Trends in antimicrobial resistance amongst pathogens isolated from blood and cerebrospinal fluid cultures in Pakistan (2011-2015): A retrospective cross-sectional study

Abstract

While antimicrobial resistance (AMR) continues to be a major public health problem in Pakistan, data regarding trends of resistance among pathogenic bacteria remains scarce, with few studies presenting long-term trends in AMR. This study was therefore designed to analyze long-term AMR trends at a national level in Pakistan. We report here results of a comprehensive analysis of resistance, among pathogens isolated from blood and cerebrospinal fluid (CSF), between 2011 and 2015. Susceptibility data was obtained from a local laboratory with collection points all across Pakistan (Chughtai Laboratory). Resistance proportions to most commonly used antimicrobials were calculated for each pathogen over a period of five years. While Acinetobacter species demonstrated highest resistance rates to all tested antimicrobials, a sharp increase in carbapenem resistance was the most noticeable (50%-95%) between 2011-2015. Our results also highlight the presence of third and fourth generation cephalosporins resistance in Salmonella enterica serovar Typhi in Pakistan. Interestingly, where rise in AMR was being observed in some major invasive pathogens, decreasing resistance trends were observed in Staphylococcus aureus, against commonly used antimicrobials. Overall pathogens isolated from blood and CSF between 2011-2015, showed an increase in resistance towards commonly used antimicrobials.

Fig 1. Flow of cases.

Flow of the cases through the study has been shown.

Fig 2. Antimicrobial resistance in Escherichia coli (E. coli).

A: Each section of the diagram represents the resistance observed in E. coli against the antibiotic. Size of each section is proportional to the proportion of E. coli resistant to the antibiotic over the study period. Antibiotics of the same class are shown in similar colors. B: Line graphs show temporal trends of proportion of resistant E. coli in a clockwise direction from 2011 to 2015. C: Bar charts show the comparison of susceptibility to resistant strains in patients of different age groups. Moving from out to inward, bars represent proportion of resistant E. coli reported in children <5 years of age, young adults between 6 to 18 years, middle aged 19 to 45 years old, 45 to 65 years old patients, and elderly over 65 years of age, respectively. D: Gender-wise comparison to susceptibility to resistant E. coli is shown in form bars. Outer circle and inner circle shows proportion of resistant E. coli isolated from women vs. men, respectively. E: For co-resistance analysis, antibiotics belonging to the same class with same susceptibility profile for all isolates of E. coli were merged into a single variable. F: Proportion of E. coli isolates resistant to one antimicrobial resistant to another antimicrobial are shown in the connections. The area covered by the connection on E is proportional to the level of co-resistance observed. Co-resistance proportions were scaled down to 1/15^th of the actual overlap for visualization. Abbreviations: AMI: Amikacin, GEN: Gentamicin, TOB: Tobramycin, IMI: Imipenem, MER: Meropenem, CPL: Cephalexin, CPD: Cephradine, CFC: Cefaclor, CFU: Cefuroxime, CFT: Cefotaxime, CFD: Ceftazidime, CFN: Ceftriaxone, CFX: Cefixime, CPZ: Cefoperazone, CFP: Cefepime, CPZ-S: Cefoperazone-Sulbactam, PIP-T: Piperacillin-Tazobactam, AMX-C: Amoxicillin-Clavulanic acid, AMP-S: Ampicillin-Sulbactam, CIP: Ciprofloxacin, LEV: Levofloxacin, OFL: Ofloxacin, MOX: Moxifloxacin, AZT: Aztreonam, TRI-S: Trime-Sulphamethoxazole, and DOX: Doxycycline.

Fig 3. Antimicrobial resistance in Acinetobacter.

A: Each section of the diagram represents the resistance observed in Acinetobacter species against the antibiotic. Size of each section is proportional to the proportion of Acinetobacter species resistant to the antibiotic over the study period. Antibiotics of the same class are shown in similar colors. B: Line graphs show temporal trends of proportion of resistant Acinetobacter species in a clockwise direction from 2011 to 2015. C: Bar charts show the comparison of susceptibility to resistant isolates in patients of different age groups. Moving from out to inward, bars represent proportion of resistant Acinetobacter species reported in children <5 years of age, young adults between 6 to 18 years, middle aged 19 to 45 years old, 45 to 65 years old patients, and elderly over 65 years of age, respectively. D: Gender-wise comparison to susceptibility to resistant Acinetobacter species is shown in form bars. Outer circle and inner circle shows proportion of resistant Acinetobacter species isolated from women vs. men, respectively. E: For co-resistance analysis, antibiotics belonging to the same class with same susceptibility profile for all isolates of E. coli were merged into a single variable. F: Proportion Acinetobacter species isolates resistant to one antimicrobial resistant to another antimicrobial are shown in the connections. The area covered by the connection on E is proportional to the level of co-resistance observed. Co-resistance proportions were scaled down to 1/10^th of the actual overlap for visualization. Abbreviations: DOX: Doxycycline, TRI-S: Trime-Sulphamethoxazole, PIP-T: Piperacillin-Tazobactam, AMP-S: Ampicillin-Sulbactam, AMX-C: Amoxicillin-Clavulanic acid, CIP: Ciprofloxacin, LEV: Levofloxacin, OFL: Ofloxacin, MOX: Moxifloxacin, CFN: Ceftriaxone, CFD: Ceftazidime, CFT: Cefotaxime, CPZ: Cefoperazone, CFX: Cefixime, CFP: Cefepime, CPZ-S: Cefoperazone-Sulbactam, IMI: Imipenem, MER: Meropenem, TOB: Tobramycin, GEN: Gentamicin, and AMI: Amikacin.

Fig 4. Antimicrobial resistance in Salmonella enterica serovar Typhi (S. Typhi).

A: Each section of the diagram represents the resistance observed in S. Typhi against the antibiotic. Size of each section is proportional to the proportion of S. Typhi resistant to the antibiotic over the study period. Antibiotics of the same class are shown in similar colors. B: Line graphs show temporal trends of proportion of resistant S. Typhi in a clockwise direction from 2011 to 2015. C: Bar charts show the comparison of susceptibility to resistant isolates in patients of different age groups. Moving from out to inward, bars represent proportion of resistant S. Typhi reported in children <5 years of age, young adults between 6 to 18 years, and middle aged 19 to 45 years old, respectively. D: Gender-wise comparison to susceptibility to resistant S. Typhi is shown in form bars. Outer circle and inner circle show proportion of resistant S. Typhi isolated from women vs. men, respectively. E: For co-resistance analysis, antibiotics belonging to the same class with same susceptibility profile for all isolates of E. coli were merged into a single variable. F: Proportion S. Typhi isolates resistant to one antimicrobial resistant to another antimicrobial are shown in the connections. The area covered by the connection on E is proportional to the level of co-resistance observed. Co-resistance proportions were scaled down to 1/10^th of the actual overlap for visualization. Abbreviations: CFN: Ceftriaxone, CFD: Ceftazidime, CFT: Cefotaxime, CPZ: Cefoperazone, CFX: Cefixime, CFP: Cefepime, CIP: Ciprofloxacin, LEV: Levofloxacin, OFL: Ofloxacin, MOX: Moxifloxacin, NAL-A: Nalidixic acid, AMP-S: Ampicillin-Sulbactam, AMX-C: Amoxicillin-Clavulanic acid, AMP: Ampicillin, AMX: Amoxicillin, and TRI-S: Trime-Sulphamethoxazole.

Fig 5. Antimicrobial resistance in Staphylococcus aureus (S. aureus).

A: Each section of the diagram represents the resistance observed in S. aureus against the antibiotic. Size of each section is proportional to the proportion of S. aureus resistant to the antibiotic over the study period. Antibiotics of the same class are shown in similar colors. B: Line graphs show temporal trends of proportion of resistant S. aureus in a clockwise direction from 2011 to 2015. C: Bar charts show the comparison of susceptibility to resistant strains in patients of different age groups. Moving from out to inward, bars represent proportion of resistant S. aureus reported children in <5 years of age, young adults between 6 to 18 years, middle aged 19 to 45 years old, 45 to 65 years old patients, and elderly over 65 years of age, respectively. D: Gender-wise comparison to susceptibility to resistant S. aureus is shown in form bars. Outer circle and inner circle show proportion of resistant S. aureus isolated from women vs. men, respectively. E: For co-resistance analysis, antibiotics belonging to the same class with same susceptibility profile for all isolates of S. aureus were merged into a single variable. F: Proportion of S. aureus isolates resistant to one antimicrobial resistant to another antimicrobial are shown in the connections. The area covered by the connection on E is proportional to the level of co-resistance observed. Co-resistance proportions were scaled down to 1/10^th of the actual overlap for visualization. Abbreviations: AMI: Amikacin, GEN: Gentamicin, TOB: Tobramycin, AMP: Ampicillin, AMX: Amoxicillin, IMI: Imipenem, MER: Meropenem, CPL: Cephalexin, CPD: Cephradine, CFC: Cefaclor, CFU: Cefuroxime, CFT: Cefotaxime, CFD: Ceftazidime, CFN: Ceftriaxone, CFX: Cefixime, CPZ: Cefoperazone, CFP: Cefepime, AMX-C: Amoxicillin-Clavulanic acid, AMP-S: Ampicillin-Sulbactam, CIP: Ciprofloxacin, LEV: Levofloxacin, OFL: Ofloxacin, MOX: Moxifloxacin, CLI: Clindamycin, AZI: Azithromycin, ERY: Erythromycin, TRI-S: Trime-Sulphamethoxazole, and DOX: Doxycycline.