Knowledge, Attitude, and Practices (KAPS) of the Inhabitants of Punjab, Pakistan toward XDR Typhoid Outbreak During COVID-19

Background Typhoid fever, caused by the bacterium Salmonella typhi , is the most prevalent in areas that have poor hygienic conditions. The most alarming situation is the development of the resistant strains of Salmonella typhi, first reported in 2016 in Hyderabad, Sindh. Later, there was a widespread outbreak of extensively drug-resistant (XDR) typhoid. This survey aims to investigate the risk factors for the spread of XDR typhoid in Pakistan based on the knowledge, attitude, and practices (KAPs) of the affected or at-risk population to help plan preventive actions. Method For this purpose, a community-based random KAP study was conducted in Punjab, Pakistan. Data was collected online and also by face-to-face interaction from those who had no access to the Internet. Result More than half of the respondents were aware of the fact that bacteria is the causative agent (60.6%) of XDR. Similarly, with regard to practice, it was found that 67.7% of them washed their hands before eating and 88.8% washed their hands after using the toilet. A common practice in the form of using filtered water for drinking purposes was adhered to by 73.8% of respondents. Conclusion The study concluded that preventative and control measures are necessary to avoid XDR typhoid pandemic spread.


Highlights
• Pakistani population lacks awareness about the XDR typhoid outbreak amidst the challenges of COVID-19.
• Inadequate preventive measures and treatment were practiced during the XDR typhoid outbreak that occurred during the COVID-19 pandemic.

INTRODUCTION
Salmonella enterica serovar Typhi is the agent that causes typhoid fever [1].The bacterium has an incubation period of 3-30 days.Its symptoms include progressive onset of fever, loss of appetite, headache, abdominal discomfort, and constipation followed by malaise, dry cough, diarrhea, rash, and bradycardia [2].The bacterium is frequently present in poor hygienic and sanitary conditions, marked with a short supply of clean water, poor hand-washing practices, intake of unsafe foods, and close contact with cases or carriers [3].Infection is transmitted through the fecal-oral route by contaminated water or food; humans are the only identified reservoir [4].S. typhi can only be treated successfully with antibiotics [5].
Currently, the development of a resistant strain of S. typhi is a major threat to efficiently controlling typhoid fever in Pakistan.Multiple drug-resistant (MDR) strains of S. typhi show resistance to all of the first line antibiotics suggested by the WHO, namely chloramphenicol, trimethoprim-sulfamethoxazole, and ampicillin.According to a study conducted at Agha Khan University in Karachi, Pakistan between 2001 and 2006, the prevalence of MDR S. typhi strains increased from 34.2% to 48.5% during the said period, while quinolone resistance increased from 1.6% to 64.1% [6].Following the development of a fluoroquinolone-resistant S. typhi, 3rd generation cephalosporins, such as ceftriaxone, have become the treatment of choice.
Since November 2016, ceftriaxoneresistant typhoid fever reports have increased in the Sindh province of Pakistan.This type has the potential to change from MDR to XDR by conjugation.XDR strain of S. typhi exhibits resistance to cotrimoxazole, ampicillin, fluoroquinolones, and chloramphenicol, along with 3rd generation cephalosporins [7].The symptoms of XDR are generally nonspecific and indistinguishable from other febrile diseases and even COVID-19 [8].
According to the WHO, S. typhi recorded cases are between 11 and 21 million worldwide per annum, out of which 128,000 to 161,000 individuals die.Vulnerable populations and even whole communities lacking scheduled vaccination, adequate sanitation, and safe drinking water are the most susceptible to becoming infected from typhoid.In specific areas of Pakistan where these circumstances have been recorded, the frequency of XDR typhoid has increased from 7/100,000 to 15/100,000 cases [9].
Pakistan, a developing country, has been encountering COVID-19 since February 2020.The outcomes of COVID-19 appear to be highly concerning, with a low level of abidance to lockdown events due to lethargy and socioeconomic dysfunction.The potential overlap of typhoid fever and COVID-19 is particularly concerning but has received little attention thus far 8.In Pakistan and other middleincome countries, XDR typhoid fever is a serious public health hazard.Not only poor waste management and hygiene conditions but the misuse and overuse of azithromycin has also resulted in chaos [9].From January to December 2020, 2510 XDR cases of typhoid were stated in Pakistan.With the outbreak of the pandemic, the treatment of COVID-19 with azithromycin has gained ground [8].
Another factor contributing to the overlap between COVID-19 and typhoid fever are the diagnostic limitations in Asian countries, particularly in Pakistan, due to false-positive Widal testing in COVID-19 patients.Moreover, the lack of diagnostic approaches has not only strengthened the overuse of azithromycin but has also made it difficult to clinically distinguish between malaria, dengue, and COVID-19 [10].
Awareness is essential to attain optimum health.Likewise, increasing community awareness about typhoid fever is an effective way to promote preventive behavior.To adopt adequate preventive and control methods, it is critical to determine community KAPs towards typhoid fever, S. Typhi prevalence, and their associated factors [11].
This study aimed to evaluate the knowledge about the causes, treatment, and prevention of typhoid fever, as well as the practices regarding food, water, and hygiene, and attitude towards antibiotics use in the era of COVID-19.

Data Collection
Data was collected from all adult age groups in Punjab, Pakistan through a structured questionnaire from January 2022 to May 2022.The questionnaire was based on previous literature and composed of five sections, namely demographic information, knowledge, attitude, practices, and effects of COVID-19 on XDR [12].The information regarding gender, age, educational background, and residence in a developed or under developed area were included in demographic information.Knowledge about typhoid causes, treatment, and preventive measures was assessed.Practices of sanitation, hygiene, and safe use of water and food were also monitored.Attitude towards the use of antibiotics was also recorded.Data was generated online as well as through face-to-face interaction where participants had no access to the Internet.Furthermore, the questionnaire was translated into the native language for proper understanding where needed.

SPSS (version 21
) was used to code and analyze each response.Descriptive statistics were used to assess the respondents' knowledge, attitude, and practices.The findings were displayed as numbers and percentages.Correlation was determined through Pearson chi-square.For this purpose, the respondents were divided into groups according to their scores.These groups included Poor Knowledge -participants who scored <70% for knowledgeable questions, Good Knowledge -participants who scored 70% or >70% for knowledgeable questions, Bad Attitude -"Yes" answer to attitude based questions, Good Attitude -"No" response to the survey's attitude based questions, Poor Practice -participants who keep count <70% for correct practices, and Good Practice -participants who keep a record of 70% or >70% for correct practices [13].

Knowledge of Typhoid Fever Causes, Treatment, and Prevention
The majority of respondents (304, 60.6%) were aware of bacteria as a typhoid causative agent because they had an educational background in biological sciences.Three causes of typhoid fever reported by the respondents were the consumption of unsafe drinking water (341, 68.2%), unsafe food (296, 59.2%), and poor hygiene (251, 50.2%), as enlisted in Table 2.A good aspect was that nearly all (412, 82%) the respondents preferred to go to the hospital or a clinic for its treatment.

Practices of Water, Food, Sanitation, and Hygiene
It was observed that the majority of the respondents followed good hygiene practices, that is, washing hands after using the toilet (446, 88.8%) and before eating (340, 67.7%).The participants who preferred outdoor dining at street food stalls were 266 (53.2%), mobile food vendors were 167 (33.4%), and diners at restaurants were 346 (69.2%).Drinking filtered water was commonly practiced (369, 73.8%).A total of 409 (81.5%) respondents used covered sewage systems.It was found that preference regarding the use of household toilets not only depends on personal choices but is also determined by available circumstances, that is, private 250 (49.4%), shared 223 (46.7), and open defecation 29 (3.9%), as mentioned in Table 3.

Knowledge and Attitude among People towards Antibiotics Use
The trend among the respondents towards antibiotics use when they encountered typhoid and/or COVID-19 was analyzed (Figure 2).A total of 315 (63%) respondents were aware that antibiotics are used to treat bacterial infections.Furthermore, 232 (46.2%) knew that amoxicillin and penicillin are antibiotics.Positive responses to the questions regarding the use of antibiotics showed that their overuse and misuse is commonly practiced.

Figure 2. Knowledge and Attitude among People Regarding Use of Antibiotics
Multivariate analysis of data showed that washing hands before eating (p = 0.05) and gender (p = 0.05) were significantly associated with using antibiotics not prescribed by the doctor.While educational background (p = 0.000799) was strongly associated with using antibiotics that were not prescribed.It was also found that the correlation of variables with usually taking antibiotics following a phone contact with the doctor was not significant (p = > 0.05) (Table 4A).Multivariate analysis showed that gender (p = 0.005) and washing hands before eating (p = 0.005) were associated with stop taking antibiotics when start to feel better.Educational background (p = 0.043) and washing hands after using toilet (p = 0.021) were correlated with using left over antibiotics without consulting a doctor (Table 4B).

COVID-19 Insinuations on XDR Typhoid Strain in Pakistan
From a total of 502 respondents, 124 (24.7%) were infected by COVID-19, 56 (11.2%) were not sure whether they were infected or not, and 322 (64.1%) individuals reported that they were not infected by COVID-19.Similarly, out of the 502 respondents 78 (15.6%) were infected by typhoid, of which 64 (82.1%) cases were diagnosed by a laboratory test, 55 (70.5%) cases were medicated by a doctor, and 23 (29.5%) were treated by selfmedication or other means.A total of 54 (69.2%) cases recovered from fever with prescribed medicines, while for 24 (30.8%)cases prescription was modified after they failed to recover at first.It was observed that 53 (67.9%) typhoid patients used antibiotics either to prevent or treat COVID-19 (Table 5).The results showed that there is a significant correlation (p = 0.000) between typhoid and COVID-19 infected individuals.As such, 41 individuals infected by COVID-19 were also infected by typhoid.Another significant correlation (p = 0.000) was between COVID-19 and the use of antibiotics used to treat or prevent COVID-19.Of COVID-19 infected individuals, 37 had used antibiotics to treat the infection.While, among non-infected individuals, 9 had used antibiotics to prevent the infection.Both of these groups remain at the risk to develop resistance against antibiotics used in S. typhi.Moreover, data showed no significant correlation (p = 0.5) between laboratory test diagnosis and COVID-19.

DISCUSSION
The current study's findings are almost in accordance with those of a study conducted in Ethiopia (61.5% females) [12].In terms of the participants' educational status, 60.2% graduated with a biological sciences background.
Typhoid fever can be prevented by sustaining a safe water supply, proper sanitation, vaccination, food safety, and health education aimed to build public awareness and persuade behavioral changes.This may be achieved after ascertaining gaps of knowledge, attitude, and practices (KAPs) and by acclimatizing it to local situations in the study area.Regarding knowledge about typhoid fever in the current study, only 60.6% of respondents knew that it is a bacterial disease.This percentage does not fall under the operational definition of 'good knowledge'.Furthermore, 82% of respondents knew that they should go to a clinic or hospital when infected by typhoid and this percentage reflects good knowledge.The mean score of the causes of typhoid fever was 41.5%, which is poor knowledge.The mean score of preventive measures against typhoid was 49.7%, which indicates an overall poor knowledge.This percentage was less than the percentage in the research carried out in the Ethiopian state of Amhara [11].
The study conducted by Nahimana, Ngoc, Olu, Nyamusore, Isiaka, Ndahindwa, Dassanayake, Rusanganwa [14] in a Burundian refugee camp displayed that 38.6% and 34.6% of participants had knowledge about the prevention and spread of typhoid fever, respectively.The study of food handlers at Mettu University, Ethopia reported 50.6% and 47.2% knowledge regarding the prevention and transmission of typhoid [15].
Concerning the practices of hygiene, it was found that 88.8% of respondents followed the 'good practice' of washing hands with water and soap after using the toilet.On the other hand, only 67.7% washed their hands before eating and it is not a good practice.As shown in the graph, the level of eating outdoors at the restaurants is 69.2% (near 70%), a good practice among Pakistani people because it is somewhat safe to eat at restaurants, rather than to eat at mobile food vendors and street food stalls.Moreover, the respondents maintained good practice towards the safe use of drinking water.The majority treated water by different methods, such as 36.2%used boiling and 73.8% used filtered water.The findings of this study are lesser than those of the one conducted at Mendida Town, Ethiopia [12].
Numerous studies have shown that individuals with higher levels of education know more about antibiotic resistance than those with lower levels of education.The lack of awareness about diseases that may or may not be treated with antibiotics is an important factor in their misuse.Indeed, this ignorance can result in the emergence of resistance [16][17][18].In the current study, 46.2% of people were found to be misusing and overusing antibiotics.Concerning the knowledge regarding antibiotics, 63% knew that these are used to treat bacterial infections, while 46.2% recognized them as antibiotics.Mallah, Orsini, Figueiras, Takkouche [19] reported the meta-analysis of 85 studies from 42 different countries.They determined that medium education (> 9-12 years) is linked to a 20% lower risk of antibiotic misuse than low education (9 years or less), while a high educational background (more than 12 years) is linked to 14% lower risk of the use of antibiotics in high-income countries.
Typhoid fever is an endemic disease that affects developing nations, particularly those in South and Southeast Asia including Vietnam, Pakistan, Bangladesh, India, Nepal, and Indonesia.The falsepositive results of the Widal test in COVID-19 infected individuals became a serious public health concern for developing countries during the pandemic [10].Due to improper diagnosis during the COVID-19 pandemic, irrational pharmacotherapy was adopted by doctors.Broad-spectrum antibiotics were used as medication to treat typhoid and this became a contributing factor towards the XDR strain of typhoid [8].After medication, if the patient did not recover and the doctor changed the antibiotics, it also indicated emerging resistance to antibiotics in Salmonella typhi.Furthermore, 67.9% of typhoid patients in the current study used antibiotics to treat or prevent COVID-19, which might have developed resistance in Salmonella typhi due to their overuse and misuse.These findings are in agreement with other studies [20].

Conclusion
KAP studies urge the need of increasing awareness regarding safe eating and drinking and the safe use of antibiotics.In a nutshell, education plays a significant role in disease prevention and control.Furthermore, there is still a need to spread awareness regarding typhoid and its resistant strains.To conclude, it would be sagacious to introduce courses and training programs about antibiotics.In the curriculum of medical colleges and universities, there should be an emphasis on the right prescribing rules.

Figure 1 .
Figure 1.Map of Punjab Province in Pakistan Showing Response Rate in Different Districts

Table 2 .
Knowledge of Causes, Treatment, and Prevention of Typhoid Fever

Table 3 .
Practices Regarding Water, Food, Sanitation, and Hygiene

Table 4A :
Multivariate results based on attitude among people towards antibiotics use

Table 4 B
: Multivariate results based on attitude among people towards antibiotics use

Table 5 .
Multivariate analysis of COVID-19 Insinuations on XDR typhoid strain in Pakistan