1. Epidemiology and Global Health
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Epidemiology and burden of multidrug-resistant bacterial infection in a developing country

  1. Cherry Lim
  2. Emi Takahashi
  3. Maliwan Hongsuwan
  4. Vanaporn Wuthiekanun
  5. Visanu Thamlikitkul
  6. Soawapak Hinjoy
  7. Nicholas PJ Day
  8. Sharon J Peacock
  9. Direk Limmathurotsakul  Is a corresponding author
  1. Mahidol University, Thailand
  2. Ministry of Public Health, Thailand
  3. University of Oxford, United Kingdom
  4. London School of Hygiene and Tropical Medicine, United Kingdom
  5. University of Cambridge, Addenbrooke’s Hospital, United Kingdom
Research Article
Cite this article as: eLife 2016;5:e18082 doi: 10.7554/eLife.18082
7 figures, 8 tables and 2 additional files

Figures

Location of participating hospitals.

These were situated in (1) Nong Khai, (2) Udon Thani, (3) Nakhon Phanom, (4) Chaiyaphum, (5) Mukdahan, (6) Yasothon, (7) Burirum, (8) Sisaket, and (9) Ubon Ratchathani provinces.

https://doi.org/10.7554/eLife.18082.003
Trends in proportions of Staphylococcus aureus bacteraemia being caused by MRSA in Northeast Thailand.

(A) community-acquired, (B) healthcare-associated and (C) hospital-acquired Staphylococcus aureus bacteraemia.

https://doi.org/10.7554/eLife.18082.005
Trends in proportions of Escherichia coli bacteraemia being caused by E. coli non-susceptible to extended-spectrum cephalosporins in Northeast Thailand.

(A) community-acquired, (B) healthcare-associated and (C) hospital-acquired E. coli bacteraemia.

https://doi.org/10.7554/eLife.18082.007
Trends in proportions of Klebsiella pneumoniae bacteraemia being caused by K. pneumoniae non-susceptible to extended-spectrum cephalosporins in Northeast Thailand.

(A) community-acquired, (B) healthcare-associated and (C) hospital-acquired K. pneumoniae bacteraemia.

https://doi.org/10.7554/eLife.18082.010
Trends in proportions of Pseudomonas aeruginosa bacteraemia being caused by P. aeruginosa non-susceptible to carbapenem in Northeast Thailand.

(A) community-acquired, (B) healthcare-associated and (C) hospital-acquired Pseudomonas aeruginosa bacteraemia.

https://doi.org/10.7554/eLife.18082.012
Trends in proportions of Acinetobacter spp bacteraemia being caused by Acinetobacter spp non-susceptible to carbapenem in Northeast Thailand.

(A) community-acquired, (B) healthcare-associated and (C) hospital-acquired Acinetobacter spp bacteraemia.

https://doi.org/10.7554/eLife.18082.014
Forest plot of mortality in patients with MDR bacteraemia compared with non-MDR bacteraemia in Northeast Thailand.

(A) Community-acquired bacteraemia. (B) Healthcare-associated bacteraemia. (C) Hospital-acquired bacteraemia.

https://doi.org/10.7554/eLife.18082.016
Figure 7—source data 1

Mortality in patients with MDR and non-MDR bacteraemia in Northeast Thailand.

https://doi.org/10.7554/eLife.18082.017

Tables

Table 1

Proportions of bacteraemias being caused by multidrug-resistant (MDR) variants of those bacteria.

https://doi.org/10.7554/eLife.18082.004
PathogensCommunity-acquired bacteraemia
(CAB)
Healthcare-associated bacteraemia
(HCAB)
Hospital-acquired bacteraemia
(HAB)
p values
MDR Staphylococcus aureus94/1176 (8%)73/259 (28%)222/446 (50%)<0.001
MDR Enterococcus spp0/176 (0%)0/49 (0%)4/117 (3%)0.02
MDR Escherichia coli1177/3382 (35%)288/494 (58%)252/403 (63%)<0.001
MDR Klebsiella pneumoniae146/1010 (14%)71/196 (36%)301/455 (66%)<0.001
MDR Pseudomonas aeruginosa13/286 (5%)10/103 (10%)45/179 (25%)<0.001
MDR Acinetobacter spp125/449 (28%)58/115 (50%)374/501 (75%)<0.001
  1. NOTE: CAB was defined as the isolation of a pathogenic bacterium from blood taken in the first 2 days of admission and without a hospital stay in the 30 days prior to admission. HCAB was defined as the isolation of a pathogenic bacterium from blood taken in the first 2 days of admission and with a hospital stay within 30 days prior to the admission. HAB was defined as the isolation of a pathogenic bacterium from blood taken after the first 2 days of admission.

Table 2

Antibiogram of S. aureus causing bacteraemia in Northeast Thailand.

https://doi.org/10.7554/eLife.18082.006
Antibiotic categoryAntibiotic agentsCAB
(n = 1176 patients)
HCAB
(n = 259 patients)
HAB
(n = 446 patients)
p values
AminoglycosidesGentamicin24/484 (5%)16/84 (19%)66/151 (44%)<0.001
AnsamycinsRifampin2/129 (2%)1/19 (5%)0/38 (0%)0.37
Anti-MRSA cephalosporinsCeftarolineNANANA-
CefamycinsOxacillin *80/1145 (7%)67/247 (27%)210/441 (48%)<0.001
FluoroquinolonesCiprofloxacin3/45 (7%)2/8 (25%)4/10 (40%)0.01
MoxifloxacinNANANA-
Folate pathway inhibitorsTrimethoprim-sulphamethoxazole99/1139 (9%)57/251 (23%)185/438 (42%)<0.001
FucidanesFusidic acid33/618 (5%)4/170 (2%)12/291 (4%)0.26
GlycopeptidesVancomycin †4/833 (0.5%)0/190 (0%)2/357 (1%)0.86
Teicoplanin2/66 (3%)1/17 (6%)0/17 (0%)0.72
TelavancinNANANA-
GlycylcyclinesTigecyclineNANANA-
LincosamidesClindamycin118/1147 (10%)77/251 (31%)202/438 (46%)<0.001
LipopeptidesDaptomycinNANANA-
MacrolidesErythromycin138/1116 (12%)76/240 (32%)222/429 (52%)<0.001
OxazolidinonesLinezolid0/81 (0%)0/16 (0%)0/32 (0%)-
PhenicolsChloramphenicol6/86 (7%)4/24 (17%)2/14 (14%)0.21
Phosphonic acidsFosfomycin14/361 (4%)10/66 (15%)24/141 (17%)<0.001
StreptograminsQuinupristin-dalfopristinNANANA-
TetracyclinesTetracyclineNANANA-
DoxycyclineNANANA-
MinocyclineNANANA-
MDR94/1176 (8%)73/259 (28%)222/446 (50%)<0.001
  1. NOTE: Data are number of isolates demonstrating non-susceptible to the antimicrobial over the total number of isolates tested (%). CAB = Community-acquired bacteraemia, HCAB = Healthcare-associated bacteraemia, HAB = Hospital-acquired bacteraemia, and NA = Not available. The first isolate of each patient was used. MDR (one or more of these have to apply): (i) an MRSA is always considered MDR by virtue of being an MRSA (ii) non-susceptible to ≥1 agent in ≥3 antimicrobial categories.

  2. * Defined by using a 30 μg cefoxitin disc and an inhibition zone diameter of <21 mm.

  3. † Defined by using a 30 μg vancomycin disc and an inhibition zone diameter of <15 mm.

Table 3

Antibiogram of Enterococcus spp. causing bacteraemia in Northeast Thailand.

https://doi.org/10.7554/eLife.18082.008
Antibiotic categoryAntibiotic agentsCAB
(n = 176 patients)
HCAB
(n = 49 patients)
HAB
(n = 117 patients)
p values
AminoglycosidesGentamicin
(high level)
35/153 (23%)24/45 (53%)63/101 (62%)<0.001
StreptomycinStreptomycin
(high level)
NANANA-
Carbapenems*ImipenemNANANA-
Meropenem1/1 (100%)NA3/5 (60%)>0.99
DoripenemNANANA-
FluoroquinolonesCiprofloxacin37/44 (84%)9/10 (90%)31/37 (84%)>0.99
Levofloxacin5/18 (28%)1/6 (17%)11/15 (73%)0.01
MoxifloxacinNANANA-
GlycopeptidesVancomycin9/176 (5%)0/49 (0%)6/113 (5%)0.27
Teicoplanin0/11 (0%)0/4 (0%)0/10 (0%)-
GlycylcyclinesTigecyclineNANANA-
LipopeptidesDaptomycinNANANA-
OxazolidinonesLinezolid0/8 (0%)0/2 (0%)0/4 (0%)-
PenicillinsAmpicillin20/134 (15%)6/37 (16%)34/81 (42%)<0.001
Streptogramins*Quinupristin-dalfopristinNANANA-
TetracyclineDoxycyclineNANANA-
MinocyclineNANANA-
MDR0/176 (0%)0/49 (0%)4/117 (3%)0.02
  1. NOTE: Data are number of isolates demonstrating non-susceptible to the antimicrobial over the total number of isolates tested (%). CAB = Community-acquired bacteraemia, HCAB = Healthcare-associated bacteraemia, HAB = Hospital-acquired bacteraemia, and NA = Not available. The first isolate of each patient was used. MDR: non-susceptible to ≥1 agent in ≥3 antimicrobial categories.

  2. *Intrinsic resistance in E. faecium against carbapenems and in E. faecalis against streptogramins. When a species has intrinsic resistance to an antimicrobial category, that category is removed prior to applying the criteria for the MDR definition and is not counted when calculating the number of categories to which the bacterial isolate is non-susceptible.

Table 4

Antibiogram of E. coli causing bacteraemia in Northeast Thailand.

https://doi.org/10.7554/eLife.18082.009
Antibiotic categoryAntibiotic agentsCAB
(n = 3382 patients)
HCAB
(n = 494 patients)
HAB
(n = 403 patients)
p values
AminoglycosidesGentamicin559/3346 (17%)166/484 (34%)178/398 (45%)<0.001
TobramycinNANANA-
Amikacin72/2685 (3%)26/397 (7%)32/326 (10%)<0.001
Netilmicin68/1394 (5%)25/259 (10%)42/254 (17%)<0.001
Anti-MRSA cephalosporinsCeftarolineNANANA-
Antipseudomonal penicillins + β lactamase inhibitorsTicarcillin-clauvanic acidNANANA-
Piperacillin-tazobactam23/511 (5%)10/103 (10%)15/89 (17%)<0.001
CarbapenemsErtapenem4/1325 (<1%)1/235 (<1%)4/205 (2%)0.02
Imipenem3/2449 (<1%)0/386 (0%)3/344 (1%)0.04
Meropenem0/1988 (0%)1/314 (<1%)1/244 (<1%)0.05
Non-extended spectrum cephalosporinsCefazolin468/1095 (43%)115/174 (66%)80/102 (78%)<0.001
Cefuroxime219/1438 (15%)96/226 (42%)102/202 (50%)<0.001
Extended-spectrum cephalosporinsCefotaxime501/3076 (16%)199/455 (44%)185/361 (51%)<0.001
Ceftazidime392/3020 (13%)165/446 (37%)164/351 (47%)<0.001
Cefepime30/293 (10%)12/42 (29%)18/53 (34%)<0.001
CephamycinsCefoxitin36/1200 (3%)16/215 (7%)16/195 (8%)<0.001
CefotetanNANANA-
FluoroquinolonesCiprofloxacin728/3000 (24%)221/452 (49%)171/384 (45%)<0.001
Folate pathway inhibitorsTrimethoprim-sulphamethoxazole1738/3007 (58%)294/442 (67%)225/350 (64%)<0.001
GlycylcyclinesTigecycline0/7 (0%)NA0/1 (0%)-
MonobactamsAztreonamNANANA-
PenicillinsAmpicillin2246/2843 (79%)371/420 (88%)301/342 (88%)<0.001
Penicillins + β lactamase inhibitorsAmoxicillin-clavulanic acid790/3074 (26%)191/463 (41%)158/373 (42%)<0.001
Ampicillin-sulbactam83/296 (28%)18/48 (38%)12/25 (48%)0.06
PhenicolsChloramphenicol14/63 (22%)1/4 (25%)3/5 (60%)0.14
Phosphonic acidsFosfomycinNANANA-
PolymyxinsColistin*2/34 (6%)0/6 (0%)1/6 (17%)0.61
MDR1177/3382 (35%)288/494 (58%)252/403 (63%)<0.001
  1. NOTE: Data are number of isolates demonstrating non-susceptible to the antimicrobial over the total number of isolates tested (%). CAB = Community-acquired bacteraemia, HCAB = Healthcare-associated bacteraemia, HAB = Hospital-acquired bacteraemia, and NA = Not available. The first isolate of each patient was used. MDR: non-susceptible to ≥1 agent in ≥3 antimicrobial categories.

  2. *Defined by using an inhibition zone of <11 mm.

Table 5

Antibiogram of K. pneumoniae causing bacteraemia in Northeast Thailand.

https://doi.org/10.7554/eLife.18082.011
Antibiotic categoryAntibiotic agentsCAB
(n = 1010 patients)
HCAB
(n = 196 patients)
HAB
(n = 455 patients)
p values
AminoglycosidesGentamicin94/999 (9%)53/193 (27%)265/444 (60%)<0.001
TobramycinNANANA-
Amikacin17/815 (2%)12/157 (8%)109/398 (27%)<0.001
Netilmicin20/450 (4%)23/112 (21%)124/320 (39%)<0.001
Anti-MRSA cephalosporinsCeftarolineNANANA-
Antipseudomonal penicillins + β lactamase inhibitorsTicarcillin-clauvanic acidNANANA-
Piperacillin-tazobactam24/166 (14%)14/32 (44%)73/121 (60%)<0.001
CarbapenemsErtapenem2/432 (0%)1/100 (1%)5/264 (2%)0.17
Imipenem1/778 (0%)1/164 (1%)2/408 (0%)0.24
Meropenem0/583 (0%)1/113 (1%)2/317 (1%)0.10
Non-extended spectrum cephalosporinsCefazolin76/319 (24%)30/60 (50%)101/127 (80%)<0.001
Cefuroxime81/478 (17%)35/98 (36%)161/231 (70%)<0.001
Extended-spectrum cephalosporinsCefotaxime146/902 (16%)71/173 (41%)298/424 (70%)<0.001
Ceftazidime124/927 (13%)63/176 (36%)295/430 (69%)<0.001
Cefepime5/100 (5%)8/22 (36%)25/51 (49%)<0.001
CephamycinsCefoxitin15/396 (4%)10/95 (11%)14/230 (6%)0.03
CefotetanNANANA-
FluoroquinolonesCiprofloxacin143/894 (16%)66/176 (38%)187/430 (43%)<0.001
Folate pathway inhibitorsTrimethoprim-sulphamethoxazole198/876 (23%)69/171 (40%)219/407 (54%)<0.001
GlycylcyclinesTigecyclineNANANA-
MonobactamsAztreonamNANANA-
Penicillins + β lactamase inhibitorsAmoxicillin-clavulanic acid131/945 (14%)68/183 (37%)291/443 (66%)<0.001
Ampicillin-sulbactam20/105 (19%)9/17 (53%)23/38 (61%)<0.001
PhenicolsChloramphenicol4/19 (21%)0/2 (0%)0/3 (0%)>0.99
Phosphonic acidsFosfomycinNANANA-
PolymyxinsColistin *0/6 (0%)0/2 (0%)0/5 (0%)-
MDR146/1010 (14%)71/196 (36%)301/455 (66%)<0.001
  1. NOTE: Data are number of isolates demonstrating non-susceptible to the antimicrobial over the total number of isolates tested (%). CAB = Community-acquired bacteraemia, HCAB = Healthcare-associated bacteraemia, HAB = Hospital-acquired bacteraemia, and NA = Not available. The first isolate of each patient was used. MDR: non-susceptible to ≥1 agent in ≥3 antimicrobial categories.

  2. * Defined by using an inhibition zone of <11 mm.

Table 6

Antibiogram of P. aeruginosa causing bacteraemia in Northeast Thailand.

https://doi.org/10.7554/eLife.18082.013
Antibiotic categoryAntibiotic agentsCAB
(n = 286 patients)
HCAB
(n = 103 patients)
HAB
(n = 179 patients)
p values
AminoglycosidesGentamicin29/235 (12%)13/88 (15%)60/140 (43%)<0.001
TobramycinNANANA-
Amikacin27/284 (10%)13/100 (13%)48/177 (27%)<0.001
Netilmicin8/155 (5%)5/67 (7%)34/120 (28%)<0.001
Antipseudomonal carbapenemsImipenem14/238 (6%)6/86 (7%)37/154 (24%)<0.001
Meropenem9/163 (6%)8/73 (11%)24/125 (19%)0.001
Doripenem2/17 (12%)0/3 (0%)2/2 (100%)0.04
Antipseudomonal cephalosporinsCeftazidime29/280 (10%)16/103 (16%)68/179 (38%)<0.001
Cefepime2/36 (6%)2/18 (11%)10/28 (36%)0.01
Antipseudomonal fluoroquinolonesCiprofloxacin24/275 (9%)12/101 (12%)39/169 (23%)<0.001
Levofloxacin0/1 (0%)1/1 (100%)1/1 (100%)>0.99
Antipseudomonal penicillins + β lactamase inhibitorsTicarcillin-clauvanic acidNANANA-
Piperacillin-tazobactam8/85 (9%)6/38 (16%)8/46 (17%)0.37
MonobactamsAztreonamNANANA-
Phosphonic acidsFosfomycin1/1 (100%)NANA-
PolymyxinsColistin0/7 (0%)0/3 (0%)1/7 (14%)>0.99
Polymyxin BNANANA-
MDR13/286 (5%)10/103 (10%)45/179 (25%)<0.001
  1. NOTE: Data are number of isolates demonstrating non-susceptible to the antimicrobial over the total number of isolates tested (%). CAB = Community-acquired bacteraemia, HCAB = Healthcare-associated bacteraemia, HAB = Hospital-acquired bacteraemia, and NA = Not available. The first isolate of each patient was used. MDR: non-susceptible to ≥1 agent in ≥3 antimicrobial categories.

Table 7

Antibiogram of Acinetobacter spp. causing bacteraemia in Northeast Thailand.

https://doi.org/10.7554/eLife.18082.015
Antibiotic categoryAntibiotic agentsCAB
(n = 449 patients)
HCAB
(n = 115 patients)
HAB
(n = 501 patients)
p values
AminoglycosidesGentamicin112/390 (29%)45/105 (43%)310/455 (68%)<0.001
TobramycinNANANA-
Amikacin123/442 (28%)45/112 (40%)310/495 (63%)<0.001
Netilmicin44/203 (22%)24/64 (38%)224/381 (59%)<0.001
Antipseudomonal carbapenemsImipenem87/397 (22%)37/102 (36%)293/459 (64%)<0.001
Meropenem65/284 (23%)32/81 (40%)229/348 (66%)<0.001
Doripenem16/45 (36%)9/10 (90%)6/7 (86%)0.001
Antipseudomonal fluoroquinolonesCiprofloxacin84/413 (20%)53/106 (50%)322/481 (67%)<0.001
Levofloxacin2/5 (40%)2/2 (100%)8/9 (89%)0.11
Antipseudomonal penicillins + β lactamase inhibitorsTicarcillin- clauvanic acidNANANA-
Piperacillin-tazobactam22/98 (22%)13/28 (46%)74/106 (70%)<0.001
Extended-spectrum cephalosporinsCefotaxime242/291 (83%)89/94 (95%)407/420 (97%)<0.001
Ceftazidime133/448 (30%)61/114 (54%)377/500 (75%)<0.001
Cefepime18/53 (34%)10/22 (45%)95/133 (71%)<0.001
Folate pathway inhibitorTrimethopri-sulphamethoxazole119/356 (33%)55/99 (56%)333/435 (77%)<0.001
Penicillins + β lactamase inhibitorsAmpicillin-sulbactam43/134 (32%)16/29 (55%)79/115 (69%)<0.001
PolymyxinsColistin *2/16 (13%)0/14 (0%)0/33 (0%)0.11
Polymyxin BNANANA-
TetracyclinesTetracyclineNANANA-
DoxycyclineNANANA-
MinocyclineNANANA-
MDR125/449 (28%)58/115 (50%)374/501 (75%)<0.001
  1. NOTE: Data are number of isolates demonstrating non-susceptible to the antimicrobial over the total number of isolates tested (%). CAB = Community-acquired bacteraemia, HCAB = Healthcare-associated bacteraemia, HAB = Hospital-acquired bacteraemia, and NA = Not available. The first isolate of each patient was used. MDR: non-susceptible to ≥1 agent in ≥3 antimicrobial categories.

  2. * Defined by using an inhibition zone of <11 mm.

Table 8

Estimates of mortality attributable to multidrug-resistance (MDR) in hospital-acquired infection (HAI) in Thailand.

https://doi.org/10.7554/eLife.18082.018
PathogensNo of patients*Estimated mortality (%)Estimated mortality if the infections were caused by non-MDR organisms (%)†, ‡Estimated excess mortality caused by MDR (%)†, ‡
MDR Staphylococcus aureus18,7258262 (44%)5463 (29%)2799 (15%)
MDR Escherichia coli11,1162163 (19%)1566 (14%)597 (5%)
MDR Klebsiella pneumoniae15,2395267 (35%)4979 (33%)288 (2%)
MDR Pseudomonas aeruginosa61183966 (65%)3696 (60%)270 (4%)
MDR Acinetobacter spp36,55325,551 (70%)10,383 (28%)15,168 (41%)
Total87,75145,209 (52%)26,087 (30%)19,122 (22%)
  1. *Cumulative incidence of antimicrobial resistant HAI in Thailand 2010 estimated by Pumart et al. (2012).

  2. All parameters used to estimate the mortality and excess mortality are shown in Supplementary file 2.

  3. Excess mortality caused by MDR (mortality attributable to MDR) was defined as the difference in mortality of patients with MDR infection and their mortality if they were infected with non-MDR infections.

Additional files

Supplementary file 1

Factors associated with 30-day mortality of bacteraemia patients.

https://doi.org/10.7554/eLife.18082.019
Supplementary file 2

Parameters used to estimate mortality attributable to multidrug-resistance in Thailand.

https://doi.org/10.7554/eLife.18082.020

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