Methicillin-Resistant Staphylococcus aureus among Clinical Isolates in Indonesia: A Systematic Review

The high infection of methicillin-resistant Staphylococcus aureus (MRSA) accompanied by increased resistance to many groups of antibiotics is a major concern in the field of infection. This study aims to evaluate the prevalence of MRSA isolates and antimicrobial susceptibility to MRSA isolates in Indonesia. We did searches in Pubmed, Proquest, DOAJ, GARUDA, and google scholar for studies published in 2006-2020. Study in Indonesian (Bahasa) and English with the keywords “methicillin-resistant Staphylococcus aureus”, “MRSA” and “Indonesia”. More than 30 S.aureus isolates derived from human samples were included. A total of 738 articles based on the search results, 13 studies were included in this systematic review. The prevalence of MRSA reported from all studies is 0.3%-52%. The study with the largest prevalence of MRSA was found in Jakarta. The susceptibility of vancomycin antibiotics to MRSA isolates is known to range from 87%-100%. Based on all studies, Linezolid, Tigecycline, Nitrofurantoin, and quinupristin/dalfopristin were reported to have 100% susceptibility. The prevalence of MRSA is still found high in one of the cities in Indonesia. Surveillance of antibiotic use, monitoring of antimicrobial susceptibility patterns, and antibiotic resistance control programs need to be optimized. MRSA screening is based on a rapid diagnosis when an inpatient admission is also necessary.

Methicillin-Resistant S.aureus (MRSA) infections are a tenacious problem in many healthcare settings around the world 1 . MRSA infections can range from mild, such as skin infections to bacteremia or sepsis. These infections include endocarditis, pneumonia, osteomyelitis, device-related, cellulitis, and impetigo in health and community care for people [2][3][4] .
In 2017, WHO included S.aureus as a pathogenic bacterium in the list of "high priority" pathogenic bacteria that required a new generation of antibiotics 5 . Since the 1960s, the prevalence of MRSA has increased at a dramatic rate and is associated with higher rates of morbidity and mortality 6 . MRSA was reported to reach 20% in all regions of the World Health Organization (WHO) and more than 80% in some regions 7 . Resistant to methicillin confers resistance to all β-lactamaseresistant penicillins and cephalosporins 8 . Vancomycin has been an approved and effective option for treating S. aureus infections, especially MRSA. It has been successfully used worldwide for over 50 years. However, its effectiveness is questioned by the emergence of S. aureus strains that show intermediates to total resistance to this antibiotic 4 . Current therapeutic options approved by the Food and Drug Administration (FDA) for MRSA are limited like linezolid, teicoplanin, daptomycin, tedizolid, and streptogramins 9,10 . In contrast, least resistance was observed to vancomycin 9 .
A hospital-acquired infection caused by S.aureus is widely reported throughout the world, mainly in Asia 11 . The problem of antibiotic resistance in developing countries such as Indonesia, where infectious disease is rampant, is highly pronounced. S. aureus infections cause long hospital stays and increase health care costs 9 . S. aureus has gained resistance to most of the antibiotics shown by antimicrobial chemotherapy and once it is resistant, it will be difficult to control and eradicate 9 . To control the increase in antimicrobial resistance, it is necessary to collect data about the sensitivity and resistance of each antibiotic. Therefore, this systematic review aims to evaluate the prevalence and antimicrobial susceptibility patterns of MRSA from each study in Indonesia.

Search strategy
This study refers to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method (12). A search was conducted in April 2020 on PubMed, Proquest, Directory of Open Access Journal (DOAJ), Garuda (http://garuda.ristekbrin.go.id/),and Google Scholar. We use search terms ("methicillin-resistant Staphylococcus aureus" OR "MRSA") AND "Indonesia".We also identified a list of references to search for additional studies.

Study selection and eligibility criteria
All studies reviewed are based on inclusion criteria:(1) Report the prevalence of MRSA; (2) S.aureus isolate samples are human clinical specimens; (3)Publication of articles from January 2006 to March 2020; (4)Articles in English and Indonesian (Bahasa); (5)Isolates amount more than 30; (6) The study is an original journal article include cross-sectional, case-control and cohort. Studies that have less than 30 isolate bacteria do not accurately represent resistant bacteria (13). Excluded studies, include: (1)review studies; (2) repetitive isolates; (3) does not explain the number of isolates and sensitivity test methods.
Two authors (RS, R) screened the titles and abstracts of the articles obtained from the initial search. To complete the selected articles, two authors (RS, R) read the full text and were assessed and selected based on inclusion criteria. The disagreement between the two authors was decided by discussion.

Data Extraction and Synthesis
All articles provide the following information: first author, year of publication, study location, study period, data type, sample source, a total of isolates, prevalence of MRSA, and antimicrobial susceptibility results. The data is presented in description and synthesized with a narrative.

Selection and characteristics of studies
Database search results on Pubmed, Proquest, GARUDA, and DOAJ get 733 articles. Additional articles were identified from Google Scholar and cross-referenced articles were obtained 5 articles. After eliminating duplication, a total of 656 articles are screened for title and abstract. After screening, a total of 43 full-text articles are carried out eligibility assessments. A total of 30 studies were excluded because they did not match with inclusion criteria and duplication of isolates in some studies. The majority of studies are excluded due to the number of S.aureus isolates that do not reach 30. The total articles to be included in 13 studies (Fig. 1).
Five studies are retrospective based on patient medical record data 17,18,21,22,24 . A total of 8studies are prospective studies 14,15,16,19,20,23,25,26 . Seven studies used phenotypic sensitivity tests, two using genotypic, and five using both combinations. Based on all phenotypic tests showing that the most used are disk diffusions. MRSA isolates were taken from various clinical samples, including nose, wound, pus, blood, sputum, etc.

P re v a l e n c e o f M R S A a n d A n t i b i o t i c Susceptibility
The prevalence of MRSA reported from each study was 0.3%-52%. The study with the largest prevalence of MRSA was conducted in Jakarta 17 . The lowest prevalence of MRSA was reported in multicenter studies in Surabaya and Semarang 20 . Studies with the largest prevalence of MRSA did not perform sensitivity tests on other antibiotics. A total of 5 studies conducted antibiotic sensitivity tests on MRSA isolates ( Table 2) [14][15][16]23 .

DISCUSSION
Overall, the highest prevalence of MRSA reached 52%. This result was higher than the survey conducted through the SENTRY Antimicrobial Surveillance Program in 1997-2016 involving North America, Europe, Latin America, and the Asia-Pacific region of 40.3%. In the Asia-Pacific region, the SENTRY program reported MRSA amounting to 39.6% 27 . In 2017-2018, Indonesia is not included in the Global Antimicrobial Resistance Surveillance System as reported by WHO, so there is no available prevalence of S. aureus resistance 5 .     Once the isolate S. aureus is identified as MRSA, it is immediately classified as MDR, because resistance to cefoxitin or oxacillin causes an inability to all categories of antimicrobial β-lactam (i.e. all categories of penicillin, cephalosporins, β-lactamase inhibitors, and carbapenem) 28 . MRSA resistance to beta-lactam antibiotics is due to the order of the mecA gene, which is known to produce PB2a transpeptidase thereby lowering the affinity of organisms to bind to beta-lactam antibiotics. S.aureus resistant to penicillin can produce a penicillinase, which can hydrolyze the β-lactam penicillin ring, causing resistance to penicillin 29 . Penicillin-resistant S.aureus has long been known since 1942. After being known for penicillin resistance, scientists developed a new semisynthetic penicillin-resistant penicillinase, called Methicillin, which is more resistant to the hydrolysis of β-lactamase 30,31 .
The treatment option for MRSA is the Glycopeptide group such as Vancomycin and Teicoplanin, which can only be administered by injection 32 . Resistance to vancomycin has been reported since the year 2002 33 . The results of this study show vancomycin are still sensitive to S. aureus and can be used in invasive MRSA infections 14,21,22 . Other antibacterial agents to defy MRSA, include quinupristin/dalfopristin, linezolid, daptomycin, and tigecycline 28 . In this review, quinupristin/dalfopristin, linezolid, and tigecycline were reported to be 100% sensitive.
The choice of empiric antibiotic for the treatment of MRSA infection depends on the type of disease, the local pattern of S.aureus resistance, drug availability, side effect profile, and individual patient profile. Empiric treatment of uncomplicated skin and soft tissue infections with suspected MRSA infection can be given oral antibiotics such as trimethoprim / sulfamethoxazole, tetracyclines (such as doxycycline or minocycline) and clindamycin 34 . There were three studies in this review, tetracycline reported to be less sensitive to MRSA isolate 15,21,26 . Excessive empirical antibiotic therapy can also be one of the contributing factors to resistance.
Risk factors in someone infected with MRSA consist of many things. Increased risk with activities or places involving crowding, skin-toskin contact, and the use of shared equipment. Based on all the studies reviewed, the location of the most isolated retrieval and the largest prevalence of MRSA came from Jakarta 15,16,17,18,26 . This can be due to major cities such as Jakarta more microbiology examination laboratories with PCR for MRSA detection.Checks using PCR are quite sensitive, so it detects MRSA more. Multicenter research involving many locations including Jakarta and other cities is still needed to see the spread of MRSA in Indonesia.
In Indonesia, many large hospitals, especially vertical hospitals have performed the best standard of microbiology laboratory services following the Guidelines International (latest CLSI) and National (Ministry of Health). Based on PMK 8, 2015 national regulations on Hospitals Anti-Microbial Resistance Control Program (PPRA), antibiograms in hospitals are regularly developed and standardized at least once a year. Antibiograms must be prepared as one of the measurements elements in the ASP (National Standards Program Group) Standard 37 . This antibiogram is considered local Empirical Antibiotics guidelines. Most of these antibiograms are not published, although there are also those in the publication. Also, based on our search for local articles published, some did not meet the inclusion criteria, so we were excluded. There are some limitations to this study such as other systematic reviews, potential publication biases may exist.

CONCLUSIONS
MRSA infections are still reported quite high in some studies. Vancomycin, linezolid, and Tigecycline are reportedly still quite sensitive to MRSA isolates. Existing antimicrobial control programs need to be maximized and evaluated in line with the MRSA report found.