Antimicrobial Resistance Patterns in Hazara Division: A Cross-Sectional Study in The Pre-and Post-Covid-19 Era

doi:10.21203/rs.3.rs-3619740/v1

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Antimicrobial Resistance Patterns in Hazara Division: A Cross-Sectional Study in The Pre-and Post-Covid-19 Era

https://doi.org/10.21203/rs.3.rs-3619740/v1

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In COVID-19 there was a lot of misuse of antibiotics that caused the huge burden of antimicrobial resistance (AMR). The study focuses on the impact of COVID-19 on AMR. A total of 1200 samples of urine, PUS, wound, blood, and high vaginal swab (HVS) were collected out of which 529 samples were included while 200 were excluded. Selected samples were cultured and antibiotic disks were applied. Zone size determined antibiotic sensitivity, resistance levels. The statistical analysis was done by using R version 4.3.0. The most commonly isolated bacteria were Escherichia coli (46%) followed by the Staphylococcus spp (18.4%), Klebsiella spp (9.7%), Enterococcus spp (5.5%), Coliform spp (4.9%), Pseudomonas spp (3.6%), Enterobacter spp (3.2%), Candida spp (2.3%), Acinetobacter spp (2.1%), Salmonella typhi (1.1%), Streptococcus spp (1.1%), Proteus mirabilis (0.9%), Burkholderia cepacia (0.4%), Citrobacter freundii (0.5%), Morgenella spp (0.2%). In Females (76%) AMR while in males 23.6% AMR was observed. A total of 42 antibiotics AMR trend was seen out of which 21 antibiotics show an uptrend while others show a downtrend. During COVID-19 the increased use of antibiotics occurred so the increased AMR is seen in 2019 and 2020. Post-COVID-19 identification, reduced antibiotic usage resulted in an observed downward trend.

Biological sciences/Biological techniques

Biological sciences/Biotechnology

Biological sciences/Microbiology

The misuse of antibiotics causes AMR development in the bacteria. In the 21st century, the natural genetic evolution causes resistance in the pathogen had reached its paradoxical level and this causes the increasing AMR as a serious health issue[1]. Globally 700,000 deaths occurred due to AMR and by 2050 this number will be up to 10 million deaths [2]. According to the European Centre for Disease Prevention and Control (ECDC) report in 2019, 25000 patient deaths occurred in Europe[3]. Similarly, in developing countries like India, and Thailand approximately, 58 000 children and 38 000 adults, deaths occurred per year due to untreatable infections caused by different antimicrobial-resistant pathogens[3]. AMR is not only causing a huge burden on the health sector but also causing a huge economic burden[4]. The USA alone bears a $20 billion extra economic burden because of antimicrobial-resistant infections[5]. €1.1 to 1.5 billion extra healthcare costs occur due to the infections caused by the AMR pathogens in Europe and European Economic Area (EEA)[6]. It is estimated that by 2050, the global loss is about 1.1%-3.8% of the global annual GDP, in the treatment of the infections caused by antimicrobial-resistant infections. By 2030, approximately 24 million people will be at the line of extreme poverty, especially in low-income countries, and about one patient die in every six patients because of the AMR- related infections[4].

South Asia is thought to be the central region for antibiotic resistance, almost 70% of the antibiotic resistance rises from the Asia region which becomes a threat to the whole world[7]. Pakistan becomes the 3rd most antibiotic-consumption country in the low and middle-income countries (LMICs) and from 2000–2015 the daily defined doses of antibiotics raised to 65%[8]. From 2014–2018 in just 5 years there is almost a 65% increase in the consumption of cephalosporin. A significant increase occurred in the consumption of fluoroquinolones and ciprofloxacin[9]. In Pakistan under the Drug Act of 1967, antibiotics are not over-the-counter medication and it is officially illegal to sell antibiotics with the proper prescription of the physician[10]. According to a global study in 2011, it was estimated that almost 9% of the antibiotic sold in Pakistan is without prescription[11].

In Pakistan, the MDR and XDR bacteria are isolated e.g. a significant increase in the resistance against quinolones was observed for the Enterobacteriaceae[12]. Similarly, XDR Salmonella was also isolated which is 100% resistant to fluoroquinolones[13]. Bloodstream infections show 93.7% resistance isolates to the 3rd generation of cephalosporin. An approximately 71% high prevalence of Metallo-βlactamase (MBL) and Extended Spectrum-βlactamase (ESBL) is almost 40%, the colistin resistance is seen in the carbapenems-resistant bacteria-harboring blaNDM, blaKPC genes and mcr-1 gene [14–17]. Almost 70% of P. aeruginosa and Acinetobacter isolates are MDR even the resistance against cephalosporin, the third-generation drugs were observed higher. 85%, 84%, and 87% resistance is noted for Ceftazidime, ceftriaxone, and Cefotaxime respectively[18].

As the burst spread of COVID-19 around the world pushes all the pharmaceutical companies in the race to develop COVID-19 vaccines and other therapeutic and diagnostic tools[19]. The outbreak of COVID-19 has signaled concern about the impact of this new threat on AMR and antimicrobial stewardship[20]. In December 2019, There are a large number of cases of respiratory diseases were reported in China[21]. Later on, the causative agent was identified initially named covid-19 later on named as severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2)[22]. As the disease was rapidly progressing, so on 30-january-2020 WHO called Covid-19 as a pandemic. Initially, there is no effective treatment was not available so different antimicrobial agents as therapeutic agents[23]. After the spread of COVID-19 worldwide all the biopharmaceutical companies were focused on vaccine development and diagnostic kits for COVID-19[19, 24]. When the whole world is trying to deal with the COVID-19 another big issue was emerging, AMR causing the loss of millions of life[25]. As AMR affects globally but it mostly affects Africa and other poor and under-developing countries because of the weak antibiotic supply chain, poor regulatory framework, and over or misuse of antibiotics[26]. In Covid-19 a large number of antibiotics have been used in just a few months around the world. Azithromycin, linezolid, tigecycline, ceftriaxone, carbapenems, and vancomycin are considered critically important antimicrobials (CIA)[27]. During the covid-19 these antimicrobials may use to save millions of lives but now the over usage of antimicrobial agents is responsible for millions of deaths[20].

Antibiotics are used in the treatment of bacterial and fungal respiratory co-infections[28]. As covid-19 has more similar symptoms of respiratory infection caused by atypical bacterial pneumonia, making it is difficult to differentiate between SARS-CoV-2 infections and hospital-acquired pneumonia[24]. So most of the patients received antibiotic therapy but in reality, some of the patients need antibiotic therapy which leads to the misuse of the antibiotics[25]. A combination of antiviral and antibiotics are used to treat COVID-19 and secondary bacterial infections but a large number of patients were treated with the antibiotic without any secondary bacterial infections causing an increase in the AMR and MDR organisms[29].

The aims and objectives of this study are: To identify the prevalence of microbial pathogens among different infections in the Hazara Division, Pakistan and to find out the antimicrobial resistance trend of isolated bacteria against different antibiotics in both pre-and post covid-19 periods.

Gender wise AMR

In females, more AMR is noticed on average at 76% while in males the AMR average is about 23.6%. In females, the lowest percentage of AMR is seen in the age group 15–17 years is 21%, and the highest AMR is seen in the age group 87–89 which is 78%. Similarly, in the males the lowest and the highest are 24% and 61% seen in the age group of 3–5 years and 78–80 years respectively as shown in Fig. 1. The most commonly isolated pathogen is Escherichia coli (46%) followed by the staphylococcus spp (18.4%), Klebsiella spp (9.7%), Enterococcus spp (5.5%), Coliform spp (4.9%), Pseudomonas spp (3.6%), Enterobacter spp (3.2%), Candida spp (2.3%), Acinetobacter spp (2.1%), Salmonella typhi (1.1%), Streptococcus spp (1.1%), Proteus mirabilis (0.9%), Burkholderia cepacia (0.4%), Citrobacter freundii (0.5%), Morgenella spp (0.2%) as shown in Fig. 2.

As in (Fig. 3) shows Morgenella spp and Candida spp were isolated from the urine samples while in the HVS, Blood, Pus, and wound infection these species are not found. Similarly, almost all the portions of the Burkholderia cepacia and Salmonella typhi were found in the blood specimen. Almost about more 75% of the Escherichia coli and Klebsiella spp were isolated from the urine. In some cases, Escherichia coli was also isolated from the HVS, PUS, blood, and wound samples while Klebsiella spp was isolated from HVS and pus samples. In the case of Acinetobacter spp and Citrobacter freundii, 70% of the cases are found in the urine sample and 30% of cases were found in the PUS samples. Coliform spp was isolated from urine samples. Enterobacter spp was isolated from the Pus wound and urine samples. Enterococcus spp is more commonly isolated from urine samples but some portions are also present in the pus and blood samples. Proteus mirabilis is mainly isolated from the samples of pus and urine infections. Pseudomonas spp and Staphylococcus spp were significantly isolated from the urine, wound, pus, and blood samples with the exception that a little portion of the also lay in the HVS samples. Streptococcus spp was most commonly isolated Pus and HVS samples were also significantly found in the urine and blood samples.

Antimicrobial Resistant trend

During the COVID-19 i.e. 2019–2020 the AMR is seen in majority of the antibiotics while from 2021–2022 the declining AMR trend was seen while in some antibiotics increased AMR trend was seen as shown in Fig. 4. Ampicillin (AMP) 37%, Augmentin (AUG) 41%, Ceftriaxone (CRO) 40, Ciprofloxacin (CIP) 10, Cefotaxime (CTX) 20, Cefepime (CFP) 18%, Ceftazidime (CAZ) 42%, Cefixime (CFM) 20%, Chloramphenicol (CAP) 8%, Doxycycline (DOX) 25%, Septran (SEP) 25%, Levofloxacin (LEV) 20%, Oxacillin (OXA) 2%, Erythromycin (ERY) 5%, Tazocin (TAZ) 12%, Fosfomycin (FOF) 5%. In these antibiotics, the resistance is increased after the COVID-19 pandemic.

While in some antibiotics the decreasing antibiotic resistance pattern was observed. Amoxicillin (AMX) 18%, Cefuroxime (CU) 2%, Cephradine (RAD) 3%, Cloxacillin (OB) 8%, Colistin(CST) 30%, Rifampicin(RFP) 28%, Penicillin(PEN) 9%, Tigecycline(TGC) 13%, Tetracycline(TET) 1.5%, Azithromycin(AZM) 30%, Clindamycin (CLI) 7.5%, Sulzone (SCF) 15%, Gentamicin (GEN) 10%, and Fusidic Acid (FA) 1%, these antibiotics become more sensitive after the COVID-19 pandemic. In the case of Amikacin, Linezolid, Teicoplanin (TIP), Vancomycin (VCM), Polymyxin (PB), Imipenem (IPM), Meropenem (MOP), Oxytetracycline, Piperacillin-Tazobactam (PPT), Ertapenem (ETP) are highly sensitive against the pathogen, and significant increasing or decreasing AMR trend was not seen. The sensitivity almost remains the same as before and after the COVID-19 pandemic (Fig. 4).

As in (Figs. 5 and 6) shows the testing frequency and the impact of the antibiotics on isolated pathogens. As the Escherichia coli is the most prevalent bacteria so the testing frequency of the different antibiotics against bacteria is high. Similarly, the Staphylococcus spp and Klebsiella spp were the second and third most commonly isolated pathogens so the testing frequency of different antibiotics against these bacteria was high. Among the pathogens, Escherichia coli emerges as the most prevalent. The antibiotics Amikacin and Ampicillin demonstrate a strong efficacy against Escherichia coli, highlighting their potential as effective treatment options. Conversely, antibiotics such as Ciprofloxacin, Azithromycin, and Fusidic acid do not exhibit a significant impact on Escherichia coli, suggesting limited effectiveness against this pathogen.

Testing frequency of antibiotics

Additionally, Staphylococcus spp. represents the second most commonly isolated pathogen. The antibiotics Ampicillin, Amoxicillin, Cefotaxime, Ciprofloxacin, and Ceftriaxone exhibit a strong effect against Staphylococcus spp, indicating their potential as effective treatment options. Conversely, antibiotics such as Sulzone, Tazocin, and Polymyxin B show no significant correlation with Staphylococcus species, suggesting limited efficacy against this pathogen.

Furthermore, Klebsiella spp. demonstrates a correlation with the antibiotics Ampicillin, Ceftriaxone, Fosfomycin, Sulzone, and Fusidic acid, indicating the sensitivity of Klebsiella spp to these drugs. These findings suggest that these antibiotics could be considered potential treatment options against infections caused by Klebsiella spp. This information can inform clinical decision-making and contribute to the development of tailored treatment strategies for infections caused by Escherichia coli, Staphylococcus spp., Klebsiella spp., and other isolated pathogens.

The prolonged use of antibiotics causes the emergence of various MDR strains and reduces the potency and efficacy of the antibiotics[30]. This decreases the survival rate from different infections and also limits cancer treatment, surgery, and transplant[31]. Currently, 700 000 deaths were reported globally due to AMR out of which 230 000 deaths are only due to MDR tuberculosis. Despite of covid-19, MDR bacteria causes 10 million death every year by 2050 and force 24 million people into extreme poverty by 2030[32, 33]. Thus the AIM of the study is to identify the most prevalent pathogen and AMR trend during the pre and post COVID era in the Hazara division KPK.

A wide spectrum of antibacterial drugs is used in combination to treat the covid-19 patients[34]. Almost 15% and 71% of the patients get antifungal and antibacterial treatment. Out of 71% of the patients, 25% are medicated with a single antibiotic while 45% are treated with a combination of antibiotics[35]. Moxifloxacin (64%), ceftriaxone (25%), and azithromycin (18%) are administrated to sick patients[36]. Vancomycin and Amikacin are also administrated to neonates that have non-specific symptoms of covid-19[37]. As azithromycin inhabits the zika and Ebola viruses so the combination of hydroxychloroquine and azithromycin was seen as more effective in the covid-19 treatment[38, 39]. Azithromycin, doxycycline, and rapamycin cause the inhabitation of protein synthesis and also decreases inflammation and viral replication, so these drugs are also used in the treatment of the covid-19[40].

In the current study Escherichia coli (46%) is the most commonly isolated bacteria from the urine samples and the main cause of urinary tract infections[41]. UTI is the most common infection especially in females at least 50–60% of females suffer from this infection once in their life[42]. Untreated UTIs lead to kidney damage and renal failure[43]. Uropathogenic E.coli(UPEC) differs from other strains of E.coli that are more adapted to live in the urinary tract rather than the gastrointestinal tract. The two major mechanisms that help the UPEC to survive in the urinary tract are urothelial cell invasion and biofilm formation. Yet there is no test available to confirm the isolated E.coli is UPEC if it is isolated from the other samples rather than the urine samples[44, 45]. Some of the E.coli was also isolated from the HVS samples. The infectious agents more easily grow in the vaginal areas and from the anus or the urinary tract it is also possible these infectious agents may to the reproductive organs. In many studies, females with recurrent UTIs have a high magnitude and frequency of vaginal colonization with UPEC strains[46]. The presence of E.coli in the vaginal tract is one of the causes of female infertility[47].

In our data set the second most common isolated bacteria is Staphylococcus spp about 18.4%. Several other studies show the same trend[48]. As the staphylococcus ssp is the normal flora of the skin to the nasal cavity and gut[49, 50] so it is mostly isolated from the pus samples followed by urine, wound, blood, and HVS[51]. Some fluctuation in the prevalence of the climate conditions and the high temperature reduces the growth of S.aureus colonization[52, 53]. Klebsiella spp is the 3rd most common bacteria most isolated from the urine samples. The little portion was also isolated from the HVS and pus samples. Klebsiella spp is 2nd most prevalent pathogen in uropathogens[54]. The other uropathogens were also isolated such as Enterococcus spp (5.5%), Coliform spp (4.9%), Pseudomonas spp (3.6%), Enterobacter spp (3.2%), Candida spp (2.3%) similar to the other studies[55]. The prevalence of the salmonella typhi and Burkholderia cepacia is 1.1% and 0.4% respectively. Both of these bacteria is causes the blood infections[56].

The more AMR percentage is seen in the females as compare to the males. As the females have strong immune response than the males but the chances of the bacterial infection in females is higher due to the anatomical position and structure of female organs[57]. In the female’s urethra is shorter than the male’s counterpart that causes it easier for bacteria to reach at the bladder. Similarly, the Physical proximity of the urethral opening to the rectum and vagina causes the colonization of the enteric bacteria in the periurethral mucosa[58]. While in the man, there are some additional protective features like dryer environment at the urethral opening and prostate secretions also have antibacterial activities[59].

In data analysis, high resistance is seen in Amoxicillin, Ampicillin, Augmentin, Ciprofloxacin, Cefotaxime, Cefixime, Septran, Levofloxacin, Optochin, Oxacillin, Erythromycin, Cefepime, and Ceftazidime with the uptrend. According to the study in 2018, The Escherichia coli is highly resistance against Ampicillin, Cefotaxime, ciprofloxacin, and sulfamethoxazole [60]. Similarly, other studies documented that Klebsiella spp, Salmonella typhi, and Streptococcus spp are highly resistance to Ciprofloxacin [61–63]. The different studies from 2009 to 2018 show increasing antibiotic resistance in Escherichia coli against Ampicillin, Ciprofloxacin, and Sulfamethoxazole [64–67]. Different studies in South Asia report the widespread of fluoroquinolones together with the rapid increase in Carbapenem-resistant Enterobacteriaceae (CRE) over the past decade [68–71].

Studies have shown that the antimicrobial resistance (AMR) problem is not limited to non-prescription dispensing, but also extends to the efficacy of commonly prescribed antimicrobial agents. For instance, medium levels of resistance have been observed in several commonly used antimicrobial agents, including Sulzone, Gentamycin, Imipenem, Meropenem, Fosfomycin, Tigecycline, Piperacillin-Tazobactam (PPT), Ertapenem (ETP), Rifampicin, Nitrofurantoin (NIT), Rifampicin (RFP), and Doxycycline [61, 62, 72, 73]. Very low resistance is seen in Amikacin, Chloroamphicol, Clostin, Linezolid, Teicoplanin, Vancomycin, Polymyxin, Tazocin, and Oxytetracycline. In many studies, Amikacin is sensitive to uropathogens [74, 75]. In the Salmonella spp, the increasing pattern of resistance is seen in Asian countries [76].

Studies have also shown that several antimicrobial agents, including Amikacin, Chloramphenicol, Colistin, Linezolid, Teicoplanin, Vancomycin, Polymyxin, Tazocin, and Oxytetracycline, exhibit very low resistance rates against various bacterial pathogens. Amikacin, in particular, is effective against several uropathogens, including Escherichia coli, Klebsiella spp, Proteus spp, and Pseudomonas aeruginosa [77]. This antimicrobial agent belongs to the aminoglycoside class and is often used as an alternative treatment option for patients who are resistant to other antimicrobial agents. Chloramphenicol, on the other hand, is a broad-spectrum antibiotic that has been used for the treatment of a wide range of bacterial infections. However, due to its potential toxicity and the emergence of resistance, its use is now limited to certain indications [78]. Colistin is another antimicrobial agent that has gained attention in recent years as a last-resort treatment option for multidrug-resistant Gram-negative infections. It is administered intravenously and can cause kidney toxicity at high doses, hence careful monitoring of patients is necessary. The low resistance rates observed in these antimicrobial agents highlight the importance of appropriate antimicrobial use and the need to preserve the effectiveness of existing antimicrobial agents. The development of new antimicrobial agents is also crucial for addressing the AMR problem and ensuring that effective treatment options are available for bacterial infections [79].

However, the long-term effect of COVID-19 remains unclear [20]. In our study of some antibiotics, an increasing trend of AMR is seen. At the beginning of the pandemic, many researchers warned about the spread of antimicrobial resistance during and after the pandemic [80]. During the pandemic, there was also an increase in the consumption of antibiotics. On the other hand, during COVID-19 there was a huge increase in the usage of biocides, compounds with disinfectant, antiseptic, or even preservative properties [81], in both hospital settings and communities [82]. The overuse of the biocides may lead to an increase in AMR in many ways such as upregulation of the efflux pumps [83], plasma membrane modification [84], or even the induction of a viable but non culturable state that permits survival in unfavorable environmental conditions [85].

Study duration and location

A retrospective cross-sectional and analytical study was conducted in the Indus Lab Lahore Haripur branch and at Research Lab of Rehabilitation and Allied Health Sciences, Riphah International University from 2018–2022. The study was approved by Faculty of Rehabilitation and Allied Health Sciences Research and Ethical committee. The data was collected from the laboratory records over a period of 5 years from 1 January 2018 to 31 December 2022.

Sampling Method and Sampling Population

In this study, the retrospective data (from 2018–2022) of the patients suffering from different bacterial infections and their susceptibility results to the commonly used antibiotics were collected from the records of Indus lab Lahore, Haripur branch. Only those patients’ data were included having complete information such as type of sample, date, and site of sampling, the method used for the analysis. A total of 1200 reports were collected. The reports were collected from the five sites of the Hazara division i.e. Haripur (20%), Abbottabad (20%), Mansehra (20%), Burner (20%), and Swabi (20%). Out of 1200 reports, 200 reports were excluded 70% were urine culture reports, 18.14% were wound and pus cultures and 5.72% and 5.1% were HVS and blood culture reports. All the samples collected with consent from all from all subjects and/or their legal guardian(s). The documentation pertaining to subjects signifies the voluntary acquiescence of participants to engage in the study, having received comprehensive information regarding its objectives. The affixed signatures serve as confirmation of their comprehension. This process aligns with ethical standards, ensuring research integrity.

Microbiological Method

All the samples were collected in accordance with relevant guidelines and regulations for specific sample collection and culture. Following the guidelines of the Clinical and Laboratory Standard Institute (CLSI), the experienced Lab technologist independently performed the isolation and identification of the pathogen and antibiotic susceptibility testing. In detail, All the isolated colonies were undergone to microscopic studies (determination of size, color, and the physical appearance of the colonies) further other biochemical tests were performed for the complete identification of the isolated species, and last antibiotic susceptibility testing was performed using the disk diffusion method. According to the guidelines of the Clinical and Laboratory Standard Institute (CLSI), The minimal inhibitory concentration (MIC) was determined for all the commonly used antibiotics, and the results were interpreted [86].

Statistical Analysis

All the data were retrieved using the LMS portal of the Indus lab Lahore, Haripur branch and was meticulously recorded in Microsoft Excel 2016 database (version 15.13.3), ensuring accurate and organized data management. Subsequently, statistical analysis was performed using R version 4.3.0.

In Females higher AMR is seen than Males. In our study Escherichia coli is the most prevalent pathogen in KPK followed by Staphylococcus spp, Klebsiella spp. During the COVID-19 period 2019–2020, the uptrend of AMR was seen while from 2021–2022, in some antibiotics the up-trend while in other antibiotics down trend is seen. The Amikacin, Augmentin, Cefuroxime, Nitrofurantoin, have testing frequency and impact on the organisms isolated from the UTI while the antibiotics such as Clindamycin, Tetracycline, Oxytetracycline, Erythromycin have high testing frequency and impact on the organism isolated from the Blood, HVS, Wound and Pus samples.

Recommendations

COVID-19 will have a great impact on AMR in the future, so further studies must be conducted to observe the AMR trend. In other Provinces of Pakistan and far regions of KPK the AMR trend should be examined. The AMR trend must be reported in organisms isolated from other body samples. AMR trend in TB must be examined after COVID-19. Due to the limited resources, This study only focuses on five districts of KPK. So it is suggested that there is a need for study in the far districts of KPK. It is also observed that the knowledge regarding the usage of antibiotics is very low which causes the misuse of antibiotics so there is a need for the study to evaluate the practices and knowledge of antibiotic usage in the common population as well as in the health staff.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests.

Author Contribution

Conceptualization, data collection, and analysis, as well as manuscript draft preparation, were performed by M.A, S.F, M.W. Assisted in data analysis by M.R, U.A, K.A, W.A.A and D.K. U.A supervised the designing, execution, interpretation, and edited the manuscript. All the authors approved the final manuscript.

Acknowledgements

The authors are thankful to the participants for volunteering in the study. Authors are also thankful to the ORIC Department, Riphah International University for partial financial support for the research work.

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No competing interests reported.

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Antimicrobial Resistance Patterns in Hazara Division: A Cross-Sectional Study in The Pre-and Post-Covid-19 Era

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Abstract

Figures

Introduction

RESULTS

Gender wise AMR

Antimicrobial Resistant trend

Testing frequency of antibiotics

Discussion

Methodology

Study duration and location

Sampling Method and Sampling Population

Microbiological Method

Statistical Analysis

Conclusion

Recommendations

Declarations

Data availability

Competing interests

Author Contribution

Acknowledgements

References

Additional Declarations

Supplementary Files

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