The inappropriate use of antibiotics is a dangerous phenomenon spreading in low and middle-income countries. This can be justified by weak healthcare systems, and lack of diagnosis instruments necessary to properly handle infections [18]. In Syria, there are no regulations to limit purchasing antibiotics without prescription [19], and in a study on Syrian adult patients, about 11% of practiced self-medication using antibiotics [20]. Furthermore, multidrug resistant microbes were detected during and after the Syrian crisis [21].
Most infections in Syria were caused by Enterobacter, Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae. However, in the middle east overall, Escherichia coli was predominant, followed by Staphylococcus aureus, Acinetobacter, and Klebsiella pneumoniae [22], although Syria is part of the Middle East region, heterogeneity and inconsistencies may be present as a result to minimal harmonization in the regional surveillance system.
Different pathogens were dominant in different sources. Gram-negative pathogens were the main cause of urinary tract infections with predominance of Escherichia coli, Enterobacter, and Klebsiella pneumonia. The predominance of Escherichia coli and Klebsiella pneumonia in urine samples correlates with other studies conducted in Iran and Grenada. However, these countries had higher prevalence of Enterococci in comparison to Enterobacter in our study [23, 24]. The Gram-positive pathogens, Staphylococcus aureus and Staphylococcus epidermis, were the main pathogens causing blood sepsis. This correlates with a study conducted in Uganda, while Staphylococcus aureus was predominant in blood culture isolates [25]. Furthermore, the role of Staphylococcus epidermis in bacteremia is well-known as a biofilm-producing organism with abilities to colonize percutaneous or implanted medical devices and access the bloodstream [26]. This correlates with an international study conducted in both USA and France, where coagulase-negative staphylococci were the main cause of bloodstream infections [27]. Enterobacter and Klebsiella pneumoniae were predominant in sputum cultures. However, community acquired pneumonia in Nigeria was mostly caused by streptococcus pneumonia, and Klebsiella pneumoniae [28]. Enterobacter, Klebsiella pneumoniae, and Proteus mirabilis were frequently noted in burn swab isolates, while Staphylococcus aureus, Acinetobacter baumannii, and pseudomonas aeruginosa were responsible for burn infections in China [29]. These discrepancies might be explained by differences in study populations, common diseases in each geographical area, and antimicrobial use in the concerned community.
Enterobacter isolates were completely sensitive to doripenem and cefoperazone-sulbactam only, with high resistance rates to other antibiotics. Resistance to amoxicillin-clavulanic acid, amikacin, cefepime, cefotaxime, ceftriaxone, cefuroxime, ciprofloxacin, gentamycin, meropenem, and trimethoprim-sulfamethoxazole was significantly higher in Syria than in Ethiopia. However, resistance to nitrofurantoin was slightly higher in Ethiopia [30].
Staphylococcus aureus was completely susceptible only to doripenem, with various resistance rates to other antibiotics. Resistance to ceftriaxone, gentamycin, nitrofurantoin, cefixime, ciprofloxacin, trimethoprim-sulfamethoxazole, azithromycin, cefuroxime, and nalidixic acid was higher in this study than in Ethiopia. However, resistance rate to amoxicillin- clavulanic acid, cefotaxime, and vancomycin was close, and lower resistance rates were evident to ceftazidime and clarithromycin [31]. Although Staphylococcus aureus strains had shown various resistance levels to all antibiotics in another study, vancomycin resistance was much higher in this study [32]. The prevalence of vancomycin resistant Staphylococcus aureus in our study is 23,5%. On a global scale, this prevalence is much higher than in Europe (1.1%), Asia (1.2%), Africa (2.5%), and America (3.6%) [33]. Furthermore, linezolid was effective in treating 100% of skin infections caused by Staphylococcus aureus in Hawai [34], and resistance to linezolid among methicillin resistant Staphylococcus aureus in Europe was 0.28% [35]. While resistance to linezolid among Staphylococcus aureus isolates in this study was 24.5%. This accelerating resistance to potent antibiotics in Syria is a serious threat to public health and effective procedures are needed to limit this phenomenon.
Escherichia coli in our sample had no resistance only to meropenem, doripenem and cefoperazone-sulbactam, with various resistance rates to other antibiotics. Higher resistance rates were detected towards amoxicillin-clavulanic acid, ceftriaxone, gentamycin, nitrofurantoin, ciprofloxacin, trimethoprim-sulfamethoxazole, and nalidixic acid in comparison to Ethiopia [36]. Escherichia coli isolated from urine samples in Syria have also demonstrated higher resistance rates to nalidixic acid, ciprofloxacin, gentamycin, ceftriaxone, cefixime, nitrofurantoin, trimethoprim-sulfamethoxazole compared to Iran [37]. Furthermore, our study has detected higher resistance rates for many antibiotics among Escherichia coli isolated from urine, compared to a study conducted in Lebanon. However, resistance to amikacin and piperacillin-tazobactam was lower in our study, and no resistance to meropenem was noted in both studies [38].
Klebsiella pneumoniae has shown various resistance rates to all used antibiotics. In comparison to Bangladesh, higher resistance rates to amoxicillin-clavulanic acid, ceftriaxone, ceftazidime, cefepime, piperacillin-tazobactam, ciprofloxacin, imipenem, and cefuroxime were noted in this study. However, resistance to amikacin and colistin was lower [39]. Urine isolates of Klebsiella pneumoniae showed higher resistance rates to amoxicillin-clavulanic acid, ceftazidime, imipenem, and sulfamethoxazole-trimethoprim than in Grenada. However, resistance to gentamycin, cefuroxime, and ciprofloxacin was lower in our study [40].
According to the Centers for Disease Control and Prevention (CDC), the first-line appropriate antibiotics to treat uncomplicated cystitis are nitrofurantoin and sulfamethoxazole-trimethoprim. The second-line antibiotic is ciprofloxacin, which should be used only when other agents are not appropriate [41]. In our study, the total resistance rate of urine isolates was 28.7% to nitrofurantoin, 66,7% to sulfamethoxazole-trimethoprim, and 61,7% to ciprofloxacin. This increased antibiotic resistance in Syria, especially to second-line antibiotics, is alarming and should be handled urgently.
Imipenem and meropenem are antimicrobial agents used to treat mixed bacterial infections and serious infections caused by organisms resistant to the primary agent of choice. According to the CDC, resistance to these antimicrobials is rare and resistant species should be investigated to suppress any outbreaks [42]. In Syria, the total resistance to imipenem and meropenem was 40,9% and 25% respectively.
Our study has demonstrated that antibiotic resistance in Syria is higher than the average global rate. This can be justified by the lack of regulations on using antibiotics, absence of treatment guidelines, failure to order the proper diagnostic tests before prescribing antibiotics, lack of awareness among the community about the danger of random use of antibiotics, and inefficiency of surveillance systems in tracking this threat. Appropriate interventions should be implemented to tackle this problem. Activating surveillance systems is crucial to monitor multi-drug resistant organisms. We also suggest revising national antimicrobial use policies to develop regional treatment guidelines, in addition to implementing restrictions on purchasing antibiotics, actively using diagnostic tools to apply targeted treatments, and holding local awareness campaigns on antibiotics resistance in order to control this phenomenon and limit its disastrous effects.
Higher rates of urinary tract infections with Escherichia coli, Staphylococcus aureus, Enterobacter, and Klebsiella Pneumonia were detected among females compared to males, while only Escherichia coli and Staphylococcus aureus were more prevalent among urinary stones female patients in another study [43]. Urine isolates in males were more resistant to imipenem, nitrofurantoin, amoxicillin-clavulanic, piperacillin-tazobactam, and cefaclor. The relation between gender and antibiotic resistance was also noted in other studies. For example, higher susceptibility rates of Escherichia coli isolates to piperacillin-tazobactam, and imipenem were also associated with female gender, while nitrofurantoin susceptibility was not associated with gender [44]. On the other hand, in Bangladesh, Escherichia coli strains in male patients were more resistant to amikacin, colistin, and nitrofurantoin [45]. Further large-scale studies are required to determine the factors affecting the correlation between gender and antibiotic resistance.
Strengths and limitations
This is the first study conducted in two main tertiary care hospitals in Damascus, the capital of Syria, with an adequate sample size, to spot the light on antimicrobial resistance in various cultured samples (blood, urine, sputum, …etc.), and to demonstrate the association between gender and antibiotic resistance.
However, our research did not demonstrate whether the infections were acquired in the community or hospital. Moreover, the influence of age, pregnancy, underlying medical issues, infection timeline, and previous antibiotic treatment was not addressed. So further research in this domain is needed.