Abstract
Aim
This report presents phenotypic and genetic data on the prevalence and characteristics of extended-spectrum β-lactamases (ESBLs) and representative carbapenemases-producing Gram-negative species in Mexico.
Material and methods
A total of 52 centers participated, 43 hospital-based laboratories and 9 external laboratories. The distribution of antimicrobial resistance data for Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae complex, Acinetobacter baumannii complex, and Pseudomonas aeruginosa in selected clinical specimens from January 1 to March 31, 2020 was analyzed using the WHONET 5.6 platform. The following clinical isolates recovered from selected specimens were included: carbapenem-resistant Enterobacteriaceae, ESBL or carbapenem-resistant E. coli, and K. pneumoniae, carbapenem-resistant A. baumannii complex, and P. aeruginosa. Strains were genotyped to detect ESBL and/or carbapenemase-encoding genes.
Results
Among blood isolates, A. baumannii complex showed more than 68% resistance for all antibiotics tested, and among Enterobacteria, E. cloacae complex showed higher resistance to carbapenems. A. baumannii complex showed a higher resistance pattern for respiratory specimens, with only amikacin having a resistance lower than 70%. Among K. pneumoniae isolates, blaTEM, blaSHV, and blaCTX were detected in 68.79%, 72.3%, and 91.9% of isolates, respectively. Among E. coli isolates, blaTEM, blaSHV, and blaCTX were detected in 20.8%, 4.53%, and 85.7% isolates, respectively. For both species, the most frequent genotype was blaCTX-M-15. Among Enterobacteriaceae, the most frequently detected carbapenemase-encoding gene was blaNDM-1 (81.5%), followed by blaOXA-232 (14.8%) and blaoxa-181(7.4%), in A. baumannii was blaOXA-24 (76%) and in P. aeruginosa, was blaIMP (25.3%), followed by blaGES and blaVIM (13.1% each).
Conclusion
Our study reports that NDM-1 is the most frequent carbapenemase-encoding gene in Mexico in Enterobacteriaceae with the circulation of the oxacillinase genes 181 and 232. KPC, in contrast to other countries in Latin America and the USA, is a rare occurrence. Additionally, a high circulation of ESBL blaCTX-M-15 exists in both E. coli and K. pneumoniae.
Introduction
National and local surveillance of drug resistance and the involved genotypes is fundamental to implementing adequate infection control measures [1, 2].
The prevalence of carbapenemases from Ambler class A, B, and D, cephalosporinases (AmpCs), is rapidly increasing among Gram-negative bacteria and is rapidly increasing among Gram-negative bacteria and is now widely distributed [3, 4].
Among class A, the most reported β-lactamases are the extended-spectrum β-lactamases (ESBLs) cefotaximase (CTX-M), temoneira (TEM), and sulfhydryl variable (SHV), along with the Klebsiella pneumoniae carbapenemase (KPC) [3, 4].
Class B metallo-β-lactamases include those enzymes that confer resistance to carbapenem antibiotics as the carbapenemases the imipenem (IMP), New Delhi metallo-β-lactamase (NDM), and those encoded by vimentin (VIM) [5]. Among class D β-lactamases, the most frequently reported oxacillinases (OXA) are those encoded by blaOXA-23-like, blaOXA-24-like, and blaOXA-58-like genes in Acinetobacter baumannii and by blaOXA-48-like, especially in Enterobacteriaceae.
Some research groups from Mexico have published the drug resistance rates and involved genes for some Gram-negative bacteria, including A. baumannii, Pseudomonas aeruginosa, Enterobacter cloacae, K. pneumoniae, and Escherichia coli [6–9]. However, information available is limited, and nationwide studies are needed.
To contribute to the study of drug resistance in Mexico, the Network for the Research and Surveillance of Drug Resistance (Red Temática de Investigación y Vigilancia de la Farmacorresistencia INVIFAR, in Spanish) was created in 2018 and has reported an increase in drug resistance for several bacterial species, underlying the increase in carbapenem resistance for Enterobacter spp. and Klebsiella spp. [10, 11].
This report presents phenotypic and genetic data on the prevalence and characteristics of ESBL and carbapenemase-producing representative Gram-negative species in Mexico during the first trimester of 2020.
Materials and methods
Participating centers, data collection, and analysis
A total of 52 centers participated: 43 hospital-based laboratories and 9 external laboratories.
Identification and susceptibility test results from January 1 to March 31, 2020, from participating laboratories were deposited into the WHONET 5.6 platform and converted to the WHONET using the BacLink 2 tool. WHONET files were analyzed using macros to facilitate the revision, and only one strain per patient was included. The distribution of antimicrobial resistance for E. coli, K. pneumoniae, E. cloacae complex, A. baumannii complex, and P. aeruginosa was analyzed in clinical specimens such as urine, blood, and respiratory specimens. The results were scored according to the Clinical and Laboratory Standards Institute (CLSI) criteria in all laboratories [12].
Included isolates
Participating laboratories sent to the coordinating laboratory all recovered isolates with the following characteristics: carbapenem-resistant Enterobacteriaceae (any species); ESBL or carbapenem-resistant E. coli collected from urine or blood; ESBL or carbapenem-resistant K. pneumoniae recovered from urine, respiratory specimens (endotracheal and bronchoalveolar lavage), or blood; carbapenem-resistant A. baumannii complex and P. aeruginosa recovered from urine, respiratory specimens, or blood. Clinical isolates collected from January 1 to March 31, 2020, were included.
All identifications were confirmed at the coordinating laboratory using MALDI-TOF. After confirmation, phenotypic tests and genotyping tests were performed for each strain.
Beta-lactamase identification and characterization in Enterobacteriaceae
The ESBL phenotypic detection test was performed using the double disk method recommended by the CLSI for E. coli and K. pneumonia [12]. The molecular detection and characterization of ESBLs were performed for blaTEM, blaSHV, and blaCTX-M genes in selected isolates by PCR using previously described and newly designed primers (S1 Table) [13]. A selection of amplified products was sequenced.
Carbapenemase production in Enterobacteriaceae was detected using the CarbaNP test and modified carbapenem inactivation according to the CLSI [12].
For carbapenemase-encoding genes detection, Enterobacteriaceae were tested by PCR for blaKPC, blaGES, blaVIM, blaIMP, blaNDM-1, blaOXA-48-like, and chromosomal ampC genes as described [14–17].
All PCR products were sequenced using a Hitachi analyzer (Applied Biosystems, Hitachi High-Technologies Corporation, Tokyo, Japan). DNA sequences were aligned and edited using BioEdit software (Ibis Bioscience, Carlsbad, CA) and matched in a gene bank (www.ncbi.nlm.nih.gov/genbank).
Carbapenemase assays in A. baumannii and P. aeruginosa
For carbapenem-resistant A. baumannii, the blaOXA-23, blaOXA-24, blaOXA-51, blaOXA-58, blaVIM, blaIMP, and blaNDM-type β-lactamase genes were screened using PCR as described elsewhere [18, 19]. For P. aeruginosa, the detection of carbapenemase-encoding genes blaKPC, blaGES, blaIMP, blaNDM, and blaVIM was performed by PCR as described previously [20–24].
Ethics statement
The local ethics committee of Hospital Civil de Guadalajara “Fray Antonio Alcalde,” Jalisco, Mexico) approved this study with reference number 129/17. Informed consent was waived by the ethics committee because no intervention was involved. All participating institutions agreed with the present study.
Results
Participating centers, data, and collected strains
In this study, 52 centers collected strains and sent them to the coordinating laboratory: 43 hospital-based laboratories and 9 external laboratories. The three-month identification and susceptibility data were obtained from 46 centers (37 hospital-based laboratories and 9 external laboratories). The centers were distributed across 19 Mexican states. The characteristics of hospital-based centers are shown in Table 1.
Table 1. Characteristics of hospitals participating.
| Center | Pr/Pu | Type | Hosp beds | ICU Beds |
|---|---|---|---|---|
| Hospital General con Especialidades Juan María de Salvatierra | Pu | Spe | 120 | 18 |
| Bioclinsa, Hospital Ginequito | Pu | M&Ch | 93 | 26 |
| Centenario Hospital Miguel Hidalgo | Pu | Pu | 103 | 21 |
| Galenia Hospital | Pr | Spe | 54 | 4 |
| Hospital Ángeles Morelia | Pr | Spe | 50 | 11 |
| Hospital Clínica Nova | Pr | Spe | 44 | 4 |
| Hospital de Alta Especialidad de Veracruz | Pu | Spe | 235 | 10 |
| Hospital de Especialidades Pediátricas de Chiapas | Pu | Ped | 90 | 19 |
| Hospital General Ciudad Obregón | Pu | Univ | 156 | 5 |
| Hospital H+ Querétaro | Pr | Spe | 33 | 5 |
| Hospital Infantil de Morelia “Eva Sámano de López Mateos” | Pu | Ped | 80 | 6 |
| Hospital Regional de Alta Especialidad del Bajío | Pu | Spe | 184 | 29 |
| Hospital Regional Delicias | Pu | Spe | 67 | 8 |
| Hospital Regional Universitario de Colima | Pu | Univ | 108 | 8 |
| Hospital Ángeles Valle Oriente | Pr | Spe | 71 | 21 |
| Hospital Civil de Guadalajara “Fray Antonio Alcalde” | Pu | Univ | 1000 | 85 |
| Hospital de Especialidad Materno Infantil de León | Pu | M&Ch | 16 | 70 |
| Hospital de Especialidades Pediátricas León | Pu | Ped | 38 | 17 |
| Hospital de la Madre y Niño Guerrerense | Pu | M&Ch | 30 | 10 |
| Hospital General “Dr. Manuel Gea González” | Pu | Gen | 107 | 5 |
| Hospital General "Dr. Miguel Silva" | Pu | Gen | 300 | 14 |
| Hospital General “Dr. Raymundo Abarca Alarcón” | Pu | Gen | 108 | 8 |
| Hospital General de Chetumal | Pu | Gen | 88 | 10 |
| Hospital General de Chilpancingo | Pu | Gen | 114 | 8 |
| Hospital General de Zona No 21 | Pu | Gen | 73 | 9 |
| Hospital General del Estado “Dr. Ernesto Ramos Bours” | Pu | Univ | 200 | 20 |
| Hospital General Regional No.1 | Pu | Gen | 233 | 10 |
| Hospital General de Zona No.1 | Pu | Gen | 180 | 22 |
| Hospital General de Zona No 1 “Dr. Demetrio Mayoral Pardo” | Pu | Gen | 168 | 8 |
| Hospital Materno Infantil "Morelos" | Pu | M&Ch | 30 | 0 |
| Hospital Militar Regional de Especialidades de Mazatlán | Pu | Spe | 126 | 6 |
| Hospital para el Niño Poblano | Pu | Ped | 90 | 17 |
| Hospital Regional Bicentenario de la Independencia, ISSSTE | Pu | Spe | 206 | 8 |
| Hospital Regional de Alta Especialidad de Oaxaca | Pu | Spe | 60 | 6 |
| Hospital Regional Monterrey ISSSTE Monterrey | Pu | Spe | 141 | 25 |
| Hospital Universitario "Dr. José Eleuterio González" | Pu | Univ | 670 | 46 |
| Instituto Materno infantil del Estado de México | Pu | M&Ch | 115 | 30 |
| Instituto Nacional de Cancerología | Pu | Spe | 135 | 6 |
| Instituto Nacional de Cardiología “Ignacio Chávez” | Pu | Spe | 249 | 28 |
| Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán” | Pu | Spe | 170 | 14 |
| Instituto Nacional de Rehabilitación “Luis Guillermo Ibarra Ibarra” | Pu | Spe | 228 | 20 |
| Sanatorio La Luz | Pr | Gen | 30 | 3 |
| Swiss Hospital | Pr | Pr | Spe | 55 |
Abbreviations: Ad, adults; Gen, general; M&Ch, mother and child; Pr, Private, Pu, Public; Ped, pediatrics; Spe, specialties; Univ.
The results of drug susceptibility for 8,245 strains were included for analysis, and 2,243 clinical isolates were collected at the reference laboratory. A selection of 813 isolates (including isolates from each center and state) was included for phenotypic and genotypic analysis.
Drug resistance
Regarding urine isolates, resistance was higher than 55% for all antibiotics in A. baumannii complex. In P. aeruginosa, the lowest percentage of resistance was for piperacillin/tazobactam (29.5%). Meanwhile, carbapenem resistance was low in E. coli (<1%) but high in E. cloacae complex (10.9%) (Table 2). Also, 44.9% and 39.3% of E. coli and K. pneumoniae, respectively, were reported to be ESBLs producers.
Table 2. Percentage of resistant, intermediate, and susceptible gram-negative isolates collected from urine.
| A. baumannii complex | P. aeruginosa | K. pneumoniae | E. coli | E. cloacae complex | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Antibiotic | n | %R | %I | %S | n | %R | %I | %S | n | %R | %I | %S | n | %R | %I | %S | n | %R | %I | %S |
| AMK | ND | ND | ND | ND | 151 | 31.8 | 4.0 | 64.2 | 306 | 2.0 | 0.0 | 98.0 | 2215 | 3.0 | 0.7 | 96.3 | 49 | 20.4 | 0.0 | 79.6 |
| AMC | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | 462 | 11.7 | 14.3 | 74.0 | ND | ND | ND | ND |
| AMP | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | 2998 | 75.6 | 1.1 | 23.3 | ND | ND | ND | ND |
| AZT | ND | ND | ND | ND | ND | ND | ND | ND | 43 | 44.2 | 0.0 | 55.8 | 201 | 65.2 | 0.5 | 34.3 | ND | ND | ND | ND |
| CAZ | 41 | 87.8 | 0.0 | 12.2 | 148 | 33.8 | 6.1 | 60.1 | 301 | 46.5 | 0.3 | 53.2 | 2220 | 45.9 | 0.4 | 53.7 | 49 | 38.8 | 0.0 | 61.2 |
| FEP | 47 | 85.1 | 0.0 | 14.9 | 207 | 31.9 | 1.9 | 66.2 | 431 | 42.9 | 0.0 | 57.1 | 3017 | 43.3 | 0.6 | 56.1 | 55 | 29.1 | 1.8 | 69.1 |
| FOX | ND | ND | ND | ND | ND | ND | ND | ND | 85 | 45.9 | 1.2 | 52.9 | 999 | 41.3 | 1.1 | 57.6 | ND | ND | ND | ND |
| CIP | 63 | 82.5 | 0.0 | 17.5 | 230 | 46.5 | 1.3 | 52.2 | 530 | 40.4 | 5.8 | 53.8 | 3449 | 60.7 | 1.7 | 37.6 | 64 | 21.9 | 6.2 | 71.9 |
| CTX | 36 | 58.3 | 8.3 | 33.4 | ND | ND | ND | ND | 440 | 44.3 | 0.5 | 55.2 | 2494 | 46.3 | 0.1 | 53.6 | 47 | 38.3 | 0.0 | 61.7 |
| GEN | 65 | 63.1 | 4.6 | 32.3 | 234 | 30.8 | 10.3 | 58.9 | 548 | 33.9 | 0.7 | 65.4 | 3551 | 31.3 | 1.0 | 67.7 | 67 | 25.4 | 1.5 | 73.1 |
| IMP | ND | ND | ND | ND | 50 | 44.0 | 2.0 | 54.0 | 97 | 1.0 | 1.0 | 98.0 | 824 | 0.8 | 0.1 | 99.1 | 17 | 5.9 | 0.0 | 94.1 |
| LVX | ND | ND | ND | ND | ND | ND | ND | ND | 77 | 22.1 | 2.6 | 75.3 | 566 | 46.3 | 0.7 | 53.0 | 12 | 16.7 | 0.0 | 83.3 |
| MEM | 41 | 82.9 | 0.0 | 17.1 | 205 | 38.5 | 5.9 | 55.6 | 422 | 2.1 | 0.5 | 97.4 | 2999 | 0.7 | 0.1 | 99.2 | 55 | 10.9 | 3.6 | 85.5 |
| NIT | ND | ND | ND | ND | ND | ND | ND | ND | 389 | 32.6 | 30.6 | 36.8 | 2381 | 8.1 | 4.8 | 87.1 | 56 | 37.5 | 30.4 | 32.1 |
| NOR | ND | ND | ND | ND | 111 | 39.6 | 4.5 | 55.9 | 235 | 24.7 | 3.4 | 71.9 | 1694 | 54.5 | 1.5 | 44.0 | 36 | 25.0 | 5.6 | 69.4 |
| SAM | ND | ND | ND | ND | ND | ND | ND | ND | 299 | 49.5 | 10.0 | 40.5 | 2135 | 43.2 | 20.7 | 36.1 | ND | ND | ND | ND |
| TZP | 28 | 92.9 | 0.0 | 7.1 | 73 | 20.5 | 20.5 | 59.0 | 125 | 8.0 | 10.4 | 81.6 | 1212 | 6.4 | 7.2 | 86.4 | 24 | 25.0 | 4.2 | 70.8 |
| SXT | 39 | 69.2 | 0.0 | 30.8 | ND | ND | ND | ND | 384 | 53.6 | 0.0 | 46.4 | 2532 | 55.8 | 0.0 | 44.2 | 56 | 35.7 | 0.0 | 64.3 |
Abbreviations: AMC, amoxicillin-clavulanic acid; AMK, amikacin; AMP, ampicillin; AZT, aztreonam; CAZ, ceftazidime; CIP, ciprofloxacin; CTX, cefotaxime; FEP, cefepime; FOX, cefoxitin; GEN, gentamicin; IMP, imipenem; LVX, levofloxacin; MEM, meropenem; NIT, nitrofurantoin; NOR, norfloxacin; SAM, ampicillin-sulbactam; SXT, trimethoprim-sulfamethoxazole; TZP, piperacillin-tazobactam. R, resistant; I, intermediate; S, susceptible. ND, Not determined.
Among blood isolates, A. baumannii showed more than 68% resistance for all antibiotics tested, and P. aeruginosa had 37.1% resistance to meropenem. Among Enterobacteriaceae, E. cloacae showed higher resistance to carbapenems (4.4% for meropenem), whereas K. pneumoniae and E. coli had more than 59% resistance for cefepime (Table 3).
Table 3. Percentage of resistant, intermediate, and susceptible gram-negative isolates collected from blood.
| A. baumannii complex | P. aeruginosa | K. pneumoniae | E. coli | E. cloacae | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Antibiotic | n | %R | %I | %S | n | %R | %I | %S | n | %R | %I | %S | n | %R | %I | %S | n | %R | %I | %S |
| AMK | 20 | 70.0 | 5.0 | 25.0 | 54 | 16.7 | 3.7 | 79.6 | 79 | 2.5 | 1.3 | 96.2 | 136 | 2.9 | 0.7 | 96.4 | 41 | 2.4 | 0.0 | 97.6 |
| AMP | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | 83 | 86.7 | 0.0 | 13.3 | ND | ND | ND | ND |
| CAZ | 73 | 85.0 | 1.4 | 13.6 | 55 | 16.4 | 20.0 | 63.6 | 78 | 64.1 | 1.3 | 34.6 | 135 | 66.7 | 0.0 | 33.3 | 41 | 24.4 | 0.0 | 75.6 |
| FEP | 76 | 83.0 | 0.0 | 17.0 | 71 | 15.5 | 11.3 | 73.2 | 102 | 59.8 | 0.0 | 40.2 | 197 | 61.9 | 0.5 | 37.6 | 45 | 11.1 | 4.4 | 84.5 |
| FOX | ND | ND | ND | ND | ND | ND | ND | ND | 48 | 62.5 | 0.0 | 37.5 | 83 | 71.1 | 1.2 | 27.7 | ND | ND | ND | ND |
| CIP | 90 | 83.0 | 0.0 | 17.0 | 68 | 14.7 | 5.9 | 79.4 | 106 | 32.1 | 13.2 | 54.7 | 180 | 67.8 | 0.6 | 31.6 | 44 | 4.5 | 2.3 | 93.2 |
| CTX | 41 | 78.0 | 9.8 | 12.2 | ND | ND | ND | ND | 40 | 65.0 | 0.0 | 35.0 | 55 | 60.0 | 1.8 | 38.2 | 20 | 25.0 | 0.0 | 75.0 |
| GEN | 92 | 71.0 | 3.3 | 25.7 | 70 | 12.9 | 8.6 | 78.5 | 113 | 38.1 | 0.9 | 61.0 | 201 | 44.3 | 2.0 | 53.7 | 47 | 21.3 | 0.0 | 78.7 |
| IPM | 16 | 69.0 | 0.0 | 31.0 | 26 | 46.2 | 0.0 | 53.8 | 44 | 4.5 | 2.3 | 93.2 | 103 | 1.0 | 0.0 | 99.0 | 15 | 7.1 | 0.0 | 92.9 |
| LVX | 17 | 82.0 | 0.0 | 18.0 | 11 | 36.4 | 9.1 | 54.5 | 19 | 15.8 | 5.3 | 78.9 | 26 | 57.7 | 0.0 | 42.3 | ND | ND | ND | ND |
| MEM | 75 | 81.0 | 1.3 | 17.7 | 70 | 37.1 | 15.7 | 47.2 | 104 | 2.9 | 0.0 | 97.1 | 197 | 1.5 | 0.0 | 98.5 | 45 | 4.4 | 0.0 | 95.6 |
| SAM | 73 | 75.0 | 8.2 | 16.8 | ND | ND | ND | ND | 84 | 52.4 | 9.5 | 38.1 | 169 | 51.5 | 14.2 | 34.3 | ND | ND | ND | ND |
| SXT | 47 | 75.0 | 0.0 | 25.0 | ND | ND | ND | ND | 50 | 56.0 | 0.0 | 44.0 | 81 | 63.0 | 0.0 | 37.0 | 23 | 30.4 | 0.0 | 69.6 |
| TZP | 48 | 90.0 | 0.0 | 10.0 | 45 | 15.6 | 13.3 | 71.1 | 79 | 10.1 | 13.9 | 76.0 | 144 | 6.2 | 6.2 | 87.6 | 30 | 16.7 | 10.0 | 73.3 |
Abbreviations: AMK, amikacin; AMP, ampicillin; CAZ, ceftazidime; CIP, ciprofloxacin; CTX, cefotaxime; FEP, cefepime; FOX, cefoxitin; GEN, gentamicin; IMP, imipenem; LVX, levofloxacin; MEM, meropenem; NIT, nitrofurantoin; SAM, ampicillin/sulbactam; SXT, trimethoprim-sulfamethoxazole; TZP, piperacillin-tazobactam. R, resistant; I, intermediate; S, susceptible. ND, Not determined
Also, 60% and 49.3% of E. coli and K. pneumoniae, respectively, were reported to be ESBLs producers.
A. baumannii showed a higher resistance pattern in respiratory specimens, with only amikacin exhibiting a resistance less than 70%. In general, K. pneumoniae had higher resistance to antibiotics than E. cloacae (Table 4). Also, 47% of K. pneumoniae isolates were reported to be ESBLs producers.
Table 4. Percentage of resistant, intermediate, and susceptible gram-negative isolates collected from respiratory specimens.
| A. baumannii complex | P. aeruginosa | K. pneumoniae | E. cloacae | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Antibiotic | n | %R | %I | %S | n | %R | %I | %S | n | %R | %I | %S | n | %R | %I | %S |
| AMK | 39 | 69.0 | 15.0 | 16.0 | 105 | 15.2 | 4.8 | 80.0 | 62 | 0.0 | 0.0 | 100.0 | 33 | 0.0 | 0.0 | 100.0 |
| AMC | ND | ND | ND | ND | ND | ND | ND | ND | 16 | 18.8 | 18.8 | 62.5 | ND | ND | ND | ND |
| AMP | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | ND | 21 | 90.5 | 0.0 | 9.5 |
| CTX | 68 | 79.0 | 7.4 | 13.6 | ND | ND | ND | ND | 43 | 60.5 | 0.0 | 39.5 | 20 | 35.0 | 0.0 | 55.0 |
| CAZ | 130 | 89.0 | 1.5 | 9.5 | 105 | 23.8 | 12.4 | 63.8 | 62 | 48.4 | 1.6 | 50.0 | 33 | 27.3 | 0.0 | 72.7 |
| FEP | 174 | 89.0 | 1.1 | 9.9 | 141 | 15.6 | 5.0 | 79.4 | 96 | 46.9 | 0.0 | 53.1 | 58 | 5.2 | 3.4 | 91.4 |
| FOX | ND | ND | ND | ND | ND | ND | ND | ND | 31 | 45.2 | 0.0 | 54.8 | ND | ND | ND | ND |
| CIP | 160 | 86.0 | 0.0 | 14.0 | 139 | 27.3 | 2.9 | 69.8 | 87 | 31.0 | 4.6 | 64.4 | 42 | 4.8 | 2.4 | 92.8 |
| GEN | 163 | 73.0 | 7.4 | 20.0 | 146 | 16.4 | 8.2 | 75.4 | 104 | 34.6 | 1.0 | 64.4 | 57 | 5.3 | 0.0 | 94.7 |
| IPM | 62 | 90.0 | 0.0 | 10.0 | 64 | 50.0 | 0.0 | 50.0 | 51 | 0.0 | 0.0 | 100.0 | 38 | 0.0 | 7.9 | 92.1 |
| LVX | 65 | 92.0 | 0.0 | 8.0 | 31 | 3.2 | 6.5 | 90.3 | 43 | 20.9 | 2.3 | 76.8 | 25 | 4.0 | 0.0 | 96.0 |
| MEM | 163 | 87.0 | 0.6 | 12.4 | 137 | 33.6 | 16.1 | 50.4 | 97 | 2.1 | 0.0 | 97.9 | 59 | 1.7 | 0.0 | 98.3 |
| SAM | 131 | 81.0 | 5.3 | 14.0 | ND | ND | ND | ND | 68 | 48.5 | 2.9 | 48.6 | ND | ND | ND | ND |
| TZP | 113 | 93.0 | 1.8 | 5.3 | 92 | 21.7 | 10.9 | 67.4 | 80 | 16.2 | 7.5 | 76.3 | 44 | 13.6 | 2.3 | 84.1 |
| SXT | 82 | 79.0 | 0.0 | 21.0 | ND | ND | ND | ND | 71 | 50.7 | 0.0 | 49.3 | 40 | 17.5 | 0.0 | 82.5 |
Abbreviations: AMC, amoxicillin-clavulanic acid; AMK, amikacin; AMP, ampicillin; CAZ, ceftazidime; CIP, ciprofloxacin; CTX, cefotaxime; FEP, cefepime; FOX, cefoxitin; GEN, gentamicin; IMP, imipenem; LVX, levofloxacin; MEM, meropenem; SAM, ampicillin-sulbactam; SXT, trimethoprim-sulfamethoxazole; TZP, piperacillin-tazobactam; TGC, tigecycline; TOB, tobramycin. R, resistant; I, intermediate; S, susceptible.
ESBL phenotype and genotype
A total of 1059 E. coli and 370 K. pneumoniae from selected specimens were received. A selection of isolates was evaluated for further analysis (including representative isolates from each center).
Among isolates selected for analysis, 173/215 K. pneumoniae and 419/425 E. coli were confirmed to be ESBLs using the double disk method. All were screened using PCR to detect ESBL-encoding genes blaTEM, blaSHV, and blaCTX.
Among K. pneumoniae isolates, blaTEM, blaSHV, and blaCTX were detected in 119/173, 68.8%, 125/173,72.3%, and 159/173, 91.9% of isolates, respectively, with 124/173 (71.7%) isolates carrying both blaSHV and blaCTX. A selection of ESBL PCR products were sequenced and most of the blaCTX-M genes were detected to be blaCTX-M-15 (15/17, 88.23%) followed by blaCTX-M-55 (7/17,41.17%). Among the blaSHV gene, a great diversity was detected, including blaSHV-11, blaSHV-28, blaSHV-158, blaSHV-171, blaSHV-176, blaSHV-196, blaSHV-205, blaSHV-213, and blaSHV-228. Some of them with no evidence of ESBL activity (Table 5).
Table 5. Distribution of ESBL genotypes among E. coli and K. pneumoniae selected isolates.
| n | blaTEM-1 | blaSHV | blaCTX |
|---|---|---|---|
| E. coli | |||
| 8 | blaCTX-M-15 | ||
| 7 | blaCTX-M-15, blaCTX-M-55 | ||
| 7 | blaTEM-1 | blaCTX-M-15, blaCTX-M-55 | |
| 3 | blaTEM-1 | blaCTX-M-15 | |
| 1 | blaTEM-1 | blaSHV-5 | blaCTX-M-15, blaCTX-M-55 |
| 1 | blaTEM-1 | blaCTX-M-15, blaCTX-M-14 | |
| 1 | blaTEM-1 | blaSHV-11 | blaCTX-M-15 |
| 1 | blaTEM-1 | blaCTX-M-15, blaCTX-M-177 | |
| 1 | blaTEM-1 | blaSHV-171 | blaCTX-M-15 |
| 1 | blaTEM-1 | blaSHV-38 | blaCTX-M-15, blaCTX-M-55 |
| 1 | blaTEM-1 | blaCTX-M-15 | |
| 1 | blaTEM-166 | blaCTX-M-55 | |
| 1 | blaCTX-M-27 | ||
| K. pneumoniae | |||
| 2 | blaSHV-213 | blaCTX-M-15, blaCTX-M-55 | |
| 1 | blaTEM-1 | blaSHV-171 | blaCTX-M-15 |
| 1 | blaTEM-1 | blaSHV-11 | blaCTX-M-15 |
| 1 | blaTEM-1 | blaSHV-228 | blaCTX-M-15, blaCTX-M-55 |
| 1 | blaTEM-1 | blaSHV-205 | blaCTX-M-15, blaCTX-M-55 |
| 1 | blaTEM-1 | blaSHV-28 | blaCTX-M-15, blaCTX-M-55 |
| 1 | blaTEM-1 | blaSHV-158 | blaCTX-M-15 |
| 1 | blaTEM-1 | blaCTX-M-15 | |
| 1 | blaTEM-228 | blaCTX-M-15 | |
| 1 | blaSHV-171 | ||
| 1 | blaSHV-176 | blaCTX-M-15 | |
| 1 | blaSHV-11 | blaCTX-M-15, blaCTX-M-55 | |
| 1 | blaSHV-196 | blaCTX-M-15 | |
| 1 | blaSHV-11 | blaCTX-M-15, blaCTX-M-101 | |
| 1 | blaSHV-11 | ||
| 1 | blaCTX-M-15, blaCTX-M-55 |
Among E. coli isolates, blaTEM, blaSHV, and blaCTX were detected in 87/419, 20.76%, 19/419, 4.53%, and 359/419, 85.68% of isolates, respectively, with 18 (4.29%) isolates carrying both blaSHV and blaCTX.
A selection of ESBL PCR products were sequenced and most of the blaCTX-M encoding genes were detected to be blaCTX-M-15 (32/34, 94.1%), followed by blaCTX-M-55 (17/34, 50.0%). Among the blaSHV gene, blaSHV-5 and blaSHV-11 (with reported ESBL activity), blaSHV-38 (with reported carbapenemase activity), and blaSHV-171 (with no report of ESBL activity) were detected (Table 5).
Carbapenemase-encoding genes
A total of 26 carbapenem-resistant Enterobacteriaceae isolates were received for genotyping (one of them with a subpopulation). Carbapenem-encoding genes were detected primarily in E. coli, followed by K. pneumoniae. The most frequently detected carbapenemase-encoding gene was blaNDM-1 (81.5%), followed by blaOXA-232 (14.8%) and blaoxa-181(7.4%). One K. pneumoniae isolate was detected to harbor both blaKPC and blaNDM-1. (Table 6).
Table 6. Distribution of carbapenemase-encoding genes among selected carbapenem-resistant Enterobacteriaceaea.
| Isolate | Specimen | Species | blaKPC-like | blaOXA-48-like | blaNDM-1 | blaIMP-2 | blaCTXM-15 | ampC |
|---|---|---|---|---|---|---|---|---|
| 53 | Blood | Enterobacter cloacae | - | - | + | - | + | - |
| 223 | Blood | Enterobacter cloacae | - | - | + | - | + | - |
| 255 | Blood | Klebsiella pneumoniae | - | - | + | - | + | - |
| 303 | Blood | Serratia marcescens | - | - | + | - | - | - |
| 463 | Blood | Escherichia coli | - | - | + | + | + | - |
| 489 | Catheter | Klebsiella pneumoniae | - | - | + | + | + | - |
| 562 | Urine | Providencia rettgeri | - | - | + | - | - | - |
| 591 | Urine | Klebsiella variicola | - | - | + | - | + | - |
| 849 | Abscess | Escherichia coli | - | blaOXA-181 | - | - | - | - |
| 850 | BAL | Escherichia coli | - | - | + | - | + | - |
| 851 | BAL | Escherichia coli | - | blaOXA-181 | - | - | + | - |
| 853 | Blood | Escherichia coli | - | - | + | - | + | - |
| 854 | Urine | Escherichia coli | - | - | + | - | + | - |
| 861 | Wound | Klebsiella oxytoca | - | - | + | - | + | - |
| 882 | Urine | Escherichia coli | - | - | + | - | + | - |
| 891 | Urine | Klebsiella pneumoniae | blaKPC-2 | - | + | - | - | - |
| 1202 | Blood | Escherichia coli | - | blaOXA-232 | - | - | - | - |
| 1203 | Blood | Klebsiella pneumoniae | blaKPC-2 | - | + | - | + | - |
| 1457 | BAL | Escherichia coli | - | - | + | - | + | - |
| 1627 | Urine | Klebsiella variicola | - | - | + | + | + | - |
| 2063 | No data | Enterobacter xiangfangensis | - | - | + | - | + | + |
| 2177 | Blood | Escherichia coli | - | blaOXA-232 | - | - | + | - |
| 2178 | Urine | Escherichia coli | - | blaOXA-232 | - | - | - | - |
| 2175–1 | Abscess | Escherichia coli | - | blaOXA-232 | - | - | - | - |
| 2175–2 | Abscess | Escherichia coli | - | - | + | - | + | + |
| 1562–1 | Blood | Escherichia coli | - | - | + | - | + | - |
| 1562–2 | Blood | Escherichia coli | - | - | + | - | + | - |
Abbreviation: BAL, bronchoalveolar lavage.
aAll strains were negative for blaGES, blaIMI-1, blaIMP-1, and blaVIM.
A total of 102 carbapenem-resistant A. baumannii isolates were received, and the most frequent carbapenemase-encoding gene was blaOXA-24 (76%), followed by blaOXA-23 (18.5%). Other genes detected were blaVIM and blaNDM (Table 7). All the isolates were negative to blaKPC, blaGES, and blaOXA-58.
Table 7. Distribution of carbapenemase-encoding genes among A. baumannii complexa.
| n | blaOXA23 | blaOXA24 | blaVIM | blaNDM |
|---|---|---|---|---|
| 66 | - | + | - | - |
| 15 | + | - | - | - |
| 9 | - | + | + | - |
| 4 | - | - | + | - |
| 3 | + | + | - | - |
| 3 | - | - | - | - |
| 1 | - | - | + | + |
| 1 | + | - | + | - |
a All strains were negative for blaKPC and blaGES and positive for blaOXA51
Regarding carbapenem-resistant P. aeruginosa, 93 isolates were received, and the carbapenemase-encoding genes most frequently detected were blaIMP (25.3%), blaGES, and blaVIM (13.1% each), with 44 (47.31%) isolates containing none of the screened carbapenemase-encoding genes (Table 8).
Table 8. Distribution of carbapenemase-encoding genes among P. aeruginosa carbapenem-resistant clinical isolates *.
| n | Specimen | blaGES | blaVIM | blaIMP |
|---|---|---|---|---|
| 24 | Respiratory | - | - | - |
| 10 | Blood | - | - | - |
| 10 | Urine | - | - | - |
| 23 | Urine | - | - | + |
| 5 | Urine | + | - | - |
| 5 | Respiratory | + | - | - |
| 4 | Blood | - | + | - |
| 4 | Urine | - | + | - |
| 3 | Respiratory | - | + | - |
| 2 | Blood | + | - | - |
| 1 | Urine | - | + | + |
| 1 | Blood | - | - | + |
| 1 | Urine | + | + | - |
an All strains were negative for blaKPC and blaNDM
Discussion
This report presents phenotypic and genetic data on the frequency and characteristics of ESBL and representative carbapenemase-producing Gram-negative species in Mexico using strains collected from 52 centers in 19 Mexican states.
OXA-48-like carbapenemases are important causes of carbapenem resistance and are now the most common carbapenemase in some populations [25]. In Enterobacteriaceae, several variants of blaOXA-48 have been identified, with blaOXA-181 and blaOXA-232 being the two most common [26, 27]. Kinetic properties of these two enzymes had been measured, and both appear broadly similar to blaOXA-48 in their activity, with blaOXA-232 demonstrating better hydrolysis of penicillin [28]. In this study, blaOXA-181 and blaOXA-232 were detected in E. coli. At present, blaOXA-232 has been reported in Mexico in two single-center reports: in E. coli, carrying blaOXA-232 plus blaCTXM-15 [8] and in a case-control-control study in which the infection by blaOXA-232 strains was associated with the previous use of β-lactam/β-lactamase antibiotics (OR, 6.2) [29]. The OXA-181 variant has been associated with other carbapenemase genes, including blaNDM-1 and blaVIM-5 [30]. No previous reports of blaOXA-181 circulation in Mexico were identified in the literature.
Enterobacteriaceae-producing OXA-48-like enzymes are rapidly spreading, and thus, laboratory detection should be optimized. This enzyme has low-level hydrolytic activity against carbapenems and, thus, may not be detected [27]. As detected in this study, blaOXA-48-like genes can co-harbor genes encoding ESBL or AmpC enzymes, or both, which confers nonsusceptibility to aztreonam, extended-spectrum cephalosporins, and carbapenem agents and renders these genes a serious menace [31].
NDM has a worldwide distribution, with multiple reports in Asia and Europe since this enzyme was first described in 2007 [32–37]. However, it has remained uncommon in Enterobacteriaceae in America, with some reports in Canada, the United States, and Latin American countries [38–41]. In this study, the most frequently detected carbapenemase-encoding gene was blaNDM-1. The NDM carbapenemase was first described in Mexico in 2013 [6], and since then, several reports have been published about it in the county [8, 41]. According to our report, NDM is now the most prevalent carbapenemase in Mexico. This study reports by Mexico the first NDM-1-positive Klebsiella variicola isolates considered an emerging pathogen in humans [42].
Within a few years, KPC producers became global as they were reported in America, Europe, and Asia [32, 43]. Interestingly, this enzyme has a lower frequency in Mexico when compared to other Latin American countries, as confirmed by our report [43]. KPC and NDM have received special attention due to limited therapeutic options and high mortality associated with infections caused by strains carrying genes that encode these enzymes [44].
A. baumannii isolates have resistance rates greater than 50.0% to carbapenems worldwide, and our results confirmed this resistance [45, 46]. In this study, we detected that the most frequent carbapenemase-encoding gene was blaOXA-24, followed by blaOXA-23. OXA-23 isolates have been primarily detected in Asia, Europe, the United States, Brazil, and South America, whereas OXA-24 has been reported in Europe, Asia, and North America [5, 47–51].
Among P. aeruginosa isolates, 44 out of 93 isolates did not contain any of the screened carbapenemase-encoding genes. The most frequent carbapenem resistance mechanism described in P. aeruginosa is the overexpression of efflux pumps and the loss of the Opr porin [52]. Less frequently, genes encoding carbapenemases have been described as an alternative mechanism, with GES variants and IMP, VIM, and NDM reported. In this study, we did not analyze the overexpression of efflux pumps and porins, but blaGES, blaVIM, and blaIMP genes were detected in approximately half of the strains (49/93) (Table 8). Similar results were reported in Mexico with a prevalence of 36.2% of carbapenemases (IMP, VIM, and GES types) on P. aeruginosa clinical isolates. These genes have been reported to be chromosomally encoded on embedded class 1 integron arrays [53].
Besides carbapenemase-encoding genes, other important mechanisms conferring carbapenem resistance have been observed, including carbapenem hydrolysis by AmpCs in combination with ESBL enzymes, rendering carbapenem resistance to Gram-negative bacteria [54]. In our study, a high frequency of ESBL-producing Enterobacteriaceae was identified, with the AMPc-encoding gene detected in two strains (Enterobacter xiangfangensis (a member of the E. cloacae complex) and E. coli harboring both blaNDM-1, blaCTXM-15, and ampC). The presence of AmpC/ESBL and the exact changes of the porins may significantly affect carbapenem resistance. Thus, these mechanisms need to be considered in future research.
The prevalence of bacterial isolates expressing the ESBL phenotype varies across different geographical regions, with rates from 10% to 58% [55]. ESBLs arise primarily due to mutations in the blaTEM, blaSHV, or blaCTX genes, and at present, the CTX-M type is known to be the most frequent non-TEM, non-SHV ESBL [55]. In our study, 72.25% of ESBL-producing K. pneumoniae isolates and 85.7% of E coli isolates harbored blaCTX-M, confirming the spread of this enzyme.
The presence of CTX-M-type enzymes is relevant because they are readily inhibited by all commercially available β-lactamase inhibitors, including avibactam, vaborbactam, and relebactam [56]; a valuable alternative therapy to the recommended ertapenem regimen.
In this study, the non-ESBL TEM-1 was frequently detected, and SHV was detected with no predominance of any subtype. Worldwide, the prevalence of TEM and SHV has diminished, mirroring the worldwide dissemination of isolates producing CTX-M-type -lactamases [57].
Some of the limitations of this study are that not all states in Mexico participated, and the analysis of porins was not included. Furthermore, we only included some bacterial species involved in ESBL production. Our network will continue to actively survey drug resistance and molecular mechanisms involved.
In conclusion, our report identifies NDM as the most frequent carbapenemase-encoding gene in Enterobacteriaceae Mexico with circulation of the oxacillinase genes 181 and 232. KPC, in contrast to other countries in Latin America and the USA, is a rare occurrence. Additionally, a high circulation of ESBL blaCTX-M-15 existed in E. coli and K. pneumoniae.
Supporting information
(DOCX)
Acknowledgments
We acknowledge the enthusiastic work of the Network for the Research and Surveillance of Drug Resistance (Invifar), which at present includes 86 centers from 27 out of 32 states of Mexico.
We acknowledge the technical support from Maria de la Luz Acevedo-Duarte and form Myriam Aseret Zamora-Márquez.
Data Availability
All relevant data are within the manuscript and its Supporting information files.
Funding Statement
The author(s) received no specific funding for this work.
References
- 1.Stamm W, M.L. Grayson, L. Nicolle, and M. Powell. WHO Global Strategy for Containment of Antimicrobial Resistance (Document no: WHO/CDS/CSR/DRS/2001.2). Geneva, World Health Organization; 2001.
- 2.Rios R, Reyes J, Carvajal LP, Rincon S, Panesso D, Echeverri AM, et al. Genomic Epidemiology of Vancomycin-Resistant Enterococcus faecium (VREfm) in Latin America: Revisiting The Global VRE Population Structure. Sci Rep. 2020;10(1):5636. Epub 2020/03/27. 10.1038/s41598-020-62371-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Schaufler K, Nowak K, Düx A, Semmler T, Villa L, Kourouma L, et al. Clinically Relevant ESBL-Producing. Front Microbiol. 2018;9:150. Epub 2018/02/09. 10.3389/fmicb.2018.00150 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Iovleva A, Doi Y. Carbapenem-Resistant Enterobacteriaceae. Clin Lab Med. 2017;37(2):303–15. Epub 2017/03/11. 10.1016/j.cll.2017.01.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Peleg AY, Seifert H, Paterson DL. Acinetobacter baumannii: emergence of a successful pathogen. Clinical microbiology reviews. 2008;21(3):538–82. Epub 2008/07/16. 10.1128/CMR.00058-07 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Barrios H, Garza-Ramos U, Reyna-Flores F, Sanchez-Perez A, Rojas-Moreno T, Garza-Gonzalez E, et al. Isolation of carbapenem-resistant NDM-1-positive Providencia rettgeri in Mexico. J Antimicrob Chemother. 2013;68(8):1934–6. Epub 2013/04/25. 10.1093/jac/dkt124 . [DOI] [PubMed] [Google Scholar]
- 7.Barrios H, Silva-Sanchez J, Reyna-Flores F, Sanchez-Perez A, Sanchez-Francia D, Aguirre-Torres JA, et al. Detection of a NDM-1-producing Klebsiella pneumoniae (ST22) clinical isolate at a pediatric hospital in Mexico. Pediatr Infect Dis J. 2014;33(3):335. 10.1097/INF.0000000000000173 . [DOI] [PubMed] [Google Scholar]
- 8.Aquino-Andrade A, Merida-Vieyra J, Arias de la Garza E, Arzate-Barbosa P, De Colsa Ranero A. Carbapenemase-producing Enterobacteriaceae in Mexico: report of seven non-clonal cases in a pediatric hospital. BMC Microbiol. 2018;18(1):38. Epub 2018/04/19. 10.1186/s12866-018-1166-z [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Garza-Ramos U, Morfin-Otero R, Sader HS, Jones RN, Hernández E, Rodriguez-Noriega E, et al. Metallo-beta-lactamase gene bla(IMP-15) in a class 1 integron, In95, from Pseudomonas aeruginosa clinical isolates from a hospital in Mexico. Antimicrob Agents Chemother. 2008;52(8):2943–6. 10.1128/AAC.00679-07 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Garza-González E, Morfín-Otero R, Mendoza-Olazarán S, Bocanegra-Ibarias P, Flores-Treviño S, Rodríguez-Noriega E, et al. A snapshot of antimicrobial resistance in Mexico. Results from 47 centers from 20 states during a six-month period. PLoS One. 2019;14(3):e0209865. Epub 2019/03/26. 10.1371/journal.pone.0209865 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Garza-González E, Franco-Cendejas R, Morfín-Otero R, Echaniz-Aviles G, Rojas-Larios F, Bocanegra-Ibarias P, et al. The Evolution of Antimicrobial Resistance in Mexico During the Last Decade: Results from the INVIFAR Group. Microb Drug Resist. 2020;26(11):1372–82. Epub 2020/02/06. 10.1089/mdr.2019.0354 . [DOI] [PubMed] [Google Scholar]
- 12.CLSI. M100-S30. Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Second Informational Supplement. Wayne, PA: Clinical and Laboratory Standars Institute. 2020.
- 13.Arlet G, Philippon A. Construction by polymerase chain reaction and use of intragenic DNA probes for three main types of transferable beta-lactamases (TEM, SHV, CARB) [corrected]. FEMS Microbiol Lett. 1991;66(1):19–25. 10.1016/0378-1097(91)90414-6 . [DOI] [PubMed] [Google Scholar]
- 14.Bogaerts P, Rezende de Castro R, de Mendonça R, Huang TD, Denis O, Glupczynski Y. Validation of carbapenemase and extended-spectrum β-lactamase multiplex endpoint PCR assays according to ISO 15189. J Antimicrob Chemother. 2013;68(7):1576–82. Epub 2013/03/18. 10.1093/jac/dkt065 . [DOI] [PubMed] [Google Scholar]
- 15.Hong SS, Kim K, Huh JY, Jung B, Kang MS, Hong SG. Multiplex PCR for rapid detection of genes encoding class A carbapenemases. Ann Lab Med. 2012;32(5):359–61. Epub 2012/08/13. 10.3343/alm.2012.32.5.359 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Queenan AM, Bush K. Carbapenemases: the versatile beta-lactamases. Clin Microbiol Rev. 2007;20(3):440–58, table of contents. 10.1128/CMR.00001-07 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Pérez-Pérez FJ, Hanson ND. Detection of plasmid-mediated AmpC beta-lactamase genes in clinical isolates by using multiplex PCR. J Clin Microbiol. 2002;40(6):2153–62. 10.1128/jcm.40.6.2153-2162.2002 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Perez F, Hujer A, Hujer K, Decker B, Rather P, Bonomo R. Global challenge of multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2007;51(10):3471–84. 10.1128/AAC.01464-06 . [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Mulvey MR, Grant JM, Plewes K, Roscoe D, Boyd DA. New Delhi metallo-β-lactamase in Klebsiella pneumoniae and Escherichia coli, Canada. Emerg Infect Dis. 2011;17(1):103–6. 10.3201/eid1701.101358 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Wachino J, Doi Y, Yamane K, Shibata N, Yagi T, Kubota T, et al. Nosocomial spread of ceftazidime-resistant Klebsiella pneumoniae strains producing a novel class a beta-lactamase, GES-3, in a neonatal intensive care unit in Japan. Antimicrob Agents Chemother. 2004;48(6):1960–7. 10.1128/AAC.48.6.1960-1967.2004 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Swayne RL, Ludlam HA, Shet VG, Woodford N, Curran MD. Real-time TaqMan PCR for rapid detection of genes encoding five types of non-metallo- (class A and D) carbapenemases in Enterobacteriaceae. Int J Antimicrob Agents. 2011;38(1):35–8. Epub 2011/05/05. 10.1016/j.ijantimicag.2011.03.010 . [DOI] [PubMed] [Google Scholar]
- 22.Woodford N, Ellington MJ, Coelho JM, Turton JF, Ward ME, Brown S, et al. Multiplex PCR for genes encoding prevalent OXA carbapenemases in Acinetobacter spp. Int J Antimicrob Agents. 2006;27(4):351–3. 10.1016/j.ijantimicag.2006.01.004 . [DOI] [PubMed] [Google Scholar]
- 23.Baroud M, Dandache I, Araj GF, Wakim R, Kanj S, Kanafani Z, et al. Underlying mechanisms of carbapenem resistance in extended-spectrum β-lactamase-producing Klebsiella pneumoniae and Escherichia coli isolates at a tertiary care centre in Lebanon: role of OXA-48 and NDM-1 carbapenemases. Int J Antimicrob Agents. 2013;41(1):75–9. Epub 2012/11/09. 10.1016/j.ijantimicag.2012.08.010 . [DOI] [PubMed] [Google Scholar]
- 24.Nordmann P, Poirel L. Emerging carbapenemases in Gram-negative aerobes. Clin Microbiol Infect. 2002;8(6):321–31. 10.1046/j.1469-0691.2002.00401.x . [DOI] [PubMed] [Google Scholar]
- 25.Mairi A, Pantel A, Sotto A, Lavigne JP, Touati A. OXA-48-like carbapenemases producing Enterobacteriaceae in different niches. Eur J Clin Microbiol Infect Dis. 2018;37(4):587–604. Epub 2017/10/08. 10.1007/s10096-017-3112-7 . [DOI] [PubMed] [Google Scholar]
- 26.Poirel L, Potron A, Nordmann P. OXA-48-like carbapenemases: the phantom menace. J Antimicrob Chemother. 2012;67(7):1597–606. Epub 2012/04/11. 10.1093/jac/dks121 . [DOI] [PubMed] [Google Scholar]
- 27.Pitout JDD, Peirano G, Kock MM, Strydom KA, Matsumura Y. The Global Ascendency of OXA-48-Type Carbapenemases. Clin Microbiol Rev. 2019;33(1). Epub 2019/11/13. 10.1128/CMR.00102-19 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Evans BA, Amyes SG. OXA β-lactamases. Clin Microbiol Rev. 2014;27(2):241–63. 10.1128/CMR.00117-13 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Torres-González P, Ortiz-Brizuela E, Cervera-Hernandez ME, Bobadilla-Del Valle M, Martínez-Gamboa A, Sifuentes-Osornio J, et al. Associated factors and outcomes for OXA-232 Carbapenem-resistant Enterobacteriaceae infections in a tertiary care centre in Mexico City: A case-control-control study. Diagn Microbiol Infect Dis. 2016;86(2):243–8. Epub 2016/07/07. 10.1016/j.diagmicrobio.2016.07.002 . [DOI] [PubMed] [Google Scholar]
- 30.Potron A, Nordmann P, Lafeuille E, Al Maskari Z, Al Rashdi F, Poirel L. Characterization of OXA-181, a carbapenem-hydrolyzing class D beta-lactamase from Klebsiella pneumoniae. Antimicrob Agents Chemother. 2011;55(10):4896–9. Epub 2011/07/18. 10.1128/AAC.00481-11 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Jean SS, Lee WS, Lam C, Hsu CW, Chen RJ, Hsueh PR. Carbapenemase-producing Gram-negative bacteria: current epidemics, antimicrobial susceptibility and treatment options. Future Microbiol. 2015;10(3):407–25. 10.2217/fmb.14.135 . [DOI] [PubMed] [Google Scholar]
- 32.Nordmann P, Naas T, Poirel L. Global spread of Carbapenemase-producing Enterobacteriaceae. Emerg Infect Dis. 2011;17(10):1791–8. 10.3201/eid1710.110655 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Marra A. NDM-1: a local clone emerges with worldwide aspirations. Future Microbiol. 2011;6(2):137–41. 10.2217/fmb.10.171 . [DOI] [PubMed] [Google Scholar]
- 34.Wang S, Zhao SY, Xiao SZ, Gu FF, Liu QZ, Tang J, et al. Antimicrobial Resistance and Molecular Epidemiology of Escherichia coli Causing Bloodstream Infections in Three Hospitals in Shanghai, China. PLoS One. 2016;11(1):e0147740. Epub 2016/01/29. 10.1371/journal.pone.0147740 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Kumarasamy KK, Toleman MA, Walsh TR, Bagaria J, Butt F, Balakrishnan R, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis. 2010;10(9):597–602. Epub 2010/08/10. 10.1016/S1473-3099(10)70143-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Albiger B, Glasner C, Struelens MJ, Grundmann H, Monnet DL, group ESoC-PEEw. Carbapenemase-producing Enterobacteriaceae in Europe: assessment by national experts from 38 countries, May 2015. Euro Surveill. 2015;20(45). 10.2807/1560-7917.ES.2015.20.45.30062 . [DOI] [PubMed] [Google Scholar]
- 37.Borah VV, Saikia KK, Chandra P, Hazarika NK, Chakravarty R. New Delhi metallo-β-lactamase and extended spectrum β-lactamases co-producing isolates are high in community-acquired urinary infections in Assam as detected by a novel multiplex polymerase chain reaction assay. Indian J Med Microbiol. 2016;34(2):173–82. 10.4103/0255-0857.176853 . [DOI] [PubMed] [Google Scholar]
- 38.Rasheed JK, Kitchel B, Zhu W, Anderson KF, Clark NC, Ferraro MJ, et al. New Delhi metallo-β-lactamase-producing Enterobacteriaceae, United States. Emerg Infect Dis. 2013;19(6):870–8. 10.3201/eid1906.121515 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.(CDC) CfDCaP. Notes from the field: hospital outbreak of carbapenem-resistant Klebsiella pneumoniae producing New Delhi metallo-beta-lactamase—Denver, Colorado, 2012. MMWR Morb Mortal Wkly Rep. 2013;62(6):108. [PMC free article] [PubMed] [Google Scholar]
- 40.Resurrección-Delgado C, Montenegro-Idrogo JJ, Chiappe-Gonzalez A, Vargas-Gonzales R, Cucho-Espinoza C, Mamani-Condori DH, et al. [Klebsiella pneumoniae NEW DELHI METALO-LACTAMASE IN A PERUVIAN NATIONAL HOSPITAL]. Rev Peru Med Exp Salud Publica. 2017;34(2):261–7. 10.17843/rpmesp.2017.342.2615 . [DOI] [PubMed] [Google Scholar]
- 41.Bocanegra-Ibarias P, Garza-González E, Morfín-Otero R, Barrios H, Villarreal-Treviño L, Rodríguez-Noriega E, et al. Molecular and microbiological report of a hospital outbreak of NDM-1-carrying Enterobacteriaceae in Mexico. PLoS One. 2017;12(6):e0179651. Epub 2017/06/21. 10.1371/journal.pone.0179651 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Rodríguez-Medina N, Barrios-Camacho H, Duran-Bedolla J, Garza-Ramos U.: an emerging pathogen in humans. Emerg Microbes Infect. 2019;8(1):973–88. 10.1080/22221751.2019.1634981 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Villegas MV, Pallares CJ, Escandón-Vargas K, Hernández-Gómez C, Correa A, Álvarez C, et al. Characterization and Clinical Impact of Bloodstream Infection Caused by Carbapenemase-Producing Enterobacteriaceae in Seven Latin American Countries. PLoS One. 2016;11(4):e0154092. Epub 2016/04/22. 10.1371/journal.pone.0154092 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Farhat N, Khan AU. Evolving trends of New Delhi Metallo-betalactamse (NDM) variants: A threat to antimicrobial resistance. Infect Genet Evol. 2020;86:104588. Epub 2020/10/08. 10.1016/j.meegid.2020.104588 . [DOI] [PubMed] [Google Scholar]
- 45.Perez F, Hujer AM, Hujer KM, Decker BK, Rather PN, Bonomo RA. Global challenge of multidrug-resistant Acinetobacter baumannii. Antimicrobial agents and chemotherapy. 2007;51(10):3471–84. Epub 2007/07/25. 10.1128/AAC.01464-06 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Garza-Gonzalez E, Llaca-Diaz JM, Bosques-Padilla FJ, Gonzalez GM. Prevalence of multidrug-resistant bacteria at a tertiary-care teaching hospital in Mexico: special focus on Acinetobacter baumannii. Chemotherapy. 2010;56(4):275–9. Epub 2010/08/10. 10.1159/000319903 . [DOI] [PubMed] [Google Scholar]
- 47.Manchanda V, Sanchaita S, Singh N. Multidrug resistant acinetobacter. Journal of global infectious diseases. 2010;2(3):291–304. Epub 2010/10/12. 10.4103/0974-777X.68538 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Zarrilli R, Giannouli M, Tomasone F, Triassi M, Tsakris A. Carbapenem resistance in Acinetobacter baumannii: the molecular epidemic features of an emerging problem in health care facilities. Journal of infection in developing countries. 2009;3(5):335–41. Epub 2009/09/18. 10.3855/jidc.240 . [DOI] [PubMed] [Google Scholar]
- 49.Sevillano E, Fernandez E, Bustamante Z, Zabalaga S, Rosales I, Umaran A, et al. Emergence and clonal dissemination of carbapenem-hydrolysing OXA-58-producing Acinetobacter baumannii isolates in Bolivia. Journal of medical microbiology. 2012;61(Pt 1):80–4. Epub 2011/08/30. 10.1099/jmm.0.032722-0 . [DOI] [PubMed] [Google Scholar]
- 50.Figueiredo DQ, Santos KR, Pereira EM, Schuenck RP, Mendonca-Souza CR, Teixeira LM, et al. First report of the bla(OXA-58) gene in a clinical isolate of Acinetobacter baumannii in Rio de Janeiro, Brazil. Memorias do Instituto Oswaldo Cruz. 2011;106(3):368–70. Epub 2011/06/10. 10.1590/s0074-02762011000300019 . [DOI] [PubMed] [Google Scholar]
- 51.Stietz MS, Ramirez MS, Vilacoba E, Merkier AK, Limansky AS, Centron D, et al. Acinetobacter baumannii extensively drug resistant lineages in Buenos Aires hospitals differ from the international clones I-III. Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases. 2013;14:294–301. Epub 2013/01/15. 10.1016/j.meegid.2012.12.020 . [DOI] [PubMed] [Google Scholar]
- 52.Walsh C. Molecular mechanisms that confer antibacterial drug resistance. Nature. 2000;406(6797):775–81. 10.1038/35021219 . [DOI] [PubMed] [Google Scholar]
- 53.Garza-Ramos U, Barrios H, Reyna-Flores F, Tamayo-Legorreta E, Catalan-Najera JC, Morfin-Otero R, et al. Widespread of ESBL- and carbapenemase GES-type genes on carbapenem-resistant Pseudomonas aeruginosa clinical isolates: a multicenter study in Mexican hospitals. Diagn Microbiol Infect Dis. 2015;81(2):135–7. 10.1016/j.diagmicrobio.2014.09.029 . [DOI] [PubMed] [Google Scholar]
- 54.Bedenić B, Plečko V, Sardelić S, Uzunović S, Godič Torkar K. Carbapenemases in gram-negative bacteria: laboratory detection and clinical significance. Biomed Res Int. 2014;2014:841951. Epub 2014/06/15. 10.1155/2014/841951 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Paterson D, Bonomo R. Extended-spectrum beta-lactamases: a clinical update. Clin Microbiol Rev. 2005;18(4):657–86. 10.1128/CMR.18.4.657-686.2005 . [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Drawz SM, Papp-Wallace KM, Bonomo RA. New β-lactamase inhibitors: a therapeutic renaissance in an MDR world. Antimicrob Agents Chemother. 2014;58(4):1835–46. Epub 2013/12/30. 10.1128/AAC.00826-13 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Doi Y, Iovleva A, Bonomo RA. The ecology of extended-spectrum β-lactamases (ESBLs) in the developed world. J Travel Med. 2017;24(suppl_1):S44–S51. 10.1093/jtm/taw102 [DOI] [PMC free article] [PubMed] [Google Scholar]
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