59 J I M D C 2 0 1 8 59 Open Access F u l l L e n g t h A r t i c l e A Pattern of Antimicrobial Sensitivity and Resistance in Large Series of Indoor Patients at a Tertiary Care Hospital Azmat Ali 1, Fyza Saleem 2, Awais Saeed Abbasi 3 1 Head of Department, Medicine Department, Khan Research Laboratory Hospital, Islamabad 2,3 PG Medicine Khan Research Laboratory Hospital Islamabad A B S T R A C T Objective: In the era of increasing antibiotic resistance, associated with increasing hospital stay and morbidity, the purpose was to define guidelines for antibiotics in different clinical situations. Patients and Methods: This study was conducted at Khan Research Laboratories Hospital, Islamabad, Pakistan, from July 2014 to December 2016. 3277 patients admitted in Medical, Surgical, Gynaecology & Obstetrics, ENT, Eye and Dental departments were included. Positive cultures from different sources including blood, urine, pus, central venous lines, bronchial washings and cervical swabs were taken. Age, gender, common pathogens, their sensitivity and resistance to 27 antimicrobial drugs were taken into account. Statistical Package for Social Sciences (SPSS) version 20 was used for data analysis. Results: 53.1% (n=1738) were females while 46.9% (n=1539) were males.2800 samples were available for analysis. Majority of the patients belonged to Medical ward, 56.9% (n=1864). Major source of culture was urine, 38.3% (n=1073). Escherichia coli (E. coli) was the most common isolate 51.3% (n=1436) followed by Staphylococcus aureus 19.9% (n=558). E. coli showed maximum sensitivity to Imipenem i.e. 94% (n=1349) followed by Amikacin, 93% (n=1335). It was resistant to ceftriaxone (77%).Staphylococcus aureus showed maximum sensitivity to Linezolid and Vancomycin i.e. 98% (n=548) followed by Chloramphenicol 84% (n=470), while being resistant to ciprofloxacin and levofloxacin (54%). Klebsiella pneumoniae showed maximum sensitivity to Imipenem i.e. 75%, while showing resistance to Amoxicillin/Clavulanic Acid (95%) and Ceftriaxone (80%).Staphylococcus epidermidis showed maximum sensitivity to Linezolid i.e.99%. Pseudomonas aeruginosa showed maximum sensitivity to Piperacillin and Tazobactam i.e. 76% . Acinetobacter baumannii showed maximum sensitivity to Colistin i.e. 91%.Salmonella typhi showed maximum sensitivity to Ceftriaxone i.e. 99% while resistance to Ciprofloxacin (94%).Enterococcus faecalis showed maximum sensitivity to Linezolid i.e.100% and Salmonella Paratyphi A showed maximum sensitivities to Cefixime and Ceftriaxone i.e 100% Conclusion: Antibiotic resistance is emerging. Rationale use of antibiotics is required to curtail the surge of antibiotic resistance. There is also a need to modify treatment guidelines in different clinical situations based on local sensitivity and resistance patterns in order to reduce hospital stay, morbidity and mortality. Key words: Antimicrobials, Bacteria, Blood culture, Culture, E. coli; Imipenem, Resistance, Sensitivity, Urine culture. Author`s Contribution 1 Conception, synthesis, planning of research and manuscript writing Interpretation and discussion 2 Data analysis, interpretation and manuscript writing, 3 Active participation in data collection. Address of Correspondence Azmat Ali Email: ali99azmat@gmail.com Article info. Received: August 20, 2017 Accepted: September 11, 2017 Cite this article. Ali A, Saleem F, Abbasi AS. A Pattern of antimicrobial sensitivity and resistance in large series of indoor patients at a tertiary care hospital. JIMDC.2018; 7(1):59- 66 Funding Source: Nil Conflict of Interest: Nil O R I G I N A L A R T I C L E 60 J I M D C 2 0 1 8 60 I n t r o d u c t i o n Antimicrobial resistance is recognized as one of the greatest threats to human health worldwide.1 Drug- resistant infections take a staggering toll in the United States (US) and across the globe. Just one organism, methicillin-resistant Staphylococcus aureus (MRSA), kills more Americans every year (∼19,000) than emphysema, HIV/AIDS, Parkinson's disease, and homicide combined.2 Antibiotic resistance is an increasing crisis as both the range of microbial antibiotic resistance in clinical settings expands and the pipeline for development of new antibiotics contracts.3 The first isolation of a bacterium, enables the design of experimental models to analyze virulence and to complete Koch's criteria, thereby establishing a link between microorganisms and infectious diseases.4 Antimicrobial agents have been greatly important cornerstones of clinical medicine since the second half of the 20th century and have saved a great number of people from life-threatening bacterial infections. However, the last decade of 20th century and the first decade of the 21th century have witnessed the emergence and spread of antibiotic resistance in pathogenic bacteria around the world, and the consequent failure of antibiotic therapy, especially in intensive care units (ICUs), which has led to hundreds of thousands of deaths annually.5 A pure bacterial culture remains essential for the study of its virulence, its antibiotic susceptibility, and its genome sequence in order to facilitate the understanding and treatment of caused diseases. The first culture conditions empirically varied incubation time, nutrients, atmosphere, and temperature; culture was then gradually abandoned in favor of molecular methods. The rebirth of culture in clinical microbiology was prompted by microbiologists specializing in intracellular bacteria.6 Bacterial culture also enables the study of the antibiotic susceptibility of bacteria and is the first step in establishing recommendations for effective treatment. 7,8 A recent study of antibiotic prescribed in primary care for urinary tract infection(UTI) in Ireland identified that only 55% of antibiotic prescriptions could be interpreted as appropriately targeted when evaluated against the laboratory report on the urine sample.9 The theme of World Health Day 2011 “antimicrobial resistance: no action today, no cure tomorrow” highlighted antimicrobial resistance as a major issue. The pathogens currently presenting the biggest problem in terms of antimicrobial resistance as the ESKAPE pathogens: Enterococcus faecium (E. faecium), Staphylococcus aureus (S. aureus), Klebsiella pneumoniae (K. pneumoniae), Acinetobacter baumannii (A. baumannii), Pseudomonas aeruginosa (P. aeruginosa), and Enterobacter species.10,11 Multiple drug resistance (MDR) is defined as non-susceptibility to at least one agent in three or more antimicrobial categories. Extensively drug resistant (XDR) is defined as non- susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories). Pan-drug resistant (PDR) is defined as non-susceptibility to all agents in all antimicrobial categories.12 There has probably been a gene pool in nature for resistance to antibiotics. For most microbes that are antibiotic producers are resistant to their own antibiotic. In retrospect, it is not surprising that resistance to penicillin in some strains of staphylococci was recognized almost immediately after introduction of the drug in 1946. Likewise, very soon after their introduction in the late 1940s, resistance to streptomycin, chloramphenicol and tetracycline was noted. By 1953, during a Shigella outbreak in Japan, a strain of the dysentery bacillus (Shigella dysentery) was isolated which was multiple drug resistant, exhibiting resistances to chloramphenicol, tetracycline, streptomycin and the sulfonamides. Over the years, and continuing into the present almost every known bacterial pathogen has developed resistance to one or more antibiotics in clinical use.13 A study conducted in Ethiopia showed that 54.2% of eye swab cultures were positive for different bacterial pathogens.14 P.aeruginosa found in urinary tract infections showed 19% multi-drug resistant strains in a German study.15 In a study conducted in China, an opportunistic pathogen, A. baumannii showed more than 30% drug resistance to most of the antibiotics tested in the study.16 In a study conducted in Karachi Pakistan, out of 312 cultured specimens, 272 (87.17%) were found to be infected with 437 microbial organisms.17 While in a study 61 J I M D C 2 0 1 8 61 on blood cultures, out of 1824 blood cultures, 508 (27.9%) yielded microorganism growth.18 In another study, the frequency of MDR P. aeruginosa among all the Pseudomonas strains isolated was found to be 22.7%.19 In view of emerging resistance, we conducted our study to ascertain the presence of pathogens in different human sources, and their antimicrobial sensitivity and resistance. P a t i e n t s a n d M e t h o d s This study was conducted at Khan Research Laboratories Hospital, Islamabad, Pakistan, from July 2014 to December 2016. In total 3277 patients admitted in Medical, Surgical, Gynaecology & Obstetrics, ENT, Eye and Dental departments were included. Positive cultures from different sources including blood, urine, pus, central venous lines, bronchial washings and cervical swabs were taken. Age, gender, common pathogens, their sensitivity and resistance to 27 antimicrobial drugs were taken into account. The tested antimicrobials included Imipenem, Meropenem, Cefoperazone/Sulbactam, Pipercillin/Tazobactam, Trimethoprim/sulfamethoxazole (TMP/SMX), Pencillin G, Ampicillin, Amoxicillin/Clavulanic acid, Chloramphenicol, Vancomycin, Linezolid, Amikacin, Gentamicin, Nalidixic acid, Ciprofloxacin, Levofloxacin, Ofloxacin, Cefixime, Ceftriaxone, Ceftazidime, Cefoperazone, Cephradine, Tigecyclin, Doxycycline, Colistin, Nitrofurantoin and fosfomycin. The Bactec blood culture system produced by Becton Dickinson (Mountain View, CA, United States) was used. The Kirby-Bauer (KB) method was used for drug sensitivity testing on Müller- Hinton agar. The results of the drug sensitivity tests were assessed according to the standards of the US Clinical and Laboratory Standards Institute (CLSI). All urine samples were cultured on cysteine lactose electrolyte deficient (CLED) medium. The plates were incubated at 37 C for 24 hours and using gram staining, morphology and biochemical characteristics, bacteria was identified. Antimicrobial susceptibility testing was performed on all isolated bacteria by Kirby Bauer's disc diffusion method as per Clinical and Laboratory Standards Institute (CLSI) recommendations. Isolates were declared as sensitive or resistant on the basis of zone of inhibition following the Laboratory standards. Bronchial washing’s samples were weighed and processed with a 4-fold volume of dithiothreitol (Sputasol, Oxoid Ltd., Hants, UK) and were cultured. Sputum samples were serially diluted and plated on chocolate agar enriched, chocolate agar with bacitracin, Haemophilus-selective agar, blood agar, and MacConkey agar. Plates were incubated for 24-48 hours at 37°C and in 5% CO2 atmosphere. Microorganisms were identified by colony morphology, Gram staining and specific culture conditions. For CSF culture, 0.15 ml of uncentrifuged CSF specimen was inoculated onto each of one 5% sheep blood plate and one chocolate agar plate (Becton Dickinson Microbiology Systems, Cockeysville, Md.), and 1.0 ml was inoculated into 5 ml of BD blood culture bottles. Agar plates were incubated at 37°C in 5% carbon dioxide and examined daily for 3 days. Broth cultures were incubated at 37°C. Cervical swab specimens were placed in Blood Agar (BA) and Sabouraud Agar (SA) for 18-24 hr in 5% CO2 atmosphere at 37℃. Statistical Package for Social Sciences (SPSS) version 20 was used for data analysis. Data of study patients were stated as number of patients and percentages. R e s u l t s Present study comprised of 3277 patients. Total 1738(53.1%) were females while 1539 (46.9%) were males. Only 176 (5.4%) patients were below 20 years of age, 1081 (32.9%) patients were between 20 to 50 years, 1143 (34.9%) patients were between 50 to 70 years and 877 (26.8%) patients were above 70 years. More than half 1864 (56.9%) patients were admitted in Medical ward (Figure 1). Figure 1: Distribution of patients in different wards 62 J I M D C 2 0 1 8 62 Figure 2: Source of cultures Out of 3277 patients, culture samples of 2769 (84.5%) patients were available for analysis (Figure 2) Table 1 illustrates frequency of microorganisms isolated. As shown in the table, Escherichia coli (E. coli) was the most common isolate 51.3% (n=1436), followed by S. aureus 19.9% (n=558) (Table 1) Table: 1 Frequency of common isolates Organism Frequency (%) Escherichia coli 1436 (51.3) Staphylococcus aureus 558 (19.9) Klebsiella pneumonia 405 (14.5) Staphylococcus epidermidis 325 (11.6) Pseudomonas aeruginosa 244 (8.7) Acinetobacter baumannii 233 (8.3) Salmonella typhi 228 (8.1) Enterococcus faecalis 121 (4.3) Salmonella paratyphi A 59 (2.1) Antimicrobial sensitivity and resistance of the above mentioned microorganisms have been shown in table 2 D i s c u s s i o n We conducted our study to determine sensitivity and resistance patterns of microorganisms in different clinical settings. Susceptibility pattern of pathogens has been changing over the years, implying the need for periodic monitoring in order to decrease the number of therapeutic failures and boost an effort to arrest the growing occurrence of antibiotic resistance. Proper collection, transportation and inoculation are other steps required for enhancing bacterial growth on culture media. Microbiologists have to work in collaboration with clinicians in installing newer and appropriate antibiotic discs according to emerging resistance patterns and local antibiogram. In our study, E. coli was found to be the most predominant isolated organism (51.3%). In a study conducted in Saudi Arabia, E. coli was found to be the most common isolate (38.3%).20 In another study conducted in India, E. coli was also the most common isolate having frequency of 59.6%.21 This warrants the need of suspecting E. coli in different clinical conditions and starting appropriate empiric treatment targeting E. coli apart from other microorganisms. E. coli and K. pneumoniae showed greater resistance to Ampicillin, Amoxicillin and TMP/SMX, these results are comparable to another study in which E.coli (34.6%), coagulase- negative staphylococci (19.2%), P. aeruginosa (15.4%), and Klebsiella spp. (11.5%) were common bacterial isolates, where most of them were resistant against ampicillin, amoxicillin, tetracycline, TMP/SMX, and chloramphenicol.22 Of particular interest is the resistance to Ceftriaxone of E.coli(77%) and K.pneumoniae(80%) in this study. These two gram negative organisms showed greater sensitivity to three commonly chosen antibiotics Imipenem, Amikacin and Meropenem.According to a study conducted in Quaid-i-Azam University, Islamabad, the antibiotics showing greater susceptibility towards E. coli and K. pneumoniae isolates were imipenem, piperacillin-tazobactam, ampicillin-sulbactam and amikacin. The antibiotics having the highest resistance, particularly against the Extended Spectrum Beta Lactamases (ESBLs) producers were amoxicillin/clavulanic acid, TMP/SMX, cefuroxime, cefpirome, ceftriaxone and ciprofloxacin and should be removed from the line of treatment for common urinary tract infections23, while a study conducted in Saudi Arabia showed that E.coli is more than 78% resistant to Amikacin.20 P. aeruginosa showed alarming resistance to the once commonly prescribed antibiotics including 63 J I M D C 2 0 1 8 63 Table 2: Sensitivity and resistance pattern of Various Organism Escherichia coli (E.coli) (n=1436) Sensitivity Resistance Antibiotic n % Antibiotic n % Imipenem 1349 94 Ampicillin 1293 90 Amikacin 1335 93 Cefixime 1136 79 Meropenem 1250 87 Amoxicillin/Clavulanate 1111 77 Cefoperazone/Sulbactam 1045 73 Ceftriaxone 1105 77 Pipercillin/Tazobactam 979 68 TMP/SMX 1082 75 Staphylococcus aureus (n=558) Linezolid 548 98 Penicillin G 535 96 Chloramphenicol 470 84 Ampicillin 532 95 Amikacin 457 82 Ciprofloxacin 304 54 Doxycycline 447 80 Levofloxacin 299 54 Vancomycin 548 98 Ofloxacin 245 44 Klebsiella pneumoniae (n=405) Imipenem 304 75 Ampicillin 395 98 Meropenem 297 73 Amoxillin/clavulanic acid 384 95 Amikacin 270 67 Cefixime 336 83 Cefoperazone/Sulbactam 210 52 Ceftriaxone 326 80 Pipercillin/Tazobactam 181 45 TMP/SMX 300 74 Staphylococcus epidemidis (n=325) Linezolid 323 99 Ampicillin 316 97 Amikacin 294 90 Penicillin G 314 97 Vancomycin 277 85 Ciprofloxacin 208 64 Chloramphenicol 270 83 Levofloxacin 207 64 Gentamicin 215 66 Ofloxacin 177 54 Pseudomonas aeruginosa (n=244) Piperacillin/tazobactam 186 76 Levofloxacin 95 39 Amikacin 183 75 Ciprofloxacin 90 37 Cefoperazone/sulbactam 182 75 Ceftazidime 80 33 Imipenem 179 73 Cefoperazone 80 33 Gentamicin 164 67 Gentamicin 74 30 Acinetobacter baumannii (n=233) Colisitin 213 91 Amoxillin/clavulanic acid 231 99 Tigecycline 187 80 Ceftriaxone 227 97 Gentamicin 91 39 Ampicillin 226 97 Amikacin 70 30 Cefixime 225 97 Cefoperazone/sulbactam 60 26 Ciprofloxacin 224 96 Ceftazidime (33%), Ciprofloxacin (37%) and Gentamicin (30%). Similar pattern of resistance was observed in another study with resistance to ceftazidime (41%), gentamicin (27%) and ciprofloxacin (26%).24 In our study S. aureus was sensitive to Vancomycin & Linezolid (98%). S. epidermidis showed 99% sensitivity to 64 J I M D C 2 0 1 8 64 Table 2a: Sensitivity and Resistance Pattern of Various Organism (n=228) Sensitivity Resistance Antibiotic n % Antibiotic n % Salmonella Typhi (n=228) Ceftriaxone 227 99 Ciprofloxacin 214 94 Cefixime 222 97 Levofloxacin 212 93 Ampicillin 99 43 Naladixic acid 200 88 TMP/SMX 95 42 Ofloxacin 179 79 Chloramphenicol 77 33 TMP/SMX 133 58 Enterococcus Faecalis (n=121) Linezolid 121 100 Ceftriaxone 108 89 Vancomycin 109 90 Ciprofloxacin 108 89 Amoxillin/clavulanic acid 74 61 Levofloxacin 108 89 Ampicillin 70 58 Cefixime 107 88 Nitrofurantoin 55 45 Cephradine 94 78 Salmonella Paratyphi A (n=59) Cefixime 59 100 Ciprofloxacin 57 97 Ceftriaxone 59 100 Levofloxacin 57 97 Ampicillin 54 92 Naladixic acid 57 97 TMP/SMX 53 90 Ofloxacin 56 95 Chloramphenicol 50 85 Ampicillin 5 8 Linezolid and 85% to Vancomycin. However, in a study conducted in Saudi Arabia it was found that resistant and susceptibility profile of S. aureus showed high resistance to both ampicillin and linezolid (94.1%) and high sensitivity to more than one antibiotic such as daptomycin, penicillin, Synercid, teicoplanin, vancomycin, and TMP/SMX, which have sensitivity rate more than 88%.21 E. faecalis which frequently cause urinary tract infection, endocarditis and bacteremia, showed resistance to generally prescribed empiric antibiotics regimen like Ceftriaxone, Levofloxacin and Ciprofloxacin (89%). E. faecalis was sensitive to Linezolid (100%), Vancomycin (90%) and Amoxicillin/Clavulanic acid (61%). Linezolid, vancomycin and teicoplanin are currently widely used drugs for the effective treatment of enterococcal infections.25-27 A baumannii showed sensitivity to Colistin (91%) and Tigecyclin (80%), while is resistant to Amoxicillin/Clavulanic acid (99%), Ceftriaxone, Ampicillin and Cefixime (97%). Therefore, it is sensitive to antibiotics prescribed for ventilator associated pneumonia(VAP) (A. baumannii is a common cause of VAP). Colistin and tigecycline are in many cases the unique options for the treatment of many episodes of VAP caused by multiple drug resistant- gram negative bacteria (MDR-GNB ).28 S. typhi and S. paratyphi A showed high degree of resistance to Quinolones. Ciprofloxacin (94%), Levofloxacin (93%) for S.typhi; Ciprofloxacin and Levofloxacin (97%) for S.paratyphi A. Both these organisms showed almost no resistance to Ceftiaxone and Cefixime. According to a study conducted in Islamabad the prevalence of MDR and fluoroquinolone resistance was very high among salmonella serovars. No resistance was found to third-generation cephalosporins.29 C o n c l u s i o n Antibiotic resistance is an emerging problem. Rationale use of antibiotics is required to curtail the surge of antibiotic resistance. 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