Antimicrobial Resistance and Antibiotic Consumption at a Tertiary Hospital in Riyadh, Saudi Arabia

Introduction

The first Antibiotic, penicillin, was discovered by Alexander Fleming in 1928 (Fleming, 1929). Since then, doctors were able to save millions of lives. However it didn’t take long until the threat of infections return back when some bacteria strains were found not susceptible to penicillin. Before penicillin started to be used clinically to treat infections 1943, bacterial resistance has already been described by some researchers in 1940. In 1962, methicillin resistant staphylococcus aureus (MRSA) were isolated in USA.

But on the other hand, new antibiotics also were being discovered which made people feel safe from infection threat (Ventola, 2015). Recently, the development of resistance to antibiotics has become faster and the emergence of strains which have no treatment, such as carbapenem-resistant Enterobacteriaceae and colistin resistant bacteria have been reported in different countries (Laxminarayan et al., 2013). To handle this issue, there have been initiatives to the development of new antibiotics and the emphasis on the rational use of existing ones. The aim of this work was to assess the bacterial resistance and annual antibiotic consumption at a tertiary hospital in Riyadh, Saudia Arabia over 2 year period.

Methods

This was a retrospective cohort study conducted to investigate the prevalence of antibiotic resistance bacteria over a period of two years and the antibiotic prescription during this period at a tertiary hospital.

The study involved data collected from King Saud Medical City; a tertiary hospital in the city of Riyadh, Saudi Arabia. The hospital has 1400 bed capacity and the service covers most of the medical specialties. The data included in this study was recorded for two years from January 2016 to December 2017. All bacterial susceptibility testing had been sent to the laboratory department of the concerned hospital.

Data Collection Procedure

Bacteria Isolates Results

The data of the bacterial cultures which included the bacteria isolates and their sensitivity to antibiotics were collected from the hospital’s laboratory department. The data were obtained from the health information system or the bacteriology section reports and antibio-gram.

Antibiotics Prescription/Consumption

Data concerning the antibiotics consumed in the hospital were collected also form the hospital information system (Medisys) for the defined period.

Hospital Infection Control Measures

Relevant data were also collected from the infection control department. The included Data described reports containing data about some activities conducted to minimize the chance of infection spread.

Ethical Consideration and Patients Confidentiality

The study was approved by the Institutional Review Board number (H1-RI-29-Mar18-01). The research had been approved and registered at Riyadh Elm University under the number (FPGRP/43739017/199).

Statistical analysis

Data were analyzed using the SPSS v22 (IBM, Chicago, USA). Descriptive statistics and Mann-Whitney test for the comparison between the variables were used. P-values less than 0. 05 were considered as statistically significant.

Results

The results showed that there was no significant difference between year 2016 and 2017 as regard patients’ characteristics like bed occupancy rate, average length of stay and number of admissions also bacterial characteristics like number of bacteria, % of isolates in Group and MDR% (P>0. 05). (Table 1) An overall increase in usage of antibiotics was detected. There was a consistence increase in the use of carbapenems and cephalosporins (third gen. ). Exception to this was the colistin, tigecycline, amikacin and linezolid where there was a slight decrease. The amount of cefipime and gentamicin remained almost unchanged. Other agents showed fluctuation in their usage. Data collection revealed a faulty method of calculation of the prescribed antibiotics that made it difficult to quantify or compare. The WHO metrics for quantifying the defined daily dose (DDD) were meant to be used in this study.

However, because the query available in the hospital information system did not provide how many days each antibiotic was used for; it was not possible to calculate the results in these metrics. Regarding colistin, between 2016 and 2017, there was a slight reduction in the sensitivity of E. coli CRE (97%, 86%) and K. pneumonia CRE (80%, 76%). In contrast, there was a slight increase in sensitivity of A. baumannii MDRO (82%, 86%) and P. aeruginosa (98%, 99%). For tigecycline, there was a decrease in the sensitivity of A. baumannii MDRO from 42% to 29% respectively. However, there was an increase in the sensitivity of K. pneumonia CRE (33%, 50%) and E. coli CRE (76%, 82%). The percentage of MDR strains in gram positive bacteria showed that more than half of staphylococcus aureus are gram methicillin resistant (61%, %59%). only 1% of E. faecailis bacteria were VRE in both years. The percentage of VRE among E. faecium in 2016 and 2017 were 45% and 44% respectively. There was a reduction in the percentage of MDR strains in some gram negative bacteria types such as P. aeroginosa MDRO (24%, 19%), E. coli ESBL (56%-50%), E. coli CRE (4%, 1%), K. pneumonia CRE (49%, 33%), A. bumanni CRE (90%, 76%), and P. mirabilis ESBL (54%, 50%). On the other hand, there was an increase in the percentage of MDR strains in K. pneumonia ESBL (22%, 26%).

Discussion

WHO’s new Global Antimicrobial Surveillance System (GLASS) reveals widespread occurrence of antibiotic resistance among 500, 000 people with suspected bacterial infections across 22 countries. The most commonly reported resistant bacteria were Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, and Streptococcus pneumoniae, followed by Salmonella spp. Among patients with suspected bloodstream infection, the proportion that had bacteria resistant to at least one of the most commonly used antibiotics ranged tremendously between different countries – from zero to 82%. (WHO, 2018)

Antibiotic resistance is a substantial economic burden to the whole world. In the USA alone, antibiotic-resistant pathogen-associated hospital-acquired infections (HAIs) cause 99, 000 deaths annually (Guidos, 2011). The insignificant difference between the two years in terms of the number, type of bacteria and the corresponding tested antibiotics may be due to the increased awareness of about antibiotic use and prescribing. Another integral reason is the strict measures from the hospital in controlling infections and cross-contamination. On the other hand, the results of the study showed that there were 12 AMR bacteria in 2016 and 12 AMR bacteria 2017 as well. The majority of these isolates were gram negative bacteria which are in consistence with what was reported from a study carried out at a tertiary care facility in Riyadh where the gram negative organisms were most common 82. 2% (Baig et al., 2015). In agreement with these results, it was reported that high rates of resistance to commonly used antibiotics were from gram negative bacteria (Asghar and Faidah, 2009).

These findings also agree with what was mentioned in another study which reported that most of causative pathogens for nosocomial infections were Gram-negative bacteria and they were resistant to different classes of antimicrobials (Kollef, 2005). Colistin is considered the last choice for eradicating gram negative bacteria and therefore it is reserved for those strains which are resistant to all other antibiotics. Several carbapenems resistant bacteria E. coli CRE, K. pneumonae CRE, A. bumannii MDRO and P. aeroginosa MDRO were sensitive to colistin 97%, 80%, 82% and 98% respectively. Apart from the change in K. pneumonae CRE sensitivity (76%), which is considered as intermediate sensitive, a minor change in the sensitivity of other bacteria E. coli (CRE), A. bumanii (MDRO) and P. aeroginosa (MDRO) to colistin 86%, 86%, 99% in 2017. These finding are similar to some studies that showed the spread of colistin resistance worldwide with varying levels. A. baumannii resistance to colistin had been reported from different regions such as Saudi Arabia 4. 7%, Asia, Europe, North America and South America 7%. Bulgaria and Spain showed even higher rates 16. 7% and 19. 1%, respectively. The Figures from Spain and Korea were even higher 40. 7% and 30. 6%, respectively (Kharaba, 2017). The reduction in usage of colistin and linezolid can be considered as a good practice to prevent or delay the resistance against these two antibiotics. This reduction was accompanied by the increase in the consumption in other groups of antibiotics such as cephalosporins and carbapenems.

The reason behind saving these items is that they are considered last choices for gram negative and gram positive bacterial infections (Zowawi, 2016; Klare et al., 2015). The hospital is Central Board for Accreditation of Healthcare Institutions (CBAHI) and Joint Commission International (JCI) accredited which mean they are implementing standards for infection prevention and control. In 2016, MDR bacteria are E. coli ESBL, K. penumonia ESBL and P. morabilis. The XDR organisms found were MRSA, E. faecalis VRE, E. faecium VRE, P. aeruginosa MDRO, E. coli CRE, K. pneumonia CRE, A. baumannii MDRO and P. mirabilis (ESBL). In 2017, The MDRO bacteria includes E. coli CRE, K. pneumonia CRE, A. baumannii MDRO, P. mirabilis (ESBL), P. stuartii, M. morganii. The only two MDR were E. faecalis and K. penumonia ESBL. In a tertiary facility in Riyadh, it was found that “A. baumannii isolates detected during the study period were almost resistant to all the drugs being tested.

All the A. baumannii isolates would have been classified as extensive drug resistant (XDR) i. e. resistant to three classes (all penicillins, cephalosporins, fluroquinolones, and aminoglycosides) and carbapanems” (Baig et al., 2015). According to the Code of Conduct of Healthcare Practitioners in Saudi Arabia, published in December 2005, pharmacist is not allowed to dispense any medication without a prescription written by a locally registered physician. However, this regulation was not strictly implemented and it was possible to obtain antibiotic even without a prescription. There were calls from healthcare professionals to correct this issue (Bin Nafisah et al., 2017).

Therefore, in 2018, the Ministry of Health has reemphasized the regulations that prevent dispense of Antibiotics without a prescription and introduced a new penalty for violating the regulations. A report highlighted the presence of the mcr-1 gene in 4 E. coli that were isolated between 2012-2015 from Saudi Arabia, Bahrain, and the United Arab Emirates. (Sonnevend, et al., 2016) It is likely though that mcr-1 carrying GNB are widely disseminated in more isolates and between other species in the Arabian Peninsula. Other studies from The Gulf Cooperation council region 5, 13 affirmed that the region harbours other rare and novel antibiotic resistance mechanisms. For example, PME-1 ESBL producing Pseudomonas aeruginosa (P. aeruginosa) from Qatar, (Zowawi et al., 2015) and the pandrug-resistant K. pneumoniae from neighboring UAE. 5 A Saudi national surveillance on Gram-positive cocci demonstrated that 32% of Staphylococcus aureus (S. aureus) are methicillin-resistant (MRSA), and 33% of Streptococcus pneumoniae are resistant penicillin G and 26% are resistant to erythromycin. (Shibl et al., 2014) A study from Riyadh (Al-Humaidan et al., 2015) demonstrated that total prevalence of MRSA among health workers was 18%.

It is evident that the non-optimized use of antibiotics, over-the-counter antibiotics without prescription in Saudi community pharmacies, non-adherence to infection control measures and trying to satisfy patients are a major factor for AMR development. A hospital in Riyadh has well demonstrated the overuse of antimicrobial agents from 4 adult ICUs in 2010, where the highest use was meropenem, followed by piperacillin-tazobactam. On the other hand, in 37 ICUs in the United States the highest use was for carbapenems followed by antipseudomonal penicillins. About 77. 6% of the pharmacies in Riyadh dispensed antibiotics without a prescription. (Zowawi et al., 2013) Heavy international travel activities due to Hajj event where in a recent study( Leangapichart et al., 2016) showed that returned travellers from Hajj have acquired MDR A. baumannii and NDM producing E. coli, ceftazidime resistance is evident in 24. 6% of E. coli, 34. 4% of K. pneumoniae, and 52. 7% of P. aeruginosa. The hand hygiene compliance rate in a hospital in Makkah in 2011 was 50. 3%.

The effectiveness of hand hygiene compliance was well demonstrated in controlling a nosocomial outbreak caused by carbapenem-resistant K. pneumoniae in Riyadh. (Zowawi et al., 2013) The World Health Organization launched the Global Action Plan on Antimicrobial Resistance. (WHO, 2015) This plan was signed off by most of member states, including Saudi Arabia during the World Health Assembly in 2015. The plan consists of 5 pillars; Improving awareness, stringing knowledge through surveillance, reducing the incidence of infection, optimizing the use of antimicrobial agents, and developing the economic case for sustainable investment to support the need in all countries in regards to new medicines, diagnostic tools, vaccines, and other interventions. Trying to satisfy patients can be linked to patients’ attitude to antibiotics and average time doctor spent in consultation. (Cadieux et al., 2007) Like many worldwide countries, Saudi Arabia patients are more likely to use antibiotics, even for treating viral illnesses. [EC, 2007)

There are some ways to solve the AMR problem in Saudia arebia which involve:

1. Raising public, medical, and veterinary awareness of AMR is an important element that is urgently needed to tackle AMR in Saudi Arabia.
2. Multilevel and countrywide awareness campaigns and use of social media platforms addressing all segments and socioeconomic groups in Saudi Arabia to disseminate awareness messages. (Zowawi et al., 2015)
3. Conducting educational programs for healthcare workers regarding the importance of hand hygiene compliance can limit the spread of outbreak stains within hospitals, and potentially to the community.
4. Appling screening scheme for high-risk patients prior to admission to identify carriers of MDR pathogens and also isolation or contact precautions.
5. Active surveillance, from our side we tried by this Active surveillance on AMR, to track emerging resistance to antibiotics and to identify outbreaks and aid the development of tailored treatment guidelines for empirical antibiotic therapy, particularly for community-acquired infections.
6. Well equipped Microbiology laboratories should be present to provide up-to-date antibiograms and valid and reliable identification for pathogen.

Active antibiotic stewardship guidelines should be implemented to restrict the irrational use of antibiotics in Saudi Arabia. The WHO and Advisory Group on Integrated Surveillance of Antimicrobial Resistance (AGSIR) have published an updated list of antimicrobials according to their importance in human medicine. (Collignon et al., 2016)

Strength and Limitations of the Study

• The hospital had taken several actions to control the spread of MDR infections. During a colistin resistance outbreak, for instance, a multidisciplinary committee has been constructed. The committee recommended several actions such as environmental screening, training the staff for hand hygiene and use of precaution protective equipment, disinfecting ICU equipment, restricting ICU visitors and sorting the patient according type of infection and colonization.
• Several initiatives have been taken to monitor and control incidence of MDRO infections across the hospital and recording type of organisms and their level of resistance in state of resistant bacteria. Antimicrobial Stewardship Programs (ASPs) have been conducted in the hospital to optimize antimicrobial therapy, reduce treatment-related cost, improve clinical outcomes and safety, and reduce or stabilize antimicrobial resistance (Lee et al., 2013).
• This study is not free of limitations. There was difficulty in retrieving data from the hospital information system. The duration chosen for retrospective cohort study was not enough to indicate correlation, differences and variance between AMR bacteria and prescription of antibiotics.

Conclusion

This study showed the high incidence of MDR bacteria in this hospital. The majority of these were gram negative. Although, there was no reported Pan-Drug Resistant (PDR) bacteria but there was a wide spread of XDR. The highest number of isolated bacteria included K. pneumoniae (18%), S. aureus (15. 4%), A. baumannii (16%), and P. aeruginosa (14. 2%) in 2016. In 2017, E. coli (20. 9%), K. pneumoniae (17. 4%), S. aureus (16. 5%) and P. aeruginosa (13. 3%) were the highest. Additional work is needed to reduce the threat of MDR bacterial infections. Additional work is needed to reduce the threat of MDR bacterial infections. The hospital will need to implement a more advanced information system which will produce a more comprehensive characterization of factors contributing to the problem.