the AMR concerning XDR Salmonella Typhi in Pakistan.6-7 Besides, strengthening the surveillance to monitor known resistance, detect new and emerging trends is the need of the hour.

Emergence of an Extensively Drug-Resistant Salmonella enterica Serovar Typhi Clone Harboring a Promiscuous Plasmid Encoding Resistance to Fluoroquinolones and Third-Generation Cephalosporins.

ABSTRACTAntibiotic resistance is a major problem in Salmonella enterica serovar Typhi, the causative agent of typhoid. Multidrug-resistant (MDR) isolates are prevalent in parts of Asia and Africa and are often associated with the dominant H58 haplotype. Reduced susceptibility to fluoroquinolones is also widespread, and sporadic cases of resistance to third-generation cephalosporins or azithromycin have also been reported. Here, we report the first large-scale emergence and spread of a novel S. Typhi clone harboring resistance to three first-line drugs (chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole) as well as fluoroquinolones and third-generation cephalosporins in Sindh, Pakistan, which we classify as extensively drug resistant (XDR). Over 300 XDR typhoid cases have emerged in Sindh, Pakistan, since November 2016. Additionally, a single case of travel-associated XDR typhoid has recently been identified in the United Kingdom. Whole-genome sequencing of over 80 of the XDR isolates revealed remarkable genetic clonality and sequence conservation, identified a large number of resistance determinants, and showed that these isolates were of haplotype H58. The XDR S. Typhi clone encodes a chromosomally located resistance region and harbors a plasmid encoding additional resistance elements, including the blaCTX-M-15 extended-spectrum β-lactamase, and carrying the qnrS fluoroquinolone resistance gene. This antibiotic resistance-associated IncY plasmid exhibited high sequence identity to plasmids found in other enteric bacteria isolated from widely distributed geographic locations. This study highlights three concerning problems: the receding antibiotic arsenal for typhoid treatment, the ability of S. Typhi to transform from MDR to XDR in a single step by acquisition of a plasmid, and the ability of XDR clones to spread globally.