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Background: Enteric fever is caused by Salmonella enterica serovars Typhi (S. Typhi) and Paratyphi A, B, and C. It continues to be a significant cause of morbidity and mortality worldwide. In highly endemic areas, children are disproportionately affected, and antimicrobial resistance reduces therapeutic options. It is estimated that 2–5% of enteric fever patients develop chronic asymptomatic infection. These carriers may act as reservoirs of infection; therefore, the prospective identification and treatment of carriers are critical for long-term disease control. We aimed to find the frequency of Salmonella Typhi carriers in patients undergoing cholecystectomy. We also compared the detection limit of culturing versus qPCR in detecting S. Typhi, performed a geospatial analysis of the carriers identified using this study, and evaluated the accuracy of anti-Vi and anti-YncE in identifying chronic typhoid carriage. Methods: We performed a cross-sectional study in two centers in Pakistan. Gallbladder specimens were subjected to quantitative PCR (qPCR) and serum samples were analyzed for IgG against YncE and Vi by ELISA. We also mapped the residential location of those with a positive qPCR result. Findings: Out of 988 participants, 3.4% had qPCR-positive gallbladder samples (23 S. Typhi and 11 S. Paratyphi). Gallstones were more likely to be qPCR positive than bile and gallbladder tissue. Anti-Vi and YncE were significantly correlated (r = 0.78 p<0.0001) and elevated among carriers as compared to qPCR negative controls, except for anti-Vi response in Paratyphi A. But the discriminatory values of these antigens in identifying carriers from qPCR negative controls were low. Conclusion: The high prevalence of typhoid carriers observed in this study suggests that further studies are required to gain information that will help in controlling future typhoid outbreaks in a superior manner than they are currently being managed. Author summary: Enteric fever, caused by bacteria Salmonella Typhi or Paratyphi, is a serious global illness particularly affecting children in areas with inadequate hygiene and sanitation facilities. It is transmitted through the oral-fecal route. In Pakistan, prevalence of extensively drug resistant S. Typhi resistant strain further complicates its treatment. Some infected individuals develop chronic infections and become carriers of these pathogens. These asymptomatic carriers may potentially spread the disease by shedding the bacteria in urine or stool. To assess the frequency of the carrier state, we examined gallbladder specimens (bile, stones, and tissue) from patients who underwent gallbladder removal surgeries at Aga Khan University and Jinnah Post-graduate Medical Centre. We demonstrated that PCR had a higher sensitivity in detecting Salmonella carriage with a detection limit of 102 CFU/ml and identified 3.4% of typhoid carriers. Additionally, we investigated whether specific antibodies could identify these carriers using various serological tests. The results underscore the need for further research to promptly detect and appropriately treat this disease, thereby enhancing control and preventing future outbreaks. [ABSTRACT FROM AUTHOR]

Objective: To determine the current sensitivity patterns of Salmonella typhi in population of Khyber Pakhtunkhwa province of Pakistan. Materials and methods: This descriptive study was conducted in Lady Reading Hospital, Peshawar, Pakistan. A total of 388 blood culture-proven salmonella typhi patients were included in the study. Patients whose culture reported salmonella typhi or paratyphi and above sixteen year of age were included in the study and those whose culture reported any other organism were excluded. All samples reported salmonella typhi. Results: Among a total of 388 patients, 245 (63%) were male and 143 (37%) were female. The mean age was 28.61±14.87 years. Fever was the predominant symptom (99.5%), affecting mainly young patients (84%). Salmonella typhi showed 100% sensitivity to Imipenem and Meropenem, and 92% to azithromycin. S. typhi showed 95% resistance to ciprofloxacin, 92% to cefixime, and 86% to ceftriaxone. Multidrug-resistant (MDR) S. typhi was found in around 91.4% of blood cultures, whereas extended-drug-resistant (XDR) S. typhi was isolated from 91% of cultures. Conclusion: Our study showed high percentage of XDR and MDR Salmonella typhi which is an alarming situation, especially in younger population of the province. The carbapenems showed 100% sensitivity whereas the commonly used antibiotics, like Ciprofloxacin and Ceftriaxone were mostly ineffective in vitro. [ABSTRACT FROM AUTHOR]

Objective: The number of extremely drug-resistant (XDR) Salmonella typhi isolates is growing in the northwest of Pakistan, where health-care facilities are already under strain due to the coronavirus disease 2019 (COVID-19) issue. In Khyber Pakhtunkhwa, Pakistan, we currently describe the first widespread appearance of an XDR Salmonella typhi epidemic during the COVID-19 pandemic. This strain of Salmonella typhi is resistant to all first- and second-line drugs and even the third-generation cephalosporin. Methods: Salmonella species isolated from pediatric blood samples shown a high level of resistance to the various antibiotic classes evaluated between November and December 2020. Gender, age, address, and clinical symptoms were among the demographic information that was recorded. A total of 562 blood cultures from symptomatic patients have been collected by the Pathology Laboratory at a tertiary care institution of Rehman Medical Institute, Peshawar. All samples have been processed in accordance with regulatory requirements and incubated in BacT/ALERT 3D. Results: Of the 562 blood samples, 71 included Salmonella typhi, of which 66 (92.9%) and 5 (7%) were multidrug resistant (MDR) and XDR, respectively. Ciprofloxacin (100%), chloramphenicol (100%), ceftriaxone (100%), ampicillin (100%), and cotrimoxazole (93%) were completely resistant to all isolates. Azithromycin and carbapenems were effective against every Salmonella typhi isolate that was MDR or XDR. Males (76%) were more commonly affected than females (24%), and the frequency was substantially higher in children under 15 years of age (88%) than in adults (P = 0.0016). Conclusion: The emergence of XDR Salmonella typhi with a high level of resistance is in fact alarming. Due to the lack of viable treatment alternatives, the current situation necessitates the immediate implementation of efficient preventive measures, such as campaigns for typhoid vaccination and food and water safety. [ABSTRACT FROM AUTHOR]

Background: Salmonella meningitis is a rare but serious complication of Salmonella infection, primarily affecting infants, children, and immunocompromised individuals. Case presentation: We present a case of a two-and-a-half-year-old Asian boy who developed Salmonella meningitis along with pneumonia and respiratory failure. Initially, he experienced symptoms of loose motions, fever, and irritability, which progressed to neck stiffness and brisk reflexes. Cerebrospinal fluid (CSF) analysis confirmed Salmonella typhi in the CSF. Due to the worsening condition, the patient was admitted to the intensive care unit, intubated, and switched to meropenem as the antibiotic of choice after an initial empiric therapy with ceftriaxone and vancomycin. With appropriate treatment, the patient showed significant improvement, including resolution of fever and respiratory symptoms. Conclusion: Management of Salmonella meningitis is often challenging primarily because of the fact that the empiric therapy for meningitis may not always provide coverage to the multi-drug resistant Salmonella species found in South Asia. Prompt administration of appropriate antibiotics based on sensitivity testing is crucial for successful management. This case emphasizes the importance of early recognition and effective management of this uncommon yet severe complication of Salmonella infection. [ABSTRACT FROM AUTHOR]

Salmonella Typhi infection in a patient in Pakistan initially responded to standard treatment but failed to respond to subsequent treatment. The first strain was susceptible to carbapenems and azithromycin; subsequent strains harbored the NDM-5 gene. Treatment with a combination of intravenous meropenem and colistin was successful. Carbapenem-resistant Salmonella Typhi emergence will hinder treatment. [ABSTRACT FROM AUTHOR]

Objective: To assess the antibiotic resistance in enteric fever in our population. Study Design: Observation study. Setting: OPD and indoor patients in three tertiary care hospitals of Lahore. Period: May 2018 to September 2018. Material & Methods: We selected patients with symptoms and signs of enteric fever randomly in our out door and ER departments. Blood cultures were sent before start of any antibiotic. Patients with Positive culture were enrolled for this study. Results: We enrolled 180 patients, including 123 (68.3%) male patients and 57 (31.7%) were female patients. We divided these patients in three groups, below 25 years 38(21.1%) patients, from 26 to 50 years 98(54.4%), and above 50 years 44(24.4%) patients. Out of 180 patients 138(76.7%) patients took antibiotic before coming to us, 42 (23.3%) were naïve patients. We found 108 (60%) patient having quinolone resistance and 72 (40%) were sensitive to floroquinolones, 88 (48.9%) patients were cephalosporin resistant and 12 (6.7%) were macrolide resistant. We did not check the sensitivity of chloramphenicol, ampicillin and nalidixic acid as it is already proven resistance of these antibiotics. Among all patients quinolones resistance was much higher and resistance against cephalosporin is also increasing and few cases were found to be resistant to even macrolides, although resistance against macrolides is low up to now. Conclusion: Antibiotic resistance is gradually increasing rapidly even against those drugs which were proven very effective against salmonella typhi and paratyphi infections. Younger population (26-50years) had much more resistance than below 25 and above 50 years patients. Due to such prevalence of antibiotic resistance, few antibiotics are left for the treatment of enteric fever, which lead not only to high morbidity and mortality in these patients but a great financial burden for developing countries like Pakistan. Patients with positive blood culture of salmonella were included in this study. Patients with other causes of fever, malaria, Tb, respiratory infections, and with negative blood culture. [ABSTRACT FROM AUTHOR]

Background Extensively drug-resistant (XDR) typhoid fever is a threat to travelers to Pakistan. We describe a multicontinental case series of travel-acquired XDR typhoid fever to demonstrate the global spread of the problem and encourage preventive interventions as well as appropriate empiric antimicrobial use. Methods Cases were extracted from the GeoSentinel database, microbiologic laboratory records of two large hospitals in Toronto, Canada, and by invitation to TropNet sites. All isolates were confirmed XDR Salmonella enterica serovar Typhi (Salmonella typhi), with resistance to ampicillin, ceftriaxone, ciprofloxacin and trimethoprim–sulfamethoxazole. Results Seventeen cases were identified in Canada (10), USA (2), Spain (2), Italy (1), Australia (1) and Norway (1). Patients under 18 years represented 71% (12/17) of cases, and all patients travelled to Pakistan to visit friends or relatives. Only one patient is known to have been vaccinated. Predominant symptoms were fever, abdominal pain, vomiting and diarrhoea. Antimicrobial therapy was started on Day 1 of presentation in 75% (12/16) of patients, and transition to a carbapenem or azithromycin occurred a median of 2 days after blood culture was drawn. Antimicrobial susceptibilities were consistent with the XDR S. typhi phenotype, and whole genome sequencing on three isolates confirmed their belonging to the XDR variant of the H58 clade. Conclusions XDR typhoid fever is a particular risk for travelers to Pakistan, and empiric use of a carbapenem or azithromycin should be considered. Pre-travel typhoid vaccination and counseling are necessary and urgent interventions, especially for visiting friends and relatives travelers. Ongoing sentinel surveillance of XDR typhoid fever is needed to understand changing epidemiology. [ABSTRACT FROM AUTHOR]

Objective: To identify demographic patterns and etiologies of CNS infections and to identify the clinical presentations, diagnostic accuracy, and clinical outcomes of various CNS infections in hospitalized patients in a tertiary care hospital. Study Design: Cross sectional study. Place and Duration of Study: Pak Emirates Military Hospital, Rawalpindi Pakistan, from Oct 2019 to Jun 2020. Methodology: A total of 97 adult patients presenting with clinical features of Central Nervous System (CNS) infection were enrolled for this in-hospital study. Cerebrospinal fluid (CSF) was collected for a routine examination, bacterial culture, and viral Polymerase Chain Reaction (PCR) test. Human Immunodeficiency Virus (HIV) serology and neuroimaging were done in all cases. The diagnosis was established based on World Health Organization guidelines for infectious diseases. Infections were classified into four major categories for analysis purposes. Results: Of 97 enrolled patients, the mean age was 38.8±18.5 years. CNS tuberculosis was the most common infection seen in 46(47.4%) cases, 25(25.7%) patients had viral encephalitis, and 17(17.5%) had bacterial meningitis. The rest of the patients (n=9) had fungal (3%) or parasitic infections (4%). In contrast, two patients were found to have focal cerebritis, one due to Brucella and the other due to Salmonella typhi. Conclusion: Tuberculosis is the most common (CNS infection in this region. First, patients with CNS infections, especially chronic ones, present very late in our setting, leading to increased morbidity and mortality. Secondly, Molecular diagnosis is obtainable in only a small percentage of cases for various reasons. [ABSTRACT FROM AUTHOR]

Medicinal plant Fagonia cretica L., is well known in traditional medicines for curing various complaints of human beings from ancient times and is locally known as Dhamasa. Previous many studies have reported the presence of many phytochemicals, antimicrobial, and antioxidant properties in the various parts of this plant. Therefore, here in this study, we have presented a comprehensive study on the presence of similar medicinal and chemical properties of Dhamsa found in Jamshoro District, Pakistan. For this study, extracts of the root, stem, leaf, and pod of the plant were prepared separately from three different solvents, water, ethanol, and methanol. Then the amount and presence of various phytochemicals, antimicrobial, antioxidant properties, and allelopathic effects were determined in all the extracts. The obtained results of this study confirm the presence of medicinal important phytochemicals in the plant extracts. The antimicrobial testing of this plant proved its highest activity against E. coli (16 ±1.4mm), Salmonella typhi (18±0.7mm), and Pseudomonas aeruginosa (15±1.4mm) in methanol, water, and ethanol extracts respectively. The presence of antioxidant activities was also observed in the ethanolic extract of the leaf at about 0.98 mg/ml. While this plant showed allelopathic effects on the growth of radish and spinach plants. So, we have concluded this study that Fagonia cretica L., collected from Jamshoro has the same or more important properties compared to the same plant from other regions, which proves the similar significant value of the Fagonia cretica plant of Jamshoro in various fields of medicinal sciences. [ABSTRACT FROM AUTHOR]

Background: Taxus wallichiana is an evergreen tree species found in the Himalayan region of Pakistan. The tree possesses important secondary metabolites such as Taxol that has been implicated in treating breast, ovarian and colon cancer. Therefore keeping in view the importance of this plant species, silver nanoparticles were synthesized using Taxus wallichiana aqueous leaf extract and evaluated for their anti-bacterial and anti-cancer properties. Methods: Silver (Ag) nanoparticles (NPs) were characterized for their optical, morphological and structural features using techniques such as UV-visible spectroscopy, X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM) and energy dispersive X-ray (EDX) and were evaluated for their antibacterial activity and anti-cancer activity using U251 cell line. Results: The study showed that the UV-absorbance peak of Ag2O NPs at 450 nm shifted to 410 nm, affirming the formation of leaf extract Ag NPs. Similarly structural studies revealed the crystalline nature of the cubic structure of the Ag crystal with an average crystallite size of 29 nm. FTIR analysis exhibited the existence of different functional elements including O-H and N-H and phenolic groups. Non-spherical glomerular shaped Taxus wallichiana Ag NPs were observed from SEM studies and EDX profile showed Ag as the main element along with constituent of biological origin. The synthesized Ag NPs showed significant antibacterial activity against Salmonella typhi, and Staphylococcus aureus. The cytotoxic activity of Ag NPs on U251 brain cancer cells showed a synergistic effect with 10 ug/mL concentration after 48 and 72 h incubation based on cell viability assay indicating promising glioblastoma drug potential. [ABSTRACT FROM AUTHOR]

Introduction: Antibiotic resistance has become a significant problem in typhoid fever due to the emergence of extensively drug resistant (XDR) Salmonella enterica serovar typhi. In Pakistan, an outbreak of ceftriaxone-resistant typhoid was first reported in November 2016. Methods: A retrospective chart review was conducted at Liaquat National Hospital and Medical University, in Karachi, Pakistan. Patient records were identified from the microbiology laboratory data of all admitted patients who had blood culture positive for XDR Salmonella typhi from January 2017 to December 2019. Results: Out of 254 patients, 179 (70%) were male with an average age of 11.7 ± 10.9 years. Around 190 (74%) patients were treated with combination therapy, 126 (49%) were given azithromycin and meropenem and 61 (24%) received azithromycin and imipenem. A total of 64 (25%) patients received single drug therapy, 33 (12%) were given azithromycin, 23 (9%) meropenem, and 8 (3%) imipenem. Analysis indicated that single drug therapy resulted in an earlier onset of defervescence compared with combination therapy (5.03± 2.98 days vs 3.45± 2.48 days; P < 0.001), with a decreased occurrence of pancytopenia (P < 0.001). Conclusion: Single antimicrobial therapy achieved defervescence earlier than combination therapy, with carbapenems performing better than azithromycin. [ABSTRACT FROM AUTHOR]

Salmonella enterica serotype Typhi (S Typhi) associated urinary tract infections are exceedingly rare, accounting for less than 1% of cases. Such infections have known to occur in immune-compromised or individuals with urogenital structural abnormalities. With the emergence of extensively drug resistant S Typhi strains in Pakistan, the management of its various unique presentations poses therapeutic challenges. We report the first documented case of a 74 years old male patient presenting with relapsed urinary tract infection secondary to extensively drug resistant S Typhi. [ABSTRACT FROM AUTHOR]

Background: This study aimed to assess the longevity of serologic response and seroconversion rates at several time points following TCV vaccination among children living with HIV aged 6 months to 15 years in Pakistan., Methods: From November 20, 2020, to January 2, 2021; 336 children were enrolled and followed up prospectively for 12 months. Blood samples were collected before the administration of TCV and at 4-6 weeks, 6 months, and 1 year after administration of a single dose (0.5 ml) of intramuscular Typbar TCV®. Samples were analyzed for anti-Vi-IgG antibodies using ELISA. Geometric mean titers (GMTs), seroconversion rates (fourfold rise in anti-Vi-IgG from baseline) were assessed, and factors associated with sustained seroconversion at 1 year were evaluated using generalized linear mixed models., Findings: The seroconversion rates were significantly lower in children aged 6 months to 5 years compared to children > 5 years; (127/216 (58·8%)) versus (81/111 (73·0%)) at 6 months and (110/217 (50·7%)) versus (78/109 (71·6%)) at 1 year, only two-third; 188/326 (57·7%) remained seroconverted at 1 year. The GMTs (95 % CI) were significantly lower in children aged 6 months to 5 years compared to children > 5 years, 9·6 (7·6, 12·0) versus 28·9 (20·2, 41·4) at 6 months, and 6·6 (5·4, 8·0) versus 23·1 (16·4, 32·5) at 1 year time point. The odds of sustained seroconversion significantly decreased with time (adjusted odds ratio (aOR): 0.23; 95 % CI: 0.14, 0.40). The odds of sustained seroconversion following 1 year of TCV vaccination were significantly higher among children with non-severe HIV clinical disease (aOR: 10·61; 95% CI: 1·52, 73·98) and children in elder age group (aOR: 7·45; 95% CI: 1·18, 47·03)., Conclusions: A significant decrease in seroconversion rates was observed among children living with HIV following one year of TCV administration. The decline was significantly higher in children with severe or advanced HIV clinical disease and children younger than five years of age., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: To investigate and document the clinical course of typhoid fever and the sensitivity pattern of Salmonella typhi to antibiotics among patients admitted to Pakistan Naval Ship Shifa Hospital. Study Design: Cross-sectional study. Place and Duration of Study: Pakistan Naval Ship Shifa Hospital, from Jul to Dec 2021. Methodology: The patients admitted with typhoid fever to the hospital during the study period were included using consecutive sampling. After getting informed consent, the patients' demographic characteristics, course of the disease, blood culture sensitivity, the treatment administered, the complications that emerged, and the length of their hospital stay were noted. Results: There were 77 patients with culture-proven typhoid fever admitted during the study period. The mean age was 18.6±11.84 years (range 1-55 years). The most frequent presenting complaints were fever, abdominal pain, and vomiting. Additional symptoms included a rash, bodily aches, and weariness. Out of the 77 patients, 76(99%) were extensively drugresistant (sensitive to Meropenem and Azithromycin only). The complications noted were hepatitis, myocarditis, ascites, pleural effusion, and shock. The mean length of stay in the hospital was 16.56+3.87 days. The typical time gap between commencing culture-specific antibiotics and fever defervescence was 4.03±2.84 days. Conclusion: Almost all (99%) patients admitted with typhoid fever in PNS Shifa are extensively drug-resistant and require a relatively longer hospital stay for management. [ABSTRACT FROM AUTHOR]

Objective: To determine the variations in minimal inhibitory concentrations (MIC) of Azithromycin amongst Salmonella typhi isolates. Study Design: Cross-sectional study. Place and Duration of Study: Department of Microbiology, Combined Military Hospital, Lahore Pakistan, from Jan to Dec 2020. Methodology: Three hundred and eighty-four samples yielding the growth of Salmonella typhi were processed. Antibiotic susceptibility testing was done using the Kirby-Bauer Disk Diffusion technique, and the MIC of Azithromycin was determined using the E-strip method. Clinical and Laboratory Standards Institute (CLSI) recommended that MIC breakpoints be used for susceptibility testing of Azithromycin. Results: Of 384 tested isolates, 103(26.8%) were multidrug-resistant (MDR). Resistance to Ciprofloxacin was as high as 367(95.6%) isolates, whereas extensively drug-resistant (XDR) isolates were calculated to be 204(53.1%). No resistance against Azithromycin was observed. All the isolates were in the susceptible MIC range of 0.5 and 8 µg/ml. The lowest MIC observed was 0.5 µg/ml by 12(5%) of the isolates. The highest MIC value of 8 µg/ml was observed in 6(1.5%) isolates, all of which were XDR. 231(60.2%) isolates had one µg/ml MIC, followed by MIC 4 µg/ml of 72(18.8%) isolates. The mean MIC value of all the isolates was calculated to be 1.82±1.3µg/ml. Conclusion: The rise in XDR Salmonella typhi could lead to Azithromycin resistance. Antimicrobial stewardship is of prime importance, and Azithromycin MICs should be reported to keep the trends in check. [ABSTRACT FROM AUTHOR]

Aims: Antibiotic resistance is a major problem in Salmonella enterica serovar Typhi. The objective of this study was to evaluate the prevalence of XDR Salmonella among local population of Lahore and genotyping of isolates for antibiotic‐resistant genes. Methods and Results: A total of 200 blood samples from suspected typhoid fever patients were collected. One hundred and fifty‐seven bacterial samples were confirmed as Salmonella Typhi and 23 samples were confirmed as Salmonella Paratyphi after biochemical, serological and PCR based molecular characterization. Antibiogram analysis classified 121 (67·2%) Salmonella isolates as MDR and 62 isolates (34·4%) as XDR. The predominant resistance gene was ampC with 47·7% prevalence, followed by gyrA, catA1, tet(A), aac (3)‐la, qnrS, blaNDM‐1 and blaCTX‐M‐15 genes in 45·5, 40, 21·6, 18·3, 11·6, 2·2 and 0·5% isolates respectively. Sequence analysis showed the presence of sul1 and dfrA7 gene cassette arrays in 12 class 1 integron integrase positive isolates. Conclusion: Large number of clinical XDR S. Typhi‐resistant against third generation cephalosporins have been reported. Significance and Impact of the Study: The current study highlights the possible emergence of clinical XDR S. Typhi cases in Lahore, Pakistan. Potential attribution of phenotypic and genotypic XDR cases may help to contribute targeted therapy. [ABSTRACT FROM AUTHOR]

Objective: To determine the molecular strain typing and drug resistance pattern of Salmonella enterica serovar Typhi prevalent in Northwest Pakistan. Methodology: A total of 2,138 blood samples of suspected typhoid patients from Northwest Pakistan were collected followed by identification of Salmonella Typhi through biochemical, serological, and species-specific fliC-d gene amplification. These isolates were typed by variable-number tandem repeat (VNTR) profiling and investigated for drug resistance. Results: The overall prevalence of Salmonella Typhi was found to be 8.8% (n = 189). Thirty different VNTR strain types of Salmonella Typhi were detected and the most prevalent strain types were T1 and T4, whereas T27 was less prevalent strain. Among the 189 isolates 175 (92.5%) isolates were multidrug resistant, whereas 12 (5.8%) isolates were extensively drug resistant. Resistance to imipenem in Salmonella Typhi was not observed. Most of the isolates have genes encoding for resistance to fluoroquinolones, including gyrA (n = 164), gyrB (n = 160), parC (n = 164), parE (n = 160), ac(6′)-ib-cr (n = 163), qnrS (n = 15), and qnrB (n = 3). Similarly, chloramphinicol (cat; n = 147), azithromycin (msrA; n = 3), and co-trimoxazole (dfrA7; n = 145) resistance genes were detected among Salmonella Typhi isolates. Conclusion: In this study, T1 and T4 type Salmonella Typhi strains were predominantly prevalent in Northwest Pakistan. Antibiotic resistance among Salmonella Typhi isolates were observed. Findings of the study would be helpful to devise an appropriate antibiotic policy to control the emergence of drug-resistant Salmonella Typhi in Pakistan. [ABSTRACT FROM AUTHOR]

The disease burden of typhoid fever remains high in endemic areas in Asia and Africa, especially in children. Recent clinical trials conducted by the Typhoid Vaccine Acceleration Consortium show typhoid conjugate vaccine (TCV) to be safe, immunogenic, and efficacious at preventing blood culture-confirmed typhoid fever in African and Asian children. Pakistan, Liberia, and Zimbabwe recently introduced TCV through campaigns and routine childhood immunizations, providing protection for this vulnerable population. It is essential to continue this momentum while simultaneously filling data gaps-including typhoid complications-to inform decision-making on TCV introduction. A multidisciplinary approach including surveillance, water, sanitation, and hygiene investments, and large-scale TCV introduction is needed to decrease the burden and mortality of typhoid fever. [ABSTRACT FROM AUTHOR]

Background: In 2018 Pakistan initiated its national antimicrobial resistance (AMR) surveillance aligned with Global Antimicrobial Surveillance System (GLASS). To complement this surveillance, we conducted a situational analysis of AMR rates among GLASS organisms in the country. Data from published studies and from antibiograms was compared and role of antibiograms as potential contributors to national AMR surveillance explored.Methods: AMR rates for GLASS specified pathogen/antimicrobials combination from Pakistan were reviewed. Data sources included published studies (2006-2018) providing AMR rates from Pakistan (n = 54) as well as antibiograms (2011-2018) available on the Pakistan Antimicrobial Resistance Network (PARN) website. Resistance rates were categorized as follows: Very low: 0-10%, Low: 11-30%, Moderate: 30-50% and High: > 50%.Results: Published data from hospital and community/laboratory-based studies report resistance rates of > 50% and 30-50% respectively to 3rd generation cephalosporins, fluoroquinolones and cotrimoxazole amongst Klebsiella pneumoniae and Escherichia coli. Carbapenem resistance rates amongst these organisms remained below 30%. High (> 50%) resistance was reported in Acinetobacter species to aminoglycosides and carbapenems among hospitalized patients. The evolution of ceftriaxone resistant Salmonella Typhi and Shigella species is reported. The data showed > 50% to fluoroquinolones amongst Neisseria gonorrhoeae and the spread of methicillin resistant Staphylococcus aureus (< 30%; 2008) to (> 50%; 2010) in hospital settings. Resistance reported in published studies aligned well with antibiogram data. The latter also captured a clear picture of evolution of resistance over the study period.Conclusion: Both published studies as well antibiograms suggest high rates of AMR in Pakistan. Antibiogram data demonstrating steady increase in AMR highlight its potential role towards supplementing national AMR surveillance efforts particularly in settings where reach of national surveillance may be limited. [ABSTRACT FROM AUTHOR]

Objective: To provide a laboratory-based surveillance report of typhoid fever cases diagnosed at a tertiary care hospital in Lahore during the ongoing outbreak. Study Design: Cross-sectional study. Place and Duration of Study: Department of Microbiology, Combined Military Hospital, Lahore Pakistan, from Mar 2018 to Jun 2019. Methodology: All positive blood culture samples that yielded the growth of Salmonella Typhi were included in the study. The samples were dealt with according to standard microbiological procedures. Antimicrobial susceptibility was performed using Clinical and Laboratory Standards Institute (CLSI) guidelines. Results: During the study period, (377) Typhoidal Salmonellae were isolated, of which 327 (86.7%) were Salmonella Typhi and 50 (13.3%) were Paratyphi A. The percentage of XDR Salmonella isolates was 41.9%. Conclusion: Extensively drug-resistant typhoid fever cases reported in this study represent just the tip of an iceberg. Therefore, nationwide surveillance efforts must be undertaken along with implementing effective preventive measures. [ABSTRACT FROM AUTHOR]

• This is the first study to provide estimates of TCV effectiveness in XDR typhoid outbreak setting. • The study showed single intra-muscular shot of TCV is effective against XDR typhoid in children. • The results are encouraging for the sustained use of TCV in typhoid-endemic countries. Enteric fever, caused by Salmonella Typhi and S. Paratyphi, is a cause of high morbidity and mortality among children in South Asia. Rising antimicrobial resistance presents an additional challenge. Typhoid Conjugate Vaccines (TCV) are recommended by the World Health Organization for use among people 6 months to 45 years old living in endemic settings. This study aimed to assess the effectiveness of TCV against culture-confirmed S. Typhi in Lyari Town, Karachi, Pakistan. This peri-urban town was one of the worst affected by the outbreak of extensively drug resistant (XDR) typhoid that started in November 2016. A matched case-control study was conducted following a mass immunization campaign with TCV at three key hospitals in Lyari Town Karachi, Pakistan. Children aged 6 months to 15 years presenting with culture-confirmed S. Typhi were enrolled as cases. For each case, at least 1 age-matched hospital control and two age-matched community controls were enrolled. Adjusted odds ratios with 95% confidence intervals (CIs) were calculated using conditional logistic regression. Of 82 typhoid fever patients enrolled from August 2019 through December 2019, 8 (9·8%) had received vaccine for typhoid. Of the 164 community controls and 82 hospital controls enrolled, 38 (23·2%) community controls and 27 (32·9%) hospital controls were vaccinated for typhoid. The age and sex-adjusted vaccine effectiveness was found to be 72% (95% CI: 34% − 88%). The consumption of meals prepared outside home more than once per month (adjusted odds ratio: 3·72, 95% CI: 1·55- 8·94; p-value: 0·003) was associated with the development of culture-confirmed typhoid. A single dose of TCV is effective against culture confirmed typhoid among children aged 6 months to 15 years old in an XDR typhoid outbreak setting of a peri-urban community in Karachi, Pakistan. [ABSTRACT FROM AUTHOR]

Recent reports have established the emergence and dissemination of extensively drug resistant (XDR) H58 Salmonella Typhi clone in Pakistan. In India where typhoid fever is endemic, only sporadic cases of ceftriaxone resistant S. Typhi are reported. This study aimed at elucidating the phylogenetic evolutionary framework of ceftriaxone resistant S. Typhi isolates from India to predict their potential dissemination. Five ceftriaxone resistant S. Typhi isolates from three tertiary care hospitals in India were sequenced on an Ion Torrent Personal Genome Machine (PGM). A core genome single-nucleotide-polymorphism (SNP) based phylogeny of the isolates in comparison to the global collection of MDR and XDR S. Typhi isolates was built. Two of five isolates were additionally sequenced using Oxford Nanopore MinION to completely characterize the plasmid and understand its transmission dynamics within Enterobacteriaceae. Comparative genomic analysis and detailed plasmid characterization indicate that while in Pakistan (4.3.1 lineage I) the XDR trait is associated with bla CTX-M-15 gene on IncY plasmid, in India (4.3.1 lineage II), the ceftriaxone resistance is due to short term persistence of resistance plasmids such as IncX3 (bla SHV-12) or IncN (bla T EM-1B + bla DHA-1). Considering the selection pressure exerted by the extensive use of ceftriaxone in India, there are potential risks for the occurrence of plasmid transmission events in the predominant H58 lineages. Therefore, continuous monitoring of S. Typhi lineages carrying plasmid-mediated cephalosporin resistant genes is vital not just for India but also globally. • S. Typhi to develop cephalosporin resistance by acquiring diverse plasmids from other Enterobacteriaceae. • Independent acquisition of drug-resistant plasmids such as IncX3 and IncN with genes encoding beta-lactamases in H58 lineage II of S. Typhi. • A short-term persistence of drug-resistant plasmids in H58 lineage II can be the reason for the sporadic cases cephalosporin resistant S. Typhi in India. • Plasmid acquisition and maintenance of cephalosporin resistant S. Typhi appears to be specific to the phylogenetic lineage. • Critical strategies in monitoring and control of cephalosporin resistant S. Typhi is needed to tackle further public health crisis. [ABSTRACT FROM AUTHOR]

Background: There are approximately 300 cases of enteric fever reported annually from England and Wales; most are imported infections. Clinical management of enteric fever remains a challenge with the emergence of ESBL-producing strains, especially XDR Salmonella Typhi from Sindh, Pakistan.Methods: All strains of S. Typhi and Salmonella Paratyphi A isolated from cases presenting with symptoms of enteric fever in England and Wales, between 1 April 2014 and 31 March 2020, were characterized using WGS. Antibiotic susceptibility testing was performed using an agar dilution method.Results: ESBL strains contributed to 69 cases of enteric fever (S. Typhi n = 68, S. Paratyphi A n = 1); 68 were imported (Pakistan n = 64, Iraq n = 2, Bangladesh n = 1 and India n = 1). Ages ranged from 1 to 56 years, 36/69 (52%) were children, 52% were female and the duration of hospital stay ranged from 1 to 23 days. The ESBL phenotype was conferred by the presence of blaCTX-M-15 (S. Typhi n = 67 and S. Paratyphi A n = 1) or blaCTX-M-55 (S. Typhi n = 1). An IncY plasmid harbouring blaCTX-M-15 and qnr was detected in 56 strains from Pakistan. The IncY plasmid was absent in the remaining strains and there was evidence of a 4 kb ISEcpl-blaCTX-M-15-tnp gene cassette insertion into the chromosome at one of three integration points.Conclusions: Chromosomal integration of blaCTX-M-15 within the XDR Sindh strains may lead to the maintenance of resistance in the absence of antibiotic selection pressure. Empirical treatment of cases of complicated enteric fever returning from Pakistan will henceforth have to include a carbapenem. [ABSTRACT FROM AUTHOR]

Introduction: Typhoid fever remains a problem in developing countries, including Pakistan. The emergence of multidrug-resistant and, since 2016, of extensively drug-resistant cases is a continuous challenge for health care workers. The COVID-19 pandemic is making management more difficult. Methodology: In the present study, a total of 52 confirmed cases of typhoid have been studied during 2019. Detailed clinical features, complications and, lab findings were studied. Typhoid culture and sensitivity were recorded and patients were treated accordingly. Patients were asked about risk factors to aim at informing prevention. Results: Out of the 52 having blood culture positive for Salmonella Typhi 47 (90.4%) and Salmonella Paratyphi 5 (9.6%), 4 (7.7%) were sensitive to first-line (Non-resistant), 11 (21.2%) MDR and 37 (71.2%) patient were XDR. One case was resistant to azithromycin. Nausea, vomiting or, abdominal pain was present in 12 (23%), abdominal distension present in 9 (17.3%), abdominal tenderness in 8 (15.4%), hepatomegaly in 10 (19.2%) and, splenomegaly in 22 (42.3%). There were ultrasound abnormalities in 58% of patients and GI complications in 19% of patients. No significant difference was found in clinical findings and complications between resistant and non-resistant cases. Only 23-27% of patients were aware of typhoid prevention and vaccination measures. Conclusions: The increasing prevalence of resistance and higher degree of complications seen in typhoid fever raises the concern further about prevention and effective infection management in the community as well as clinical settings. Moreover, judicial use of antibiotics is much needed in developing countries like Pakistan. [ABSTRACT FROM AUTHOR]

Rationale for review: Enteric fever (EF) caused by Salmonella enterica subspecies enterica serovar Typhi (Salmonella Typhi) and S. Paratyphi (Salmonella Paratyphi) remains an important cause of infectious morbidity and mortality in many low-income countries and, therefore, still poses a major infectious risk for travellers to endemic countries. Main findings: Although the global burden of EF has decreased over the past two decades, prevalence of EF remains high in Asia and Africa, with the highest prevalence reported from the Indian subcontinent. These statistics are mirrored by data on travel-related EF. Widespread and increasing antimicrobial resistance has narrowed treatment options for travel-related EF. Ceftriaxone- and azithromycin-based therapies are commonly used, even with the emergence of extremely drug-resistant typhoid in Pakistan. Preventive measures among locals and travellers include provision of safe food and water and vaccination. Food and water precautions offer limited protection, and the efficacy of Salmonella Typhi vaccines is only moderate signifying the need for travellers to be extra cautious. Recommendations: Improvement in the diagnosis of typhoid with high degree of clinical suspicion, better diagnostic assays, early and accurate detection of resistance, therapy with appropriate drugs, improvements in hygiene and sanitation with provision of safe drinking water in endemic areas and vaccination among travellers as well as in the endemic population are keys to controlling typhoid. While typhoid vaccines are recommended for travellers to high-risk areas, moderate efficacy and inability to protect against Salmonella Paratyphi are limitations to bear in mind. Improved Salmonella Typhi vaccines and vaccines against Salmonella Paratyphi A are required. [ABSTRACT FROM AUTHOR]

Salmonella enterica serovar Typhi (S. Typhi) is one of the typhoidal Salmonellae that causes typhoid fever. We report the first case of an XDR S. Typhi in a suspected case of Endocarditis with Aortic Valve Replacement and deranged INR. The identification was carried out by an automated system. The antibiogram was performed according to CLSI recommendations. The XDR S. Typhi isolates were found resistant to Azithromycin. Although XDR S. Typhi has been reported in our country and elsewhere, however, till to date no complete resistant isolate of S. Typhi to Azithromycin has been reported in Pakistan. The patient had a smooth recovery on intravenous meropenem. The case highlights the importance of the acquisition of resistance to the last line antibiotics in S. Typhi in our country and is of concern to infectious disease specialists to ensure infection control to avoid its spread. [ABSTRACT FROM AUTHOR]

Typhoid fever is a major public health problem since November 2016 in developing countries, which also includes Pakistan. During the COVID-19 pandemic, a surge has been seen in the expression of extensively drug-resistant (XDR) typhoid due to poor sanitary disposal in hospitals and at other public places. The XDR strain of Salmonella typhi is still vulnerable to azithromycin, but its extensive use for the treatment might impede its effectiveness against XDR soon. And if azithromycin does develop resistance it will lead to life-threatening issues in more than 15% of untreated patients and the death toll will increase. Fighting COVID-19 and XDR simultaneously is a huge burden on the health system of Pakistan and can crush its backbone if the issue is not addressed properly at the national level thus awareness about the severity of the issue along with its management needs to reach the masses. [ABSTRACT FROM AUTHOR]

Introduction: Salmonella Typhi continues to be a significant global public health concern. The objective of this study was to evaluate the literature pertaining to S. Typhi in lower-middle-income countries from 1990 to April 31, 2023., Methodology: The bibliographic data was collected from the Web of Science database. Various bibliometric tools were utilized to conduct bibliometric analysis and visualization. Numerous bibliometric parameters were assessed, including the top publishing organizations, countries, institutions, authors, journals with the highest publication output, citation counts, commonly used keywords, and emerging research topics., Results: The current study included a total of 4,031 articles. These articles exhibited an annual growth rate of 8.17%. Over the past 33 years, there has been a gradual increase in the overall quantity of articles. On average, these articles received 18.82 citations. A total of 13,987 authors from 3,665 affiliations and 118 countries contributed to these publications. The majority of publications originated from India (50.31%), Pakistan (15.40%), Nigeria (6.32%), Bangladesh (5.03%), and Iran (4.89%). Among the institutions, Oxford University published the highest number of articles (302), followed by the University of Karachi (124). The frequently used keywords included "Salmonella Typhi" (frequency = 231), "antimicrobial activity" (frequency = 191), and "resistance" (frequency = 190)., Conclusions: The findings of this study can serve as a foundation for future studies, enabling researchers to identify knowledge gaps and areas for further investigation. The data can also aid in health planning, providing insights into the current research landscape and highlighting priority areas for intervention and resource allocation., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2024 Mustafa S Şahinoğlu, Sevil Alkan.)

Background: Typhoid fever, caused by Salmonella enterica serovar Typhi, is a significant public health concern due to the escalating of antimicrobial resistance (AMR), with limited treatment options for extensively drug-resistant (XDR) S. Typhi strains pose a serious threat to disease management and control. This study aimed to investigate the genomic characteristics, epidemiology and AMR genes of XDR S. Typhi strains from typhoid fever patients in Pakistan., Methodology: We assessed 200 patients with enteric fever symptoms, confirming 65 S. Typhi cases through culturing and biochemical tests. Subsequent antimicrobial susceptibility testing revealed 40 cases of extensively drug-resistant (XDR) and 25 cases of multi-drug resistance (MDR). Thirteen XDR strains were selected for whole-genome sequencing, to analyze their sequence type, phylogenetics, resistance genes, pathogenicity islands, and plasmid sequences using variety of data analysis resources. Pangenome analysis was conducted for 140 XDR strains, including thirteen in-house and 127 strains reported from other regions of Pakistan, to assess their genetic diversity and functional annotation., Results: MLST analysis classified all isolates as sequence type 1 (ST-1) with 4.3.1.1. P1 genotype characterization. Prophage and Salmonella Pathogenicity Island (SPI) analysis identified intact prophages and eight SPIs involved in Salmonella's invasion and replication within host cells. Genome data analysis revealed numerous AMR genes including dfrA7, sul1, qnrS1, TEM-1, Cat1, and CTX-M-15, and SNPs associated with antibiotics resistance. IncY, IncQ1, pMAC, and pAbTS2 plasmids, conferring antimicrobial resistance, were detected in a few XDR S. Typhi strains. Phylogenetic analysis inferred a close epidemiological linkage among XDR strains from different regions of Pakistan. Pangenome was noted closed among these strains and functional annotation highlighted genes related to metabolism and pathogenesis., Conclusion: This study revealed a uniform genotypic background among XDR S. Typhi strains in Pakistan, signifying a persistence transmission of a single, highly antibiotic-resistant clone. The closed pan-genome observed underscores limited genetic diversity and highlights the importance of genomic surveillance for combating drug-resistant typhoid infections., Competing Interests: Declaration of competing interest The authors declare that no competing financial interests/ personal relationships exist in relevancy to the above-subject submitted manuscript. Acknowledgement The authors acknowledge the support of the Research Center for Advanced Materials Science (RCAMS) at King Khalid University Abha, Saudi Arabia, for research grant RCAMS/KKU/024/23., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background Typhoid fever is caused by Salmonella enterica subspecies enterica serovar Typhi (S. Typhi) and can lead to systemic illness and complications. We aimed to characterize typhoid-related ileal perforation in the context of the population-based Surveillance of Enteric Fever in Asia Project (SEAP) in Bangladesh, Nepal and Pakistan. Methods Between September 2016 and September 2019, all cases of nontraumatic ileal perforation with a clinical diagnosis of typhoid were enrolled from 4 tertiary care hospitals in Karachi, 2 pediatric hospitals in Bangladesh, and 2 hospitals in Nepal. Sociodemographic data were collected from patients or their caregivers, and clinical and outcome data were retrieved from medical records. Tissue samples were collected for histopathology and blood cultures where available. Results Of the 249 enrolled cases, 2 from Bangladesh, 5 from Nepal and 242 from Pakistan. In Pakistan, most of the cases were in the 0–15 (117/242; 48%) and 16–30 (89/242; 37%) age groups. In all countries, males were most affected: Pakistan 74.9% (180/242), Nepal 80% (4/5), and Bangladesh 100% (2/2). Blood culture was done on 76 cases; 8 (11%) were positive for S. Typhi, and all were extensively drug resistant (XDR) S. Typhi. Tissue cultures was done on 86 patients; 3 (3%) were positive for S. Typhi, and all were XDR S. Typhi, out of 86 samples tested for histopathology 4 (5%) revealed ileal perforation with necrosis. Culture or histopathology confirmed total 15 (11%) enteric fever cases with ileal perforation are similar to the clinically diagnosed cases. There were 16/242 (7%) deaths from Pakistan. Cases of ileal perforation who survived were more likely to have sought care before visiting the sentinel hospital (P =.009), visited any hospital for treatment (P =.013) compared to those who survived. Conclusions Although surveillance differed substantially by country, one reason for the higher number of ileal perforation cases in Pakistan could be the circulation of XDR strain of S. Typhi in Karachi. [ABSTRACT FROM AUTHOR]

Background The Surveillance for Enteric Fever in Asia Project (SEAP) is a multicenter, multicountry study conducted in Pakistan, Nepal, and Bangladesh. The objectives of the study were to characterize disease incidence among patients with enteric fever. We report the burden of enteric fever at selected sites of Karachi, Pakistan. Methods During September 2016 to September 2019, prospective surveillance was conducted at inpatient, outpatient, surgical departments, and laboratory networks of Aga Khan University Hospital, Kharadar General Hospital, and surgery units of National Institute of Child Health and Jinnah Postgraduate Medical Centre. Socio-demographic, clinical, and laboratory data were obtained from all suspected or confirmed enteric fever cases. Results Overall, 22% (2230/10 094) of patients enrolled were culture-positive for enteric fever. 94% (2093/2230) of isolates were Salmonella Typhi and 6% (137/2230) were S. Paratyphi. 15% of isolates multi-drug resistant (MDR) to first-line antibiotics and 60% were extensively drug-resistant (XDR), resistant to first-line antibiotics, fluoroquinolones and third generation cephalosporin. Conclusion Enteric fever cases have increased during the last 3 years with large proportion of drug resistant S. Typhi cases. However, the burden of paratyphoid is still relatively low. Strengthening the existing surveillance system for enteric fever and antimicrobial resistance at the national level is recommended in Pakistan to inform prevention measures. While typhoid vaccination can significantly decrease the burden of typhoid and may also impact antimicrobial resistance, water, sanitation, and hygiene improvement is highly recommended to prevent the spread of enteric fever. [ABSTRACT FROM AUTHOR]

Enteric fever remains a public health concern in communities lacking sanitation infrastructure to separate sewage from drinking water. To bridge the gap until large-scale civil-engineering projects are implemented in high-burden countries, typhoid conjugate vaccine presents a promising disease-prevention technology. A new typhoid conjugate vaccine was prequalified by the World Health Organization in 2017 and is beginning to be introduced in countries around the world. To help inform vaccine introduction, the Surveillance for Enteric Fever in Asia Project (SEAP) conducts prospective enteric fever surveillance in Bangladesh, Nepal, and Pakistan. This supplement presents findings from Phase II of the study (2016–2019) on burden of disease, clinical presentation, the growing spread of drug-resistant strains, and policy and economic ramifications. These findings are delivered to support policymakers in their deliberations on strategies to introduce typhoid conjugate vaccine as a preventive tool against enteric fever. [ABSTRACT FROM AUTHOR]

Introduction: Salmonella 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. Methods: We 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. Results: Records 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. Conclusion: Patients 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. Author summary: Ever since the emergence of Extensively Drug Resistant (XDR) Typhoid fever in Pakistan, which is resistant to all but two classes of anti-microbials, we need to find an effective treatment plan so that S.Typhi does not also make these anti-microbials redundant in the future. In this retrospective case series review, we observed the response of XDR Typhoid fever patients treated with meropenem or azithromycin or combination of both. All 3 groups showed a similar therapeutic response based on number of complications developed and time taken for fever clearance. The higher price of meropenem however could become a deterrent to its use in poor socio-economic areas. This new knowledge may contribute to better treatment plans in handling XDR enteric fever in the future whilst also serving as a rough guide in how to treat patients with XDR Typhoid fever in the present. [ABSTRACT FROM AUTHOR]

The arise of drug-resistant pathogens is persistent in the control of pathogens. Several effective drugs have their roots in natural products, which have a traditional use in different diseases. To authenticate the efficacy of these traditional medicines, we selected the gastrointestinal tract infection as a target disease. Two plants Withania coagulans and Ehretia obtusifolia, were selected on the bases of their usage in folk medicine for the gastrointestinal tract complications. The bacteria selected were Escherichia coli, Shigella dysenteriae, Salmonella typhi, Pseudomonas aeruginosa, Vibrio cholera and Aeromonas spp. The crude extracts and fractions at three concentrations (15, 30, and 50 mg/ml) were tested for effectiveness against E. coli, S. dysenteriae, V. cholrea, S. typhi, P. aeruginosa and Aeromonas spp. The results show that the Ehretia obtusifolia has good activity against all test bacteria except S. dysenteriae while W. coagulans had activity against all the test bacteria. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• Post licensure safety data of Typbar-TCV® is not available from a population wide campaign setting. • 207,000 doses of Typbar-TCV were administered in a campaign setting of Hyderabad, Pakistan. • No death, disability or hospitalization associated with Typbar-TCV during 14 days of vaccination was observed. • Fever and local reactogenicity were the frequently observed adverse events. Pakistan is facing the world's largest outbreak of extensively drug-resistant (XDR) Typhoid. Vaccination campaign for children aged 6 months to 10 years old with Typhoid Conjugate Vaccine (Typbar-TCV®) was conducted in high-risk areas of Hyderabad during 2018. About 207,000 children were vaccinated. Here we report the adverse events following immunization (AEFI) during the campaign. The campaign was carried out using outreach and fixed centre strategy. Community mobilizers visited each household to perform line listing and mobilize parents with age-eligible children. Children were observed for 30 min post-vaccination. Two-pronged strategy was used for ascertainment of AEFI. A 24/7 hotline number was provided to all parents/caretakers (n = 199,861) to report AEFI during 14 days following immunization. An age-stratified (n = 7139 children) were actively followed at days 7 and 14 for the ascertainment of AEFI. All AEFI were examined by three trained medical officers. A structured questionnaire using Brighton collaboration criteria with level 3 diagnostic certainty was used for the recording of AEFI. Data were analysed using Microsoft Excel Office 365. Overall, 499 AEFI (433 in the subset actively followed and 66 self-reported through hotline) were observed. The rate of AEFI was significantly higher among very young children (age group 6 to 12 months) as compared to 2 to 3 years old children (0.54% vs. 0.33% respectively; p-value < 0.001). Fever was the most common AEFI self-reported through the hotline (38/199,861 = 0.02%) and among the subset followed actively for 14 days (206/7139 = 2.89%). Fever was followed by local reactogenicity 10/199,861(0.01%), and 134/7139 (1.88%) through self-reported hotline and active follow-up, respectively. No serious AEFI was observed. Administration of a single dose of Typbar-TCV among children aged 6 months to 10 years old during an outbreak setting of Hyderabad Pakistan was safe. [ABSTRACT FROM AUTHOR]

Introduction: The multidrug-resistant (MDR) Salmonella enterica serovar Typhi isolates have been increasingly reported from the Asian and African countries. The emergence of isolates with decreased susceptibility to fluoroquinolones and cephalosporins has worsened the situation. Recently, an outbreak from Sindh, Pakistan was reported caused by extensively drug-resistant (XDR) S. Typhi strains. Methodology: In the present study, a total of 82 cases of typhoid have been investigated during 2018 from the febrile children referred to a tertiary care hospital in the population-wise largest province (Punjab) of Pakistan. S. Typhi was identified by standard microbiological techniques and isolates were characterized for antimicrobial resistance profiling and minimum inhibitory concentrations were determined. The presence of various ESBL genes in S. Typhi was confirmed by the PCR. Results: Out of the 82 isolates tested, 35 (43%) were found to be XDR; resistant to the first-line drugs. The resistance to third-generation cephalosporins was mainly mediated by extended-spectrum beta-lactamases i.e. blaTEM and blaCTX-M genes. Conclusions: The higher prevalence of ESBL producing Salmonella typhi clinical strains raises the concern about transmission prevention and infection management in the community as well as clinical settings. Moreover, the study highlights the problem concerning the declining antibiotic arsenal for the therapeutic management of typhoid fever and the emergence and spread of XDR strains in Pakistan. [ABSTRACT FROM AUTHOR]

We present a case of sigmoid volvulus in a young male patient with culture-proven Salmonella Typhi in the blood which was sensitive to Meropenem and Azithromycin only, presented with fever, vomiting, loose stools, hematochezia, abdominal distention and tenderness with no signs of perforation on erect chest x-ray. Further, radiological imaging showed signs of sigmoid volvulus. An urgent colonic decompression with untwisting of the mesentery was performed. In our case, it can be said that sigmoid volvulus was developed as a complication of multiple drug-resistant strains of Salmonella Typhi. The resistance is acquired by alteration in the genome sequence. Currently, it is important to control such an unknown outbreak of multiple drug-resistant strains of Salmonella Typhi as it is a serious health care issue of disease control and prevention in Pakistan. [ABSTRACT FROM AUTHOR]

Untapped environments have been considered as potential resources of novel actinobacteria to combat multidrug resistance. The present study relates with isolation and characterization of potential antibiotic-producing soil actinobacterial diversity of district Khairpur Mir's, Pakistan. The soil actinobacteria from eighteen different soil samples were isolated on starch casein agar and preliminarily identified based on morpho-microscopic and biochemical characteristics. Four in vitro screening approaches viz. cross streak method and lawn method (primary screening) and agar-well diffusion and disc-diffusion method (secondary screening) were used to test antimicrobial potential of the isolated actinobacteria. The panel of test bacterial strains consisted of six multidrug-resistant (MDR) bacterial pathogens of clinical origin including; Staphylococcus aureus, Staphylococcus haemolyticus, Escherichia coli, Salmonella typhi, Enterobacter spp. and Pseudomonas aeruginosa. Total twenty-six (26) different actinobacterial strains were isolated and characterized. Moreover, 11/26(42.3%) actinobacteria isolates displayed broad-spectrum antagonistic activity against all the test bacterial strains. Based on significant antagonistic activity, the isolate B3d was selected and further identified using 16S rRNA genotyping as Streptomyces thermolilacinus. To the best of our knowledge, this is the first report on any S. thermolilacinus strain exhibiting significant broad-spectrum antagonistic activities against MDR pathogens that could serve as candidate for novel drug discovery. Therefore, exploration of more untapped resources is strongly needed for isolating novel actinobacterial species capable of biosynthesizing novel drug leads to combat MDR bacteria. [ABSTRACT FROM AUTHOR]

Background: With the rise in fluoroquinolone-resistant Salmonella Typhi and the recent emergence of ceftriaxone resistance, azithromycin is one of the last oral drugs available against typhoid for which resistance is uncommon. Its increasing use, specifically in light of the ongoing outbreak of extensively drug-resistant (XDR) Salmonella Typhi (resistant to chloramphenicol, ampicillin, cotrimoxazole, streptomycin, fluoroquinolones and third-generation cephalosporins) in Pakistan, places selective pressure for the emergence and spread of azithromycin-resistant isolates. However, little is known about azithromycin resistance in Salmonella, and no molecular data are available on its mechanism. Methods and findings: We conducted typhoid surveillance in the two largest pediatric hospitals of Bangladesh from 2009–2016. All typhoidal Salmonella strains were screened for azithromycin resistance using disc diffusion and resistance was confirmed using E-tests. In total, we identified 1,082 Salmonella Typhi and Paratyphi A strains; among these, 13 strains (12 Typhi, 1 Paratyphi A) were azithromycin-resistant (MIC range: 32–64 μg/ml) with the first case observed in 2013. We sequenced the resistant strains, but no molecular basis of macrolide resistance was identified by the currently available antimicrobial resistance prediction tools. A whole genome SNP tree, made using RAxML, showed that the 12 Typhi resistant strains clustered together within the 4.3.1.1 sub-clade (H58 lineage 1). We found a non-synonymous single-point mutation exclusively in these 12 strains in the gene encoding AcrB, an efflux pump that removes small molecules from bacterial cells. The mutation changed the conserved amino acid arginine (R) at position 717 to a glutamine (Q). To test the role of R717Q present in azithromycin-resistant strains, we cloned acrB from azithromycin-resistant and sensitive strains, expressed them in E. coli, Typhi and Paratyphi A strains and tested their azithromycin susceptibility. Expression of AcrB-R717Q in E. coli and Typhi strains increased the minimum inhibitory concentration (MIC) for azithromycin by 11- and 3-fold respectively. The azithromycin-resistant Paratyphi A strain also contained a mutation at R717 (R717L), whose introduction in E. coli and Paratyphi A strains increased MIC by 7- and 3-fold respectively, confirming the role of R717 mutations in conferring azithromycin resistance. Conclusions: This report confirms 12 azithromycin-resistant Salmonella Typhi strains and one Paratyphi A strain. The molecular basis of this resistance is one mutation in the AcrB protein at position 717. This is the first report demonstrating the impact of this non-synonymous mutation in conferring macrolide resistance in a clinical setting. With increasing azithromycin use, strains with R717 mutations may spread and be acquired by XDR strains. An azithromycin-resistant XDR strain would shift enteric fever treatment from outpatient departments, where patients are currently treated with oral azithromycin, to inpatient departments to be treated with injectable antibiotics like carbapenems, thereby further burdening already struggling health systems in endemic regions. Moreover, with the dearth of novel antimicrobials in the horizon, we risk losing our primary defense against widespread mortality from typhoid. In addition to rolling out the WHO prequalified typhoid conjugate vaccine in endemic areas to decrease the risk of pan-resistant Salmonella Typhi strains, it is also imperative to implement antimicrobial stewardship and water sanitation and hygiene intervention to decrease the overall burden of enteric fever. Author summary: With the outbreak of extensively resistant (XDR) typhoid fever in Pakistan, azithromycin has become the last oral drug to treat typhoid. Although no azithromycin resistant XDR isolate has been reported to date, the increasing use of azithromycin and the clear historical record of widespread dissemination of resistance to all previously widely used antimicrobials by typhoidal Salmonella, suggest we will soon face strains resistant to all oral antibiotics. This makes it imperative to elucidate the mechanism of azithromycin resistance in typhoidal Salmonella. We tested 1,082 typhoidal Salmonella isolates from the two largest pediatric hospitals of Bangladesh and identified 13 azithromycin-resistant isolates. Using comparative genomics, we identified a mutation in a specific protein called AcrB that makes these isolates resistant to azithromycin. All azithromycin-resistant strains were susceptible to cephalosporin but resistant to all other oral antibiotics. The Pakistan outbreak strain is resistant to all common oral antibiotics and only susceptible to azithromycin. Acquisition of the plasmid that confers cephalosporin resistance in XDR strains by the Bangladeshi azithromycin-resistant strains or rise of the AcrB mutation in the XDR strains could be the end of oral treatment for typhoid. This poses serious threats to the health system of LMICs where typhoid is endemic. Currently, the majority of typhoid patients are prescribed oral treatment in the outpatient department, but an azithromycin-resistant XDR strain would shift enteric fever treatment from outpatient departments to inpatient departments to be treated with injectable antibiotics like carbapenems, further burdening already struggling health systems in endemic regions. Moreover, with the dearth of novel antimicrobials in the horizon, we risk losing our primary defense against widespread mortality from enteric fever. [ABSTRACT FROM AUTHOR]

The aim of this study is to see the frequency, clinical presentation, and therapeutic response of extensively drug-resistant Salmonella enterica serovar Typhi and current susceptibility pattern of typhoidal Salmonella strains in our setup. This study was carried out at the Department of Medical Microbiology and Immunology and Department of Medicine, Pakistan Navy Ship (PNS) Shifa Hospital, Karachi, from January 1 to December 31, 2018. All the blood culture samples of patients (indoor and outdoor) with suspicion of enteric fever were processed. Isolates were cultured and identified using standard microbiological procedures. The antimicrobial sensitivity against the typhoidal Salmonellae was determined using Kirby-Bauer disc diffusion method as per the guidelines of Clinical and Laboratory Standards Institute (2018) and all the extensively drug-resistant (XDR) isolates were confirmed by Vitek 2 system. Clinical presentation and response to treatment of patients were followed. A total of 292 typhoidal Salmonella isolates were cultured. Resistance to ciprofloxacin against both Salmonella Typhi and Salmonella Paratyphi A was found to be very high (91%). Percentage of multidrug-resistant (MDR) isolates in Salmonella Typhi was 76% (182 isolates) and in Salmonella Paratyphi it was 34% (18 isolates). XDR isolates in Salmonella Typhi were significant that is 48% (115 isolates). Only 10 cases were given azithromycin who responded to treatment in mean 4.3 days. Out of 115 cases of XDR Salmonella Typhi, 103 patients were given parenteral meropenem and clinical response was seen in mean 5 days. The emergence and rapid spread of extensively drug-resistant Salmonella Typhi is alarming and highlights the significance of strict antimicrobial susceptibility surveillance programs with antimicrobial stewardship. [ABSTRACT FROM AUTHOR]

Typhoid fever, caused by the bacterium Salmonella typhi, is an often-fatal illness prevalent in Africa and South Asia. The illness has seen an alarming rise in multi-drug-resistant (MDR) and extensive drug-resistant (XDR) strains, particularly in Pakistan. The MDR strain links to the H58 haplotype, and its XDR variant exhibits fluoroquinolone resistance due to an IncY plasmid. The increasing prevalence of these resistant strains is concerning, given the global antimicrobial resistance (AMR) issue. Causes include misuse of antibiotics in self-limiting infections and an unregulated drug market. Pakistan's Sindh province first reported the XDR typhoid strain, highlighting the urgent need to investigate the relationship between AMR development and external factors. This narrative review intends to scrutinize the state of AMR in Pakistan, considering illicit drug sales, healthcare worker education gaps, and self-medication behaviors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To evaluate the activity of Methylglyoxal against the blood culture isolates of Salmonella Typhi and various Gram negative rods and to compare the activity of Methylglyoxal against S. Typhi and other Gram negative rods. Methods: It was an experimental study conducted at the Department of Microbiology, University of Health Sciences (UHS), Lahore-Pakistan in collaboration with the Department of Microbiology, CMH Lahore, from July 2011 to June 2012. Recent blood culture isolates of S. Typhi and other Gram negative rods were collected from different hospitals of Lahore and kept stored at -80°C. As per the latest CLSI guidelines, morphological, biochemical and serological identification was carried out and antimicrobial susceptibility was tested. A multi-point inoculator was used to carry out agar dilution for determination of MICs of MGO. Results were determined after compilation of data using latest SPSS version. Results: MIC90 of MGO against the clinical isolates of S. Typhi was 0.20 mg/mL (2.8 mM) and against Gram negative rods it was 0.21 mg/mL (3.0 mM). The p-value of MICs of MGO against the isolates of S. Typhi was 0.023 when compared with Gram negative rods (p<0.05; statistically significant). Conclusion: MGO has a scientifically proven in vitro antimicrobial activity against blood culture isolates of S. Typhi and various Gram negative rods. [ABSTRACT FROM AUTHOR]

Introduction: Typhoid fever, a bacterial disease caused by Salmonella typhi (S. typhi) remains a major health problem in the Asian sub-continent due to poor hygienic conditions. Aim: Our aim was to determine the prevalence of Typhoid fever among the general population of district Lower Dir, Pakistan in order to describe the disease occurrence and distribution. Material and methods: This was a descriptive-epidemiological study. 1076 subjects were enrolled; with presentation of common symptoms of typhoid at the Fazal-Rahim Clinical Laboratory as inclusion criteria. Typhidot test was performed for all participants. Data were analyzed using Chi-square test and P-values less than 0.05 were considered significant. PHStat software was used for statistical analyses. Results and discussion: The study comprised of 414 males and 662 females; 37.26% of total cases were found positive. Females (62.64%) were more affected compared to males (37.4%). Furthermore, the IgM antibodies were detected in 353 (88.02%) patients while IgG antibodies were present in only 48 (19.98%). Age group 20-40 years recorded the highest incidence of cases 242 (60.34%); also March recorded the highest incidence of cases 67 (50.38%). Overall, typhoid is a common disease in the local population of Lower Dir, it is dominant in females with the highest burden recorded in the economically-productive age group 20-40 years. Conclusions: Further studies are recommended to determine the antibiotic susceptibility pattern; there is need to launch effective programmes for the eradication of the disease and promote safe drinking water and food through public enlightenment and education. [ABSTRACT FROM AUTHOR]

• Green synthesis of AgNPs from roots of important medicinal plants of Pakistan. • Well defined morphology, uniform, spherical size distribution of synthesized AgNP. • Dose dependent relationship of AgNPs and inhibition of pathogenic bacterial strains. • AgNPs with root extracts synergistically improved the antibacterial potential. • The synthesized AgNPs could be used in pharmaceutical and homeopathic industry. In the past few years, biologically synthesized silver nanoparticles (AgNPs) have been standout amongst the most utilized nanoparticles both in the field of therapeutics and clinical practices. Therefore, the current study aimed to synthesize AgNPs for the first time using aqueous root extracts of important plants of Pakistan i.e. Bergenia ciliata, Bergenia stracheyi, Rumex dantatus and Rumex hastatus and characterize them. In addition, antibacterial activity of synthesized AgNPs at 30–150 μg/well was assessed using well diffusion method against Staphylococcus aureus, Staphylococcus haemolyticus , Bacillus cereus, Escherichia coli , Salmonella typhi and Pseudomonas aeruginosa bacterial strains that are considered most harmful bacteria for human beings. The characterization of synthesized AgNPs showed the absorption maxima ranged from 434 to 451 nm and XRD confirmed the crystalline nature of AgNPs as well as FTIR elucidated the involvement of biomolecules for reduction and capping of AgNPs. SEM determined the average size of AgNPs ranging from 25 to 73 nm and strong signals of silver were captured in EDX images. The result of antibacterial activity showed that only aqueous root extracts of all selected plants were inactive against all the tested bacterial strains. However, importantly, direct relationship between zone of inhibition of S. aureus, S. typhi and P. aeruginosa was found with increasing concentration of AgNPs of each selected plant. Moreover, S. haemolyticus was only inhibited by R. hastatus based AgNPs at only high concentrations and E. coli was inhibited by R. dantatus and R. hastatus based AgNPs. However, B. cereus was not inhibited by any AgNPs except R. hastatus and R. hastatus based AgNPs have greater antibacterial potential among all the synthesized AgNPs. These results suggest that synthesized AgNPs have improved antibacterial potential of root extracts of each selected plant and these synthesized AgNPs could be used in pharmaceutical and homeopathic industry for the cure of human diseases. [ABSTRACT FROM AUTHOR]