Coronavirus Pandemic Antibiotic consumption in hospitals during COVID-19 pandemic: a comparative study

Introduction: Coronavirus disease 2019 (COVID-19) results in similar clinical characteristics as bacterial respiratory tract infections and can potentially lead to antibiotic overuse. This study aimed to determine the changes in hospital antimicrobial usage before and during the COVID-19 pandemic. Methodology: We compared antimicrobial consumption data for 2019 and 2020. Inpatient antibiotic consumption was determined and expressed as a defined daily dose (DDD) per 100 occupied bed days, following the World Health Organization (WHO) methods. The WHO Access, Watch, and Reserve (AWaRe) classification was used. Results: The total antimicrobial consumption in 2020 increased by 16.3% compared to consumption in 2019. In 2020, there was a reduction in fourth-generation cephalosporins (-30%), third-generation cephalosporins (-29%), and combinations of penicillins (-23%). In contrast, antibiotics that were consumed more during 2020 compared with 2019 included linezolid (374%), vancomycin (66.6%), and carbapenem (7%). Linezolid is the only antibiotic from the Reserve group on the hospital’s formulary. Antibiotic usage from the Access group was reduced by 17%, while antibiotic usage from the Watch group and the Reserve group was increased by 3% and 374%, respectively. Conclusions: The findings show a significant shift in antibiotic usage from the Access group to the Watch and Reserve groups. The Watch and Reserve groups are known to be associated with increased resistance to antibiotics. Therefore, antimicrobial stewardship should be increased and maintained during the pandemic to ensure appropriate antibiotic use.


Introduction
The growth and dissemination of multidrugresistant microorganisms and low investment in antibiotic discovery hinder the successes of various contemporary medicines and cause significant public health hazards worldwide [1][2][3]. Antimicrobial abuse and misuse have increased the danger of onset and spread of antimicrobial resistance (AMR) in many parts of the world. A continuous increase in AMR will increase drug-resistant illness fatalities from 700,000 to 10 million per year, with anticipated expenses of up to $100 trillion globally by 2050 [4,5].
Antimicrobial use is considered to be one of the primary causes of AMR [6][7][8]. Monitoring and optimizing antibiotic use are critical for preventing the development of AMR [9]. The impact of AMR on the delivery of regular and urgent care services in hospitals has been widely noted. The pandemic has impacted the implementation of health awareness programs, preventive health care, and the diagnosis and ongoing management of chronic diseases [10].
Coronavirus disease 2019 (COVID-19) has resulted in a significant increase in the use of certain antibiotic agents such as carbapenems, macrolides, and lincosamides. Furthermore, studies have documented an increase in the use of Watch antibiotics during the COVID-19 pandemic in local and national hospitals [11,12]. The usual causes of this increase include increased hospital stays among patients with COVID-19 and an increase in admissions to the intensive care unit (ICU). This has led to a shortage of beds for the care of these vital patients. The potential overuse of antimicrobials happens due to the issue of bacterial coinfection [13]. This pattern is drawn from influenza, which is associated with a high co-infection prevalence (58%) [14]. In line with the latter, many of the antibiotics administered to patients with COVID-19 were potentially inappropriately indicated and unnecessary [15]. This has the potential for undesirable consequences, including an increased risk of antibiotic resistance [16].
Some researchers have already raised concerns about the pandemic's potential impact on advancing AMR hazard [17]. Based on these concerns, the World Health Organization (WHO) and several experts advise against initiating antibiotic treatment for COVID-19 cases classified as suspected or confirmed mild and against prescribing antibiotics for moderate COVID-19 (unless laboratory results confirm clinical suspicion of bacterial infection) or in critically sick patients [18]. Many low and middle-income nations, including Egypt, struggle to implement comprehensive antimicrobial stewardship programs (AMS), which have deteriorated further because of the ongoing pandemic. There have been no prior studies in Egypt to assess the utilization of antibiotics among patients hospitalized with COVID-19.
This work aimed to assess changes and patterns of antimicrobial usage before and during the COVID-19 pandemic in Beni-suef University Hospital. This was achieved by comparing annual inpatient antimicrobial consumption during one year (2019) before the COVID-19 pandemic and a year during the COVID-19 pandemic (2020).

Setting and study design
The study was carried out in Egypt at the Beni-suef University Hospital (BUH

Data collection
Data on antimicrobial use at the BUH during the years 2019 and 2020 were extracted from the pharmacy information system. This data included the consumption of intravenous and oral antibiotics prescribed to the inpatients. An Excel spreadsheet was devised and included fields for antimicrobial agents, strength, dose, quantities, and the number of occupied bed days (OBD). The collected data were then validated by manually checking for errors. The WHO/Anatomical Therapeutic Chemical (ATC) classification index was used to calculate the defined daily dose (DDD) for each antibiotic. Finally, consumption of antimicrobials was expressed as DDD per 100 OBD. All age groups, male and female, with or without comorbidities in an inpatient setting, were enrolled in the study. All datasets were anonymous with no patient identifiers and no identifiable patient information.

Statistical Analysis
Antibiotic use was analyzed using descriptive methods. A graphical representation of the data to create four quadrants was constructed using the ggplot2 package and the R statistical program [19,20]. The relative rate of change in antibiotic use (2019-2020), calculated as (DDD/100 OBD 2020 / DDD/100 OBD 2019), was represented by the y-axis. Antibiotic use (DDDs) in 2020 was represented by the x-axis. There were two antimicrobials, cefadroxil, and azithromycin, that were not used by the hospital in 2019. This renders a divide-by-zero error in the computation of the relative rate of change. Rather than omit these two antimicrobials in the graph, the rate of change was recorded to be a value greater than the largest rate of change for the remaining antimicrobials; linezolid, in this instance. A triangle symbol is used as a reference for cefadroxil and azithromycin to identify them as artificial values that have been scaled for the purpose of the chart. This chart provides a relative comparison of antibiotic use, levels, and trends. For example, antibiotics identified in the lower right quadrant represent widely used antibiotics at a lower rate when compared to the previous year. On the other hand, antibiotics identified in the upper right quadrant represent widely used antibiotics at a higher rate than in the previous year. Therefore, antibiotics identified in the upper right quadrant are potential antibiotics that may benefit from further evaluation. In order to determine antibiotics that contribute to 90% of used DDDs, we used the Drug Utilization 90% (DU90%) concept [19]. The percentage of antibiotic use (DDD%) was calculated by dividing the DDD of a certain antibiotic agent by the total use (DDD) of all antibiotics (J01); this was then expressed as a percentage by multiplying by 100. The WHO AWaRe classification (Access, Watch, and Reserve) was used to categorize the antibiotics assessed [20].

Ethics approval and consent to participate
Ethical approval was obtained from the research and ethical committee in Beni-Suef university hospital Ref. (#FWA 00015574) and is available upon request.
The distribution of hospital antibiotic consumption, grouped at the class level, considering the rate of change (2019-2020) and the proportion of use (2020), is shown in Figure 1.

Discussion
The COVID-19 pandemic is occurring simultaneously with the global health catastrophe of AMR. AMR pathogens lead to increased mortality [21][22][23], leading to a significant financial burden. Individuals infected with COVID-19 may need to be admitted to the ICU, depending on the severity of the symptoms. Those with substantial co-morbidities may require ventilator assistance [22,24].
The current study highlights the impact of the COVID-19 pandemic on antibiotic use by hospitalized patients. As far as we know, this is the first study comparing the consumption of antibiotics before and during the COVID-19 pandemic in Egypt. We identified a decrease in the use of some antimicrobial drugs during the COVID-19 outbreak (e.g., combinations of penicillins with beta-lactamase inhibitors, third and fourth-generation cephalosporins, lincosamide, and fluoroquinolones). Ryu et al. reported that reduced hospitalizations due to airway respiratory tract infections (ARTIs) during the COVID-19 pandemic led to the decrease in the consumption of penicillins and beta-lactamase inhibitors [25].
Consumption of the third and fourth generations of cephalosporin and lincosamide decreased in 2020 compared to 2019. This drop-in usage may be attributed to the increased use of other antibiotics such as azithromycin. However, other studies have reported a positive incremental change in third and fourth generation cephalosporin and lincosamide consumption [26][27][28][29][30]. This may be related to differences in race, variations in the most common infections, and the development of resistance in treated patients.   In the present study, a decrease in fluoroquinolone usage is also reported. This is in line with many studies showing a reduction in fluoroquinolones throughout the period of the COVID-19 outbreak [25,31]. This decrease may be rationalized by the narrow indication (e.g. genitourinary infections or hospital-acquired infections) for prescribing fluoroquinolone for children and adults [25]. On the other hand, a modest increase in fluoroquinolone usage has been observed in other studies. This difference in results may arise if fluoroquinolones are used for empirical therapy rather than for a single specific antimicrobial therapy against pathogenic germs [29,30].
In this study, there was an increase in the usage of specific antibiotics during the COVID-19 pandemic period. For example, the use of meropenem (carbapenem), vancomycin (glycopeptide antibacterials), sulfamethoxazole/trimethoprim, and linezolid increased. These findings are consistent with other studies. In addition, the results demonstrated an increase in the use of azithromycin in 2020, consistent with other studies reporting increased use of azithromycin during the COVID-19 pandemic, especially in combination with hydroxychloroquine [26,32,[33][34][35]. This could be due to physicians' prior experience with azithromycin for respiratory infections, or it could be related to widespread off-label usage of azithromycin for the treatment of COVID-19 in other countries. This widespread usage was reported in a recent study in Singapore that found similar trends in rising azithromycin intake [36]. In vitro antiviral effects of azithromycin include decreased viral multiplication, prevention of entry into host cells, and a possible immunomodulating impact [33,37]. Azithromycin has been demonstrated to help those with chronic obstructive pulmonary disease [38]. However, other studies do not support the use of azithromycin to treat patients diagnosed with mild to moderate COVID-19 because it did not lead to a reduction in the risk of subsequent hospital readmissions or deaths [39]. Studies have shown that azithromycin alone, or in combination with hydroxychloroquine is ineffective in treating COVID-19 patients admitted to hospitals [26,[40][41][42][43].
The current study revealed that the utilization of total antimicrobials before the pandemic period was 80.4 DDD per 100 occupied bed days, in which the percentage of oral use was 11.9%. The total utilization of antimicrobials during the pandemic was 93.5 DDD per 100 occupied bed days, in which the percentage of oral use was 27%. Many factors may have contributed to the increased usage of antimicrobials during the COVID- 19 pandemic, including initial misunderstanding of how to treat the infection, hospital overcrowding, the limited number of doctors with the necessary skills to deal with the situation, a decrease in the antimicrobial stewardship team's activity, and the lack of initial therapeutic protocols. This emphasizes the critical importance of antimicrobial stewardship in optimizing antibiotic use in hospitals, especially in emergency situations like the COVID-19 pandemic [22,27].
Strategies to optimize the rational use of antimicrobials involve encouraging local guideline implementation and timely de-escalation or discontinuation of therapy when clinical signs of unconfirmed bacterial co-infection are determined, correct antibiotic choice based on microbiological test results, and encouraging switching from intravenous to oral route as soon as appropriate. Furthermore, in order to enhance antibiotic use throughout the subsequent stages of the COVID-19 pandemic, the length of antibiotic treatment should adhere to local guidelines while closely monitoring potential multi-drug interactions or toxicity [22,27]. Total antimicrobial consumption grew by 16.3% during the COVID-19 outbreak in 2020 compared to the period before the outbreak in 2019. Changes in utilization of antimicrobials identified in relation to AWaRe classification was observed. The primary goal of the use of AWaRe is to reduce the use of antibiotics in the Watch and Reserve groups while increasing the usage of antibiotics in the Access group. By 2023, 60% of all antibiotics consumed must be from the antibiotics in the Access group [44,45]. The outcomes of this study revealed that the use of antibiotics in the Access group was (25%) in the period before COVID-19.
However, there was a significant decrease (-17%) in the percentage of people using antibiotics in the Access group (20.9%) during the pandemic. During the outbreak, usage of antibiotics in the Watch group increased by 3%, accounting for 76.5% of all cases. This category of antimicrobials is more likely to be associated with the development of AMR, demanding continuous monitoring and urgent stewardship measures; hence, the increase in antibiotic usage in the Watch group is a concern. Azithromycin and carbapenems are included in the Watch group. Our findings are consistent with a recently published study investigating the consequences of the COVID-19 period on antibiotic usage in an inpatient setting. The authors found that antibacterial consumption increased during COVID-19 [46]. Antibiotic stewardship activities in hospitals in Egypt could benefit from this knowledge. Measurement of antibiotic consumption is a critical component of antimicrobial stewardship programs because it allows us to improve good clinical practice regarding antibiotic use. A more in-depth investigation on the spread of antimicrobial resistance is needed to confirm the influence of modifications on the usage of certain broad-spectrum antimicrobials, as well as the increased use of antimicrobials in the Watch group. Our study has some limitations. The study was conducted at the hospital level, making it difficult to adjust for other factors that may have impacted the findings, for example, patient case mix and type of infections. Further research at the patient level is needed. In addition, this study was carried out in a single hospital. A multi-site study is needed to further understand the impact of the COVID-19 pandemic on antibiotic use.

Conclusions
In conclusion, the findings of this study determined the changes in antimicrobial use at the Beni Suef University Hospital in Egypt before and during COVID-19. We found a significant shift in antibiotic use from the Access group to the Watch (known to be related to increased antimicrobial resistance) and Reserve groups. More efforts are needed to monitor and improve antimicrobial stewardship actions to maintain patient safety and appropriate antibiotic usage. Furthermore, antimicrobial stewardship must be enhanced and maintained during the pandemic to ensure the rational use of antibiotics.