Carbapenem-Resistant Acinetobacter baumannii …Afghanistan Low 31.63million 633.58 60 No...

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Carbapenem-Resistant Acinetobacter baumannii and Enterobacteriaceae in South and Southeast Asia Li-Yang Hsu, a,b,c Anucha Apisarnthanarak, d Erum Khan, e Nuntra Suwantarat, f Abdul Ghafur, g Paul Anantharajah Tambyah b Saw Swee Hock School of Public Health, National University of Singapore, Singapore a ; Yong Loo Lin School of Medicine, National University of Singapore, Singapore b ; Tan Tock Seng Hospital, Singapore c ; Thammasat University Hospital, Pathum Thani, Thailand d ; Aga Khan University, Karachi, Pakistan e ; Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, Thailand f ; Apollo Hospital, Chennai, India g SUMMARY ......................................................................................... 2 INTRODUCTION................................................................................... 2 MECHANISMS OF CARBAPENEM RESISTANCE ............................................... 3 Acinetobacter baumannii ....................................................................... 3 Enterobacteriaceae .............................................................................. 4 GEOGRAPHY AND DEMOGRAPHICS ........................................................... 5 EPIDEMIOLOGY OF CARBAPENEM-RESISTANT GRAM-NEGATIVE BACTERIA ............. 5 South Asia ....................................................................................... 5 India........................................................................................... 5 (i) Acinetobacter baumannii ............................................................... 6 (ii) Enterobacteriaceae ..................................................................... 6 Pakistan ....................................................................................... 6 (i) Acinetobacter baumannii ............................................................... 6 (ii) Enterobacteriaceae ..................................................................... 6 Afghanistan................................................................................... 7 (i) Acinetobacter baumannii ............................................................... 8 (ii) Enterobacteriaceae ..................................................................... 8 Nepal .......................................................................................... 8 (i) Acinetobacter baumannii ............................................................... 9 (ii) Enterobacteriaceae ..................................................................... 9 Other countries of South Asia .............................................................. 9 (i) Acinetobacter baumannii ............................................................... 9 (ii) Enterobacteriaceae ..................................................................... 9 Southeast Asia ................................................................................. 10 Singapore ................................................................................... 10 (i) Acinetobacter baumannii ............................................................. 10 (ii) Enterobacteriaceae.................................................................... 10 Malaysia ..................................................................................... 10 (i) Acinetobacter baumannii ............................................................. 10 (ii) Enterobacteriaceae.................................................................... 11 Philippines .................................................................................. 11 (i) Acinetobacter baumannii ............................................................. 11 (ii) Enterobacteriaceae.................................................................... 11 Thailand ..................................................................................... 11 (i) Acinetobacter baumannii ............................................................. 11 (ii) Enterobacteriaceae.................................................................... 11 Vietnam ..................................................................................... 12 (i) Acinetobacter baumannii ............................................................. 12 (ii) Enterobacteriaceae.................................................................... 12 Other countries of Southeast Asia ........................................................ 13 (i) Acinetobacter baumannii ............................................................. 13 (ii) Enterobacteriaceae.................................................................... 13 DRIVERS OF CARBAPENEM-RESISTANT GRAM-NEGATIVE BACTERIA.................... 13 DISCUSSION ..................................................................................... 14 ACKNOWLEDGMENTS .......................................................................... 16 REFERENCES ..................................................................................... 16 AUTHOR BIOS ................................................................................... 21 Published 19 October 2016 Citation Hsu L-Y, Apisarnthanarak A, Khan E, Suwantarat N, Ghafur A, Tambyah PA. 2017. Carbapenem-resistant Acinetobacter baumannii and Enterobacteriaceae in South and Southeast Asia. Clin Microbiol Rev 30:1–22. https:// doi.org/10.1128/CMR.00042-16. Copyright © 2016 American Society for Microbiology. All Rights Reserved. Address correspondence to Li-Yang Hsu, [email protected], or Paul Anantharajah Tambyah, paul_anantharajah_tambyah@nuhs .edu.sg. REVIEW crossm January 2017 Volume 30 Issue 1 cmr.asm.org 1 Clinical Microbiology Reviews on May 28, 2020 by guest http://cmr.asm.org/ Downloaded from

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Carbapenem-Resistant Acinetobacterbaumannii and Enterobacteriaceae inSouth and Southeast Asia

Li-Yang Hsu,a,b,c Anucha Apisarnthanarak,d Erum Khan,e Nuntra Suwantarat,f

Abdul Ghafur,g Paul Anantharajah Tambyahb

Saw Swee Hock School of Public Health, National University of Singapore, Singaporea; Yong Loo Lin School ofMedicine, National University of Singapore, Singaporeb; Tan Tock Seng Hospital, Singaporec; ThammasatUniversity Hospital, Pathum Thani, Thailandd; Aga Khan University, Karachi, Pakistane; Chulabhorn InternationalCollege of Medicine, Thammasat University, Pathum Thani, Thailandf; Apollo Hospital, Chennai, Indiag

SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2MECHANISMS OF CARBAPENEM RESISTANCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Acinetobacter baumannii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Enterobacteriaceae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

GEOGRAPHY AND DEMOGRAPHICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5EPIDEMIOLOGY OF CARBAPENEM-RESISTANT GRAM-NEGATIVE BACTERIA . . . . . . . . . . . . . 5

South Asia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5India. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

(i) Acinetobacter baumannii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6(ii) Enterobacteriaceae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Pakistan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6(i) Acinetobacter baumannii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6(ii) Enterobacteriaceae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Afghanistan. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7(i) Acinetobacter baumannii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8(ii) Enterobacteriaceae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Nepal. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8(i) Acinetobacter baumannii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9(ii) Enterobacteriaceae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Other countries of South Asia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9(i) Acinetobacter baumannii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9(ii) Enterobacteriaceae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Southeast Asia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Singapore . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

(i) Acinetobacter baumannii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10(ii) Enterobacteriaceae. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Malaysia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10(i) Acinetobacter baumannii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10(ii) Enterobacteriaceae. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Philippines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11(i) Acinetobacter baumannii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11(ii) Enterobacteriaceae. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Thailand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11(i) Acinetobacter baumannii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11(ii) Enterobacteriaceae. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Vietnam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12(i) Acinetobacter baumannii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12(ii) Enterobacteriaceae. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Other countries of Southeast Asia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13(i) Acinetobacter baumannii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13(ii) Enterobacteriaceae. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

DRIVERS OF CARBAPENEM-RESISTANT GRAM-NEGATIVE BACTERIA. . . . . . . . . . . . . . . . . . . . 13DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14ACKNOWLEDGMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16AUTHOR BIOS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Published 19 October 2016

Citation Hsu L-Y, Apisarnthanarak A, Khan E,Suwantarat N, Ghafur A, Tambyah PA. 2017.Carbapenem-resistant Acinetobacter baumanniiand Enterobacteriaceae in South and SoutheastAsia. Clin Microbiol Rev 30:1–22. https://doi.org/10.1128/CMR.00042-16.

Copyright © 2016 American Society forMicrobiology. All Rights Reserved.

Address correspondence to Li-Yang Hsu,[email protected], or Paul AnantharajahTambyah, [email protected].

REVIEW

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SUMMARY Carbapenem-resistant Gram-negative bacteria, in particular the Acineto-bacter baumannii-calcoaceticus complex and Enterobacteriaceae, are escalating globalpublic health threats. We review the epidemiology and prevalence of thesecarbapenem-resistant Gram-negative bacteria among countries in South and South-east Asia, where the rates of resistance are some of the highest in the world. Thesecountries house more than a third of the world’s population, and several are alsomajor medical tourism destinations. There are significant data gaps, and the almostuniversal lack of comprehensive surveillance programs that include molecular epide-miologic testing has made it difficult to understand the origins and extent of theproblem in depth. A complex combination of factors such as inappropriate prescrip-tion of antibiotics, overstretched health systems, and international travel (includingthe phenomenon of medical tourism) probably led to the rapid rise and spread ofthese bacteria in hospitals in South and Southeast Asia. In India, Pakistan, and Viet-nam, carbapenem-resistant Enterobacteriaceae have also been found in the environ-ment and community, likely as a consequence of poor environmental hygiene andsanitation. Considerable political will and effort, including from countries outsidethese regions, are vital in order to reduce the prevalence of such bacteria in Southand Southeast Asia and prevent their global spread.

KEYWORDS Acinetobacter, Enterobacteriaceae, South Asia, Southeast Asia,carbapenem resistance, carbapenems, Gram-negative bacteria, mcr-1

INTRODUCTION

Carbapenems are powerful broad-spectrum �-lactam antibiotics that are widelyregarded by clinicians as “last-line” antibiotics, particularly for the management of

critically ill patients and/or those with antimicrobial-resistant Gram-negative infections(1). Currently licensed alternatives such as tigecycline or the polymyxins are potentiallyless effective and/or more toxic (2, 3). The emergence and subsequent dissemination ofcarbapenem-resistant Gram-negative bacteria, especially plasmid-borne carbapen-emases in Enterobacteriaceae, represent a global public health threat for which there isas yet no clear solution.

Carbapenem resistance rates are high among Gram-negative bacteria in the hospi-tals of South and Southeast Asia (4–11), especially in Acinetobacter baumannii-calcoaceticus complex (AB) isolates (5, 7–9). South Asia is probably the source of theNew Delhi metallo-�-lactamase-1 (NDM-1) gene, which encodes one of the most widelydistributed carbapenemases in terms of geographic spread and bacterial species (6),although virtually all other carbapenemase genes have been described in Enterobac-teriaceae and nonfermenting Gram-negative bacteria from hospitals in both South andSoutheast Asian countries (5, 7–13). Carbapenemase-producing Enterobacteriaceae (CP-CRE) have also been found in the community in India and Pakistan (14, 15) and invegetables exported out of Southeast Asia (16).

This situation has potentially been exacerbated by the discovery of transmissiblepolymyxin resistance in the form of the mcr-1 gene (17). Initially found in Escherichia colifrom food animals and raw meat in China, the plasmid-borne gene, which confersresistance to the polymyxins by mediating the addition of phosphoethanolamine tolipid A (17), has since been isolated in Enterobacteriaceae from multiple countries,including those in South Asia (18) and Southeast Asia (19). The combination oftransmissible mcr-1 and carbapenemases in Enterobacteriaceae, already seen in Enter-obacteriaceae in a few countries (19–21), further narrows the therapeutic options fortreating infections caused by such bacteria, raising the specter of untreatable infectionsin the near future.

We review the epidemiology of carbapenem-resistant AB (CRAB) and carbapenem-resistant Enterobacteriaceae (CRE) among countries in South and Southeast Asia (listedin Table 1), compiling published reports from the medical literature in an attempt topiece together the prevalence of carbapenem-resistant Gram-negative bacteria in theregion. Where the results of national or regional antimicrobial resistance surveillance

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programs are publicly available, these are preferentially used relative to individualinstitutional reports. We have also summarized reports on the presence of the mcr-1gene in Enterobacteriaceae from the two regions where such reports are available, andwe briefly evaluate the drivers of carbapenem resistance in South and Southeast Asia.

MECHANISMS OF CARBAPENEM RESISTANCEAcinetobacter baumannii

AB strains are Gram-negative coccobacilli primarily associated with health care-associated infections. They have an extensive “armamentarium” of intrinsic antimicro-bial resistance mechanisms coupled with an inherent ability to acquire new resistancedeterminants (22).

AB has primarily three different but complementary mechanisms that confer re-duced carbapenem susceptibility or outright resistance (22–24). The most importantmechanism is that of hydrolysis of the drugs, caused by a combination of diverseintrinsic and acquired carbapenem-hydrolyzing �-lactamases (carbapenemases). AB hasa native chromosomal oxacillinase (OXA-51 and its variants) that usually undergoeslow-level expression, but it can potentially confer carbapenem resistance when up-regulated following upstream insertion of the insertion element ISAba1 or ISAba9 (25).However, it is AB’s ability to acquire carbapenemases, specifically the Ambler class Bmetallo-�-lactamases and class D oxacillinases but recently class A carbapenemases aswell, that has resulted in the widespread development of carbapenem-resistant AB(CRAB).

The metallo-�-lactamases are so named because they require a divalent cation, mostcommonly zinc, for their enzymatic activity (26, 27). They evolved separately from theother carbapenemases (Ambler classes A, C, and D, which have serine at the active siteand are therefore also termed “serine carbapenemases”) and have a comparativelybroader spectrum of activity, as they exhibit strong hydrolytic activity against all�-lactam antibiotics except monobactams (i.e., aztreonam) (26). They are not inhibitedby �-lactamase inhibitors, unlike most of the serine carbapenemases, but are inhibitedby divalent cation chelators such as EDTA (26, 27). Metallo-�-lactamases are dividedinto three subclasses (B1 to B3) based on primary amino acid sequence homology, withthe majority of CRAB strains found with metallo-�-lactamases possessing subclass B1enzymes (IMP, VIM, SIM, and NDM) (27).

TABLE 1 Profiles of South and Southeast Asian countries

Region andcountry Income level Total population

Gross domesticproduct (US$)per capita

Life expectancyat birth (yr)

National antimicrobialsurveillance program(as of May 2016)

South AsiaIndia Lower middle 1.295 billion 1,582.24 68 InitiatedPakistan Lower middle 185 million 1,316.76 66 NoBangladesh Lower middle 159.1 million 1,086.74 71 NoSri Lanka Lower middle 20.64 million 3,818.80 74 EstablishedNepal Low 28.17 million 701.81 69 EstablishedMaldives Upper middle 0.40 million 7,635.91 77 NoBhutan Lower middle 0.77 million 2,560.78 69 NoAfghanistan Low 31.63 million 633.58 60 No

Southeast AsiaSingapore High 5.47 million 56,288.85 82 EstablishedThailand Upper middle 67.73 million 5,976.67 74 EstablishedMalaysia Upper middle 29.90 million 11,307.69 75 EstablishedVietnam Lower middle 90.73 million 2,052.24 76 NoIndonesia Lower middle 254.50 million 3,491.16 69 NoPhilippines Lower middle 99.14 million 2.872.71 68 EstablishedMyanmar Lower middle 53.44 million 1,203.78 66 NoLaos Lower middle 6.689 million 1,793.99 66 NoCambodia Low 15.33 million 1,094.59 68 NoTimor-Leste Lower middle 1.212 million 1,169.14 68 NoBrunei High 0.417 million 40,967.90 79 No

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Ambler class D �-lactamases are also termed oxacillinases because of their greateraffinity for and hydrolytic activity against oxacillin (26, 28). Among the class D carbap-enemases, the numerous OXA carbapenemases found in CRAB prior to 2013 belongedto five subgroups: (i) OXA-23-like (OXA-23, OXA-27, OXA-49, and OXA-239), (ii) OXA-24-like (OXA-24, OXA-25, OXA-26, OXA-40, and OXA-72), (iii) OXA-51 and its variants, (iv)OXA-58, and (v) OXA-143-like (OXA-143 and OXA-231) (28–32). In 2013, an independentOXA carbapenemase subgroup designated OXA-235-like (OXA-235, OXA-236, and OXA-237), with approximately 85% homology with OXA-143, was described in isolatesrecovered from the United States and Mexico (33). However, OXA-23, the first OXA-type�-lactamase to be identified from CRAB, still remains the most prevalent today (22, 28,29, 34).

Ambler class A carbapenemases include the largely chromosomal SME and IMIfamilies, which can confer resistance to penicillins and aztreonam but not the oxyimino-cephalosporins, as well as the plasmid-encoded Klebsiella pneumoniae carbapenemase(KPC) carbapenemases, which confer resistance to all �-lactam antibiotics (35). Thesecarbapenemases are far more commonly found in Enterobacteriaceae than in AB, butrecently detected plasmid- and/or integron-encoded Ambler class A serine carbapen-emases in CRAB include KPC-2, KPC-3, KPC-4, KPC-10, and GES-14 (34, 35). AB alsopossesses chromosomally encoded ampC (Ambler class C) �-lactamases but these havenot been linked to carbapenem nonsusceptibility (36).

The second major mechanism is related to the small number and size of certainouter membrane proteins (OMPs) present (thereby making the bacterium less perme-able to antibiotics) (22–24). Three OMPs have been associated with carbapenemnonsusceptibility: a 29-kDa protein (also known as CarO), a 33- to 36-kDa protein, andOmpW (34).

Finally, resistance-nodulation-cell division (RND)-type efflux pumps such as AdeABC,AdeFGH, and AdeIJK may also play a role in carbapenem nonsusceptibility. Their actualrole has been harder to quantify, although their overexpression may contribute syn-ergistically to carbapenem resistance when combined with carbapenemase activity(37).

Enterobacteriaceae

Enterobacteriaceae are a large family of oxidase-negative Gram-negative bacilli thatare able ferment glucose. The Enterobacteriaceae of greatest interest with regard tocarbapenem resistance are E. coli and K. pneumoniae, given that these bacteria are alsothe most common causes of infection in the clinical setting (38). Resistance viaenzymatic degradation of carbapenems is currently the most common mechanism forthe Enterobacteriaceae, with the most prevalent carbapenemases arising from Amblerclasses B, A, and D (35, 38).

As with AB, the most common metallo-�-lactamases found in Enterobacteriaceae arethose belonging to subclass B1 (IMP, VIM, and NDM), with NDM being by far the mostprevalent and widely distributed (4, 6, 10–14, 27). There are 10 variants of the NDMenzyme discovered to date (39–41), with little functional difference between them interms of carbapenem hydrolysis, although differences in thermal stability and thehydrolysis of certain cephalosporins were detected (42).

Class A carbapenemases found in Enterobacteriaceae include the largely chromo-somal SME and IMI families, as well as the plasmid-encoded GES, IMI-2, and KPCs; thelast group in particular confers resistance to all �-lactam antibiotics, and they are ableto spread very easily between Enterobacteriaceae (35, 38, 43). There are 22 variants ofKPC reported, although KPC-2 remains the most prevalent and widely distributed todate (43).

The majority of OXA carbapenemases were first discovered in Acinetobacter spp.,although they are likely to have originated from other bacterial species (28, 29). Theprevalent OXA carbapenemase subgroup among Enterobacteriaceae is OXA-48 and itsvariants (at least 10 others, including OXA-163, OXA-181, OXA-204, and OXA-232) (28,43).

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Carbapenem resistance can also occur in porin-deficient AmpC �-lactamase-or extended-spectrum-�-lactamase (ESBL)-producing Enterobacteriaceae isolates, al-though such isolates, because of the reduced risk of resistance transmission relative toplasmid-borne carbapenemases, are considered of secondary clinical and public healthimportance (23).

GEOGRAPHY AND DEMOGRAPHICS

The profiles of South and Southeast Asian countries are provided in Table 1. Thedata are obtained from the World Development Indicators database from the WorldBank (44). These countries vary considerably, not just in terms of gross domesticproduct and development but also in terms of social and cultural perspectives, ethnicgroups, and languages.

The countries of South Asia include India, Pakistan, Bangladesh, Sri Lanka, Nepal,Maldives, Bhutan, and Afghanistan. The majority lack established national or, in mostcases, even subnational regional-level comprehensive surveillance of antimicrobialresistance in either their health care institutions or the community, although activesteps have been taken to implement such surveillance in several countries, such asIndia and Sri Lanka (45–47). Nepal has had a focused antimicrobial resistance surveil-lance program since 1999, targeting primarily community bacterial pathogens (48).

The sovereign states of Southeast Asia include Singapore, Malaysia, Philippines,Thailand, Vietnam, Indonesia, Myanmar, Laos, Cambodia, East Timor, and Brunei. Coun-tries such as Singapore, Malaysia, Philippines, and Thailand have implemented nationalantimicrobial resistance surveillance programs (45–47, 49). Microbiology laboratorycapabilities remain limited in countries such as Myanmar (45–47) and East Timor.

EPIDEMIOLOGY OF CARBAPENEM-RESISTANT GRAM-NEGATIVE BACTERIA

Maps of the estimated prevalences of CRAB and CRE are shown in Fig. 1 and 2,respectively.

South AsiaIndia. There is currently no comprehensive nationwide surveillance of antimicrobial-

resistant pathogens in India (45, 46, 50), although India’s National Centre for DiseaseControl is implementing a 5-year “National Programme on Containment of Antimicro-

FIG 1 Estimated prevalence of carbapenem-resistant Acinetobacter baumannii in South and SoutheastAsian countries.

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bial Resistance” (2012 to 2017) that aims to include laboratory-based antimicrobialresistance surveillance from a network of 30 microbiology laboratories in the country(46, 51, 52).

(i) Acinetobacter baumannii. The results from recent reports (published from2010) with a high number (�100) of sequential nonduplicate AB isolates tested aresummarized in Table 2. Based on the summary in Table 2, carbapenem resistancerates in AB have generally exceeded 40% throughout all of India (53–60), and OXAenzymes are the predominant carbapenemases in AB in India (61). CRAB remains ahealth care-associated opportunistic pathogen, and there are no significant reportsof CRAB in the community in India to our knowledge.

(ii) Enterobacteriaceae. The results of prevalence studies of CRE in India are sum-marized in Table 2. Carbapenem resistance rates in Enterobacteriaceae have been morevariable than those in CRAB in India, but longitudinal studies have shown dramaticincreases in resistance rates over time (10, 53, 62–71). NDM remains consistently themajor carbapenemase found in Enterobacteriaceae in that country (72). CP-CRE havebeen identified in the environment in the community since 2010 (14, 73), likely as aconsequence of sanitation issues. The mcr gene has not been described in India per se,but Swiss investigators identified an mcr-1-positive E. coli strain after enrichmentcultures of stool from a traveler returning from India (18).

Pakistan. Pakistan also lacks a comprehensive national surveillance program forantimicrobial resistance surveillance (74). The Pakistan Antimicrobial Resistance Net-work (PARN) was set up in 2007, with surveillance being one of its objectives (75).However, updated data are available from relatively few hospitals (75).

(i) Acinetobacter baumannii. The results from the few available published reportsare summarized in Table 3. CRAB has been flagged as a leading cause of healthcare-associated infections in the country (75–80), with OXA-23 the most commoncarbapenemase found in two studies (77, 81). The prevalence of carbapenem resistanceamong AB isolates ranged from 62% to 100% in published studies (75–80).

(ii) Enterobacteriaceae. The few published prevalence reports on CRE in Pakistan aresummarized in Table 3. CRE appears to be increasingly common in Pakistan (75, 82, 83),although notably, the laboratories of two of six hospitals contributing data to PARN didnot isolate any CRE in their latest data sets in 2011 and 2012, respectively (Table 3) (75).

FIG 2 Estimated prevalence of carbapenem-resistant Enterobacteriaceae in South and Southeast Asiancountries.

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The earliest report from a university hospital in Karachi showed that just 0.1% of clinicalK. pneumoniae isolates were carbapenem resistant in the period between 2002 and2007 (82). Following the identification of NDM from South Asian countries (6), rates ofCRE and CP-CRE increased throughout Pakistan. The microbiology laboratory reportsfrom the Aga Khan University Hospital showed that carbapenem resistance had risenfrom 1% and 3% for clinical isolates of E. coli and K. pneumoniae, respectively, in 2009to 5% and 18%, respectively, by 2014 (75).

A laboratory-based study done at military hospitals in 2010 showed CP-CRE carriagerates of 18.5% from 200 stool samples (84). Two subsequent laboratory-based studiesin 2011 found high rates of CP-CRE carriage (8.6% and 18.3%, respectively) amongpatients presenting with diarrhea who had stool samples submitted to a referencelaboratory in Islamabad (85) as well as inpatients at a military hospital in Pakistan (86).As with India, CP-CRE have also been identified in different water sources in theenvironment since 2011 (87) and also in the community (15). The most commoncarbapenemase in Enterobacteriaceae in Pakistan remains NDM (83–87), althoughothers, such as OXA, KPC, and IMP, have also been found in Enterobacteriaceae isolatedfrom clinical specimens (88, 89).

No mcr-positive Enterobacteriaceae have been found in Pakistan to date.Afghanistan. Afghanistan does not appear to have any form of surveillance for

antimicrobial resistance (74). Most of the data on carbapenem-resistant Gram-negative

TABLE 2 Epidemiology and prevalence of carbapenem-resistant Gram-negative bacteria in India

Bacteria and yrof study Study type State(s)

Site of isolation; sampletype(s) % resistancea (no. of isolates) Reference

Acinetobacter spp.2009–2013 Single center Tamil Nadu Inpatient; blood samples 67–74 (332) 532011–2013 Single center Maharashtra Intensive care unit; all clinical

samples42 (368) 54

2012 Single center Tamil Nadu Unknown; urine, blood, andrespiratory samples

�50 55

2010–2011 Single center Punjab Inpatient; all clinical samples 42 (132) 562002–2008 Single center Delhi Inpatient; blood samples 0–74 (754) 57Unknown Two centers Delhi Inpatient; all clinical samples 85 (100) 58Unknown Single center Punjab Unknown; all clinical samples 40 (964) 59Unknown Single center Jammu and Kashmir Inpatient; all clinical samples 60 (165) 60

Enterobacteriaceae2003–2013 Single center Tamil Nadu Inpatient; blood samples E. coli, 0–5 (1,918);

K. pneumoniae, 0–40 (1,250)53

2012 Single center Tamil Nadu Inpatient; urine samples E. coli, 15 (300) 622012 Single center Uttar Pradesh Inpatient; all clinical samples Enterobacteriaceae, 12 (464) 632011–2012 Single center Kerala Inpatient; respiratory samples K. pneumoniae, 8 (125) 642011 Single center Punjab Inpatient; all clinical samples E. coli, 4 (200); K. pneumoniae,

12 (100)65

2010 Single center Uttar Pradesh Inpatient and outpatient; allclinical samples

Enterobacteriaceae, 8 (780) 66

2010 3 centers Maharashtra, Karnataka,Tamil Nadu

Inpatient; all clinical samples Enterobacteriaceae, 5.2 (252) 67

2008–2009 7 centers Maharashtra, Uttar Pradesh,West Bengal, Karnataka,Tamil Nadu

Inpatient; intra-abdominalsamples

Enterobacteriaceae, 21.3 (347) 10

2008–2009 Single center Puducherry Inpatient; urinary samples E. coli, 10 (2,671);K. pneumoniae, 18 (551)

68

2000–2009 Single center Delhi Inpatient; blood samples E. coli, 3–6 (1,103);K. pneumoniae, 2–52 (1,271)

69

2008 Single center Delhi Inpatient; all clinical samples Enterobacteriaceae 7 (113) 702006–2007 14 centers Kerala, Gujarat,

Maharashtra, MadhyaPradesh, Uttar Pradesh,West Bengal, Karnataka,Tamil Nadu, Telangana

Inpatient; intra-abdominalsamples

Enterobacteriaceae, 2.7 (1,443) 71

aRanges indicate the change between the first and final years of the study.

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bacteria in Afghanistan, especially CRAB, have come from military treatment facilities inthat country.

(i) Acinetobacter baumannii. As with the case in Iraq, the military conflicts inAfghanistan have led to the unique association of AB, including CRAB, with war woundinfections in both military personnel and civilians (22, 88, 90–93). The vast majority ofAB isolates were likely acquired due to nosocomial transmission within the militarytreatment facilities (22, 88, 90, 92, 93), although some have suggested extrahospital andenvironmental sources for the AB (91). There is no published work describing carbap-enemases in CRAB in Afghanistan outside the military setting, although the situation isunlikely to be different from that in the rest of the region.

(ii) Enterobacteriaceae. There are strong suggestions that CP-CRE are present inAfghanistan, although prevalence studies are lacking. The NDM gene had been de-tected in a bloodstream Providencia stuartii isolate obtained from a military medicalfacility in Bagram, Afghanistan, in 2011 (94), a colonizing Acinetobacter schindleri isolatefrom a U.S. military serviceman evacuated from the country in 2012 (95), and a Proteusmirabilis isolate from an Afghani refugee in Poland in 2014 (96). No mcr-positiveEnterobacteriaceae have been found in Afghanistan to date.

Nepal. Nepal’s Public Health Laboratory and its Ministry of Health and Population’sEpidemiology and Disease Control Division took over the antimicrobial resistancesurveillance network in 2004, but as mentioned above, the surveillance does notcurrently extend to health care-associated pathogens such as AB or even K. pneumoniae(48, 97). Carbapenem resistance among Gram-negative bacteria is a significant problem

TABLE 3 Epidemiology and prevalence of carbapenem-resistant Gram-negative bacteria in Pakistan

Bacteria and yrof study Study type State(s)

Site(s) of isolation; sampletype % resistance (no. of isolates) Reference

Acinetobacter spp.2014 Single center Sindh Inpatient and outpatient; all

clinical samples90 (unknown) 75

2013 Single center Sindh Inpatient; all clinical samples 82 (unknown) 752012 Single center Sindh Inpatient and outpatient; all

clinical samples82 (125) 75

2012 Single center Sindh Inpatient and outpatient; allclinical samples

75 (unknown) 75

2010–2011 3 centers Islamabad CapitalTerritory,Punjab

Inpatient; all clinical samples 62 (90) 76

2011 Single center Sindh Inpatient; all clinical samples 65 (459) 752011 Single center Islamabad Capital

TerritoryInpatient and outpatient;

wound samples100 (91) 77

2008 2 centers Punjab Inpatient; all clinical samples 65 (17) 782008 Single center Sindh Neonatal intensive care unit;

all clinical samples89 (122) 79

2006 Single center Sindh Inpatient; all clinical isolates 98 (100) 80

Enterobacteriaceae2014 Single center Sindh Inpatient and outpatient; all

clinical samplesE. coli, 5 (unknown); K. pneumoniae,

18 (unknown)75

2013 Single center Sindh Inpatient; all clinical isolates E. coli, 3 (unknown); K. pneumoniae,8 (unknown)

75

2012 Single center Sindh Inpatient and outpatient; allclinical samples

E. coli, 1 (232); K. pneumoniae, 21(86)

75

2012 Single center Sindh Inpatient and outpatient; allclinical samples

E. coli, 0 (unknown); K. pneumoniae,0 (unknown)

75

2011 Single center Sindh Inpatient and outpatient; allclinical samples

E. coli, 0 (unknown); K. pneumoniae,0 (unknown)

75

2002–2007 Single center Sindh Inpatient and outpatient; allclinical samples

K. pneumoniae, 0.1 (15,914) 83

Unknown 2 centers Islamabad CapitalTerritory,Punjab

Inpatient and outpatient; allclinical samples

E. coli, 34 (145); K. pneumoniae,45 (82)

82

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in several of Nepal’s health care facilities. The results from the available publishedreports are summarized in Table 4.

(i) Acinetobacter baumannii. Carbapenem resistance among AB isolates rangedfrom 17% to 98% in hospitals in Kathmandu (98–100). In a single university hospitalstudy where the AB isolates from 2013 and 2014 underwent a molecular workup, allisolates were positive for OXA carbapenemases, with OXA-23 found in all isolates (98).Interestingly, 30 isolates (25%) also tested positive for the NDM-1 gene (98). Themajority of the isolates belonged to clonal cluster 1 (CC1) (17%), CC2 (30%), or CC149(36%) (98).

(ii) Enterobacteriaceae. CP-CRE prevalence rates are approximately 18% in two largehospitals in Nepal (99, 101). The most common carbapenemase in Enterobacteriaceae isNDM (101, 102), with two new variants (NDM-8 and -12) described in Nepal recently(103, 104). No mcr-positive Enterobacteriaceae have been found in Nepal to date.

Other countries of South Asia. Among the other countries of South Asia, only SriLanka has implemented antimicrobial resistance surveillance at the national level (46,47, 74, 105). The Sri Lanka College of Microbiologists conducts two related projects: theAntibiotic Resistance Surveillance Project (blood culture isolates) since 2009 and theNational Laboratory Based Surveillance of Antimicrobial Resistance of significant urineculture isolates (NLBSA) in conjunction with the Sri Lanka Ministry of Health since 2011(105). The data from these South Asian countries are sparser, although it is clear thatsimilar challenges in terms of carbapenem-resistant Gram-negative bacteria are pres-ent.

(i) Acinetobacter baumannii. In Bangladesh, AB was isolated from a third of clinicalsamples from the intensive care unit (ICU) of a university hospital in 2010, andtwo-thirds of the isolates were resistant to carbapenems (106). In a seven-center studyon Gram-negative bloodstream infections conducted between March 2009 and Febru-ary 2010 in Sri Lanka, approximately 40% of 71 AB isolates were resistant to thecarbapenems (107). No published data on carbapenem-resistant Gram-negative bac-teria are available from Maldives and Bhutan, the final two countries of South Asia.However, a report published in 2012 by the World Health Organization (WHO) RegionalOffice for South-East Asia (SEARO) stated that multidrug-resistant bacteria were also aproblem for these countries, without further elaboration (46).

(ii) Enterobacteriaceae. CP-CRE are also present in Bangladesh hospitals, with NDMbeing the most common carbapenemase found to date (108, 109). The prevalence ofCP-CRE is unknown but is unlikely to be lower than that in Pakistani and Indianhospitals, as environmental water and sewage sampling performed in 2012 from sevenregions in Dhaka, Bangladesh, found a wide variety of NDM-1-producing Gram-negative bacteria from many sampled sites (110).

TABLE 4 Epidemiology and prevalence of carbapenem-resistant Gram-negative bacteria in Nepal

Bacteria and yrof study Study type State Site(s) of isolation; sample type % resistance (no. of isolates) Reference

Acinetobacter spp.2013–2014 Single center Kathmandu Inpatient and outpatient; all

clinical samples98 (122) 98

2011–2012 Single center Kathmandu Intensive care unit; all clinicalsamples

17 (58) 99

Unknown Single center Kathmandu Inpatient and outpatient; allclinical samples

50 (62) 100

Enterobacteriaceae2014 Single center Kathmandu Intensive care unit; all clinical

samplesK. pneumoniae, 18 (22) 99

2012–2013 Single center Kathmandu Intensive care unit and outpatient;all clinical samples

E. coli, 3 (93) 101

2012 Single center Chitwan District Inpatient and outpatient; allclinical samples

E. coli, 18 (216); K. pneumoniae,21 (185)

102

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In 2012, carbapenem-resistant K. pneumoniae was isolated from a teaching hospitalin Colombo, Sri Lanka (111), although all Enterobacteriaceae previously isolated duringthe same seven-center study performed as part of the Antibiotic Resistance SurveillanceProject in 2009 to 2010 were susceptible to carbapenems (107). The majority testedpositive for OXA-181, with a minority carrying NDM-1 (111). NDM-positive Enterobac-teriaceae have been exported from Sri Lanka via patients who had undergone treat-ment in that country’s hospitals (112), similar to the case for other South Asiancountries (6).

No published data on CRE are available from Maldives and Bhutan, except for a WHOreport in 2014 which showed that none of 40 K. pneumoniae isolates tested in Bhutan’snational referral hospital were carbapenem resistant (74).

No mcr-positive Enterobacteriaceae in these other South Asian countries have beenreported to date.

Southeast AsiaSingapore. A formal national antimicrobial resistance surveillance program was

established by Singapore’s ministry of health in 2011, but the results are not publiclyavailable. Prior to that, an academic antimicrobial resistance surveillance programinvolving the majority of the country’s public sector microbiology laboratories wasestablished (113).

(i) Acinetobacter baumannii. The prevalence of carbapenem resistance among ABclinical isolates from Singaporean public sector hospitals was approximately 62% by2010 because of outbreaks in two of six participating hospitals (L.-Y. Hsu, unpublisheddata), marking a rise from 46% in the period from 2006 to 2008 (113). In a study fromSingapore’s largest hospital, Teo and colleagues found that the prevalence of CRABremained largely unchanged, at around 50%, from 2011 to 2015 (114). OXA carbapen-emases were the prevalent contributors to carbapenem resistance in Singapore, andthe vast majority of CRAB isolates belonged to global clones I and II (8, 115, 116).

(ii) Enterobacteriaceae. The earliest known CP-CRE isolate in Singapore, an IMP-1-positive K. pneumoniae strain, dates back to 1996 (117). The prevalence of carbapenemresistance remained low in the following years at �2% of all Enterobacteriaceae isolates,with no further CP-CRE isolated locally until 2010, when NDM-1-producing Enterobac-teriaceae were multiply imported into the country (118). The introduction and spreadof the other carbapenemases, especially KPC and OXA-181, soon followed (12), withsubsequent isolation of Enterobacteriaceae carrying multiple carbapenemases (119).The major carbapenemases among Enterobacteriaceae currently are KPC and NDM-1,with carbapenem resistance rates among K. pneumoniae and E. coli increasing from 2%and 0% to 12% and 5%, respectively, between 2011 and 2015 (114). However, all majorcarbapenemases found in Enterobacteriaceae globally to date have also since beendetected in Singapore (12, 119).

Analysis of archived Enterobacteriaceae revealed the presence of a few unrelatedmcr-1-positive E. coli isolates from clinical samples, dating back to 2012 (T. H. Koh,personal communication).

Malaysia. Malaysia has published National Surveillance of Antimicrobial Resistance(NSAR) reports since 2006, with data dating back to 2003. The data are obtained fromhospital microbiology laboratories from different parts of the country and are collatedat the Institute for Medical Research, Ministry of Health (120).

(i) Acinetobacter baumannii. The latest NSAR report compiled data provided by 39microbiology laboratories in 2014, showing that 57.3% of 15,533 AB isolates wereresistant to meropenem (120). This was similar to the result in 2010, where data from16 microbiology laboratories showed that 56.8% of 9,481 isolates were resistant tomeropenem (121). The OXA-23 gene was the major carbapenemase gene associatedwith carbapenem resistance in AB at a single Malaysian institute (122), and a regionalstudy involving a small collection of CRAB isolates from Malaysia found that thesebelonged to global clone II (8).

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(ii) Enterobacteriaceae. According to the NSAR reports, carbapenem resistance rosefrom 0.5% (11,935 isolates tested) among K. pneumoniae isolates in 2010 to 1.6%(27,911 isolates tested) in 2014, while E. coli carbapenem resistance rates remainedrelatively stable, changing from 0.5% in 2010 (14,573 isolates) to 0.2% (32,215 isolates)in 2014 (120, 121). The major carbapenemase among Enterobacteriaceae in Malaysiaappears to be NDM (123–125), with IMP-4 also being found in clinical K. pneumoniaeisolates cultured between 2010 and 2012 from a university hospital in Kelantan (124).It is highly probable that NDM was imported from South Asia (123).

Malaysia was one of the initial countries where mcr-1-positive Enterobacteriaceaewere discovered (17, 126, 127). The majority of isolates were from animal or environ-mental samples (17, 126), with only one from a clinical urine sample obtained inSelangor in 2013 (127). None were associated with concomitant carbapenem resis-tance. The actual prevalence remains unknown at present.

Philippines. The Philippines Department of Health’s Research Institute for TropicalMedicine established a voluntary antimicrobial resistance surveillance program (Anti-microbial Resistance Surveillance Program [ARSP]) involving sentinel microbiologylaboratories throughout the majority of the regions of the country in 1988 (128).

(i) Acinetobacter baumannii. Based on the ARSP report, 54.1% of 3,575 AB isolateswere resistant to carbapenems in 2015, a significant rise compared to 27.2% and 22.1%in 2006 and 2010, respectively (129). Molecular workup of CRAB from the Philippinessuggested that OXA-23 is the prevalent carbapenemase; there were only 8 isolates intotal from both studies (8, 130).

(ii) Enterobacteriaceae. Based again on the 2015 ARSP report, carbapenem resis-tance rates in K. pneumoniae rose to 11.9% (8,408 isolates tested), having remainedbelow 6% in the preceding years until 2013 (129). Carbapenem resistance rates for E.coli remained relatively low at 3.5% (6,420 isolates tested) in 2015 (129). The fewavailable reports suggest that the major circulating carbapenemases among Entero-bacteriaceae in the Philippines are IMP and NDM (10, 131–133), with NDM-1 and NDM-7more recently circulating in Manila (132, 133). An IMP-4-producing K. pneumoniaeisolate was discovered in Hong Kong in a patient who had previously been hospitalizedin the Philippines (131).

No mcr-positive Enterobacteriaceae have been reported in the Philippines to date.Thailand. The National Antimicrobial Resistance Surveillance Center, Thailand

(NARST), was established by the National Institute of Health of Thailand in 1997 and haspublished annual antibiograms based on microbiology laboratory surveillance since1998 (134).

(i) Acinetobacter baumannii. According to the latest NARST report, 73.7% (12,688isolates tested) of the country’s AB isolates between January and September 2015 werefound to be resistant to meropenem, marking a significant increase from 62.5% (13,645isolates tested) in 2010 (134). Similar to the case in other countries in the region, ThaiCRAB possessed OXA-23 carbapenemases and largely belonged to global clone II (8, 9,135).

(ii) Enterobacteriaceae. Between January and September 2015, 0.9% (22,728 iso-lates) of E. coli isolates and 4.9% (14,304 isolates) of K. pneumoniae isolates testedresistant to the carbapenems according to the NARST report (134). In 2010, carbap-enem resistance rates were 0.8% (22,535 isolates) and 0.3% (15,842 isolates) in E. coliand K. pneumoniae, respectively (134). There are few data on CP-CRE in Thailand. Oneof the earliest reports was from a university hospital in Khon Khaen province, where sixNDM-1-positive Enterobacteriaceae and two IMP-14a-positive K. pneumoniae isolateswere found among 4,814 Enterobacteriaceae isolated between 2010 and 2011 (136).Concurrently, a unique KPC gene (blaKPC-13) was isolated from three urinary Enterobac-teriaceae isolates from a university hospital in Bangkok, with IMP-14a found in four K.pneumoniae isolates (137). Later studies found OXA-48-positive Enterobacteriaceae inKhon Khaen (138), and NDM-1 in Prachuab Khiri Khan (139).

Two mcr-1-positive E. coli isolates were isolated from stool samples from asymp-tomatic Thai people in 2012 (140); no further updates are available at present.

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Vietnam. There is no national or regional antimicrobial resistance surveillanceprogram in Vietnam as of this time (141).

(i) Acinetobacter baumannii. The results from recent reports (published from 2010)are summarized in Table 5. The prevalence of CRAB in Vietnamese hospitals is very high,ranging from 43% in a pediatric hospital in Ho Chi Minh City to 92% in a tertiary referralhospital in Hanoi (142–147). Unfortunately, the bulk of the studies were based on ICUs,where carbapenem resistance rates are usually higher (142–144, 147). As with the restof the region, the majority of CRAB isolates possessed OXA-23 and OXA-51 carbapen-emases and mostly belonged to global clone II (144, 146, 148). A small fraction ofisolates are also likely to be carrying the NDM-1 carbapenemase gene (148).

(ii) Enterobacteriaceae. The few reports highlighting CRE prevalence in Vietnameseinstitutions are summarized in Table 5. The multicenter ICU study conducted between2012 and 2013 showed that 15% of K. pneumoniae isolates were resistant to thecarbapenems (142), which was much higher than the 3% found in the earlier 2007 ICUstudy (147). Up to 1.1% of Enterobacteriaceae isolated between 2010 and 2012 werefound to be CRE in a surgical hospital in Hanoi (149). Finally, in a separate study lookingat Gram-negative bacteria associated with intra-abdominal infections in four hospitalsin Vietnam (2009 to 2011), 0.3% (787 isolates) of E. coli isolates and 1% (145 isolates) ofK. pneumoniae isolates were found to be carbapenem resistant, but it is not clear howsystematic the collection of isolates for the study was (150).

From the few available reports, NDM appeared to be the most common carbapen-emase carried by CRE in Vietnam (149–151), although KPC-2, OXA-48, and VIM hadbeen identified among carbapenem-resistant K. pneumoniae isolates (149). A history oftravel could not be elicited from the earliest patients identified with NDM-producingEnterobacteriaceae, suggesting earlier unsuspected importation (151). A patient whowas hospitalized in Ho Chi Minh City in 2011 was found to have NDM-positive K.pneumoniae when she was hospitalized in the United States shortly after (152). Inter-estingly, NDM-positive K. pneumoniae was also cultured from the environment (seep-age water) in Vietnam in 2011 (153), just like in South Asia.

Vietnam retains the distinction of being the country where the earliest mcr-1-positiveEnterobacteriaceae strain was isolated; this was a Shigella sonnei isolate from a patient withdysentery in 2008 (154). The gene is also present in Enterobacteriaceae from food animals

TABLE 5 Epidemiology and prevalence of carbapenem-resistant Gram-negative bacteria in Vietnam

Bacteria and yrof study Study type State(s)

Site of isolation; sampletype % resistance (no. of isolates) Reference

Acinetobacter spp.2012–2013 14 centers Vietnam-wide Intensive care unit; all

clinical samples89 (167) 142

2011–2012 Single center Ho Chi Minh City Intensive care unit; trachealaspirate samples

84 (74) 143

2010 Single center Ho Chi Minh City Intensive care unit; trachealaspirate samples

80 (35) 144

2009–2010 Single center Ho Chi Minh City Inpatient; pediatrics; bloodsamples

43 (58) 145

2009 Single center Hanoi Inpatient; all clinicalsamples

92 (58) 146

2007 2 centers Hanoi, Hai Phong Intensive care unit; allclinical samples

69 (170) 147

Enterobacteriaceae2012–2013 14 centers Vietnam-wide Intensive care unit; all

clinical samplesEnterobacteriaceae, 5 (241);

K. pneumoniae, 15 (74)142

2010–2012 Single center Hanoi Inpatient; all clinicalisolates

Enterobacteriaceae, 1.1 (4,096) 149

2009–2011 4 centers Hanoi, Ho Chi Minh City Intra-abdominal samples E. coli, 0.3 (787); K. pneumoniae,1 (145)

150

2007 2 centers Hanoi, Hai Phong Intensive care unit; allclinical samples

E. coli, 0 (61); K. pneumoniae,3 (103)

147

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in Vietnam (155, 156), with up to 22% of E. coli isolates from 6 each of pig and chicken farmstesting positive in a study conducted between 2013 and 2014 (155).

Other countries of Southeast Asia. Public domain surveillance data with regard tocarbapenem-resistant Gram-negative bacteria from the other countries of SoutheastAsia are lacking. Myanmar is perhaps the closest to having some form of nationalantimicrobial resistance surveillance, with their National Health Laboratory performingsuch work on occasion for a national network on surveillance (46, 47).

(i) Acinetobacter baumannii. In Indonesia, 50.5% of clinical isolates of AB from theICU of an academic hospital in 2011 were carbapenem resistant (157), whereas 84% (24isolates) of AB in that hospital’s neonatal unit in 2011 to 2012 were carbapenemresistant (158).

In Cambodia, the only published data are from a nongovernmental organization’shospital in Phnom Penh, where only 1 of 17 (5.9%) AB isolates cultured from bloodbetween 2007 and 2010 was resistant to carbapenems (159).

There are no publicly available data on CRAB in Myanmar, Laos, East Timor, andBrunei, although it is likely that the organism is present in these countries. There wasa case report of CRAB that was likely exported from Brunei into Japan in 2014 (160).

(ii) Enterobacteriaceae. In a single-center ICU study from a university hospital inJakarta, Indonesia, 27.6% of Enterobacteriaceae isolated in 2011 were reported as beingresistant to carbapenems (157). In a separate ICU study from a tertiary referral hospitalin Jakarta, 5.4% of K. pneumoniae isolates from between 2009 and 2010 were reportedto be resistant to carbapenems (161). Only one K. pneumoniae isolate from the 2011study was found to carry the NDM-1 gene, however, suggesting that carbapenemresistance in the other Enterobacteriaceae may not have been due to carbapenemaseproduction (157).

Myanmar reported that 8% of 58 K. pneumoniae isolates tested in 2012 as part of itsnational survey were resistant to the carbapenems (74). NDM-positive Enterobacteria-ceae are likely to be present in Myanmar health care facilities, given the report of anNDM-4-positive K. pneumoniae isolate from an Australian traveler who had stayed in ahospital in Myanmar prior to repatriation back to Sydney (162).

There are no available data on CRE in Laos, Cambodia, East Timor, and Brunei (74).Among the Southeast Asian countries listed in this section, mcr-1-positive Enterobac-teriaceae have been isolated from pigs in Laos and from humans in both Laos andCambodia (19). The actual prevalence in these countries has not been determined.

DRIVERS OF CARBAPENEM-RESISTANT GRAM-NEGATIVE BACTERIA

A complex combination of factors probably led to the rapid rise and spread of CRABand CRE in hospitals in South and Southeast Asia. One of the key factors is inappro-priate and excessive prescription of antibiotics, including carbapenems, in the healthcare setting. Studies on inpatient prescription of antibiotics have been performed andpublished in half of the South and Southeast Asian countries, and excessive andinappropriate prescription of antibiotics in the inpatient setting has been highlightedas a major issue, ranging from between 10% to 50% of all antibiotics prescribed (97,141, 163–169). It is unlikely that the situation is better in the other countries (Bangla-desh, Sri Lanka, Maldives, Bhutan, Afghanistan, Philippines, Myanmar, Laos, Cambodia,and Timor-Leste), where data are not available.

The reasons for inappropriate antibiotic prescription are, for the most part, similar.Many countries have few antibiotic prescription control policies in the hospital settingand either have no antibiotic stewardship programs in place or are just beginning toimplement such programs; a recent international survey showed that just over half(53%) of Asian countries had any form of antibiotic stewardship in their hospitals, andof those that did, fewer than half had any national (42%) or regional (16%) antibioticstewardship standards in place (170). In countries with fairly established antibioticstewardship programs such as Singapore, adherence to antibiotic prescription recom-mendations seldom exceeded 75% in published reports (171, 172). In India, it wasreported that physicians were compensated by pharmaceutical companies and phar-

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macies for prescribing antibiotics (166), but it is unclear how prevalent this practice isin other countries.

Other health system factors also contribute to the rise of CRAB and CRE in South andSoutheast Asian countries. In many countries, health systems are stretched and hospi-tals overcrowded, conceivably taxing limited resources, especially in public hospitals,with regard to nursing care and infection prevention. Unfortunately, this has neverbeen formally investigated in Asia as a cause of spread of Gram-negative antimicrobialresistance.

Interhospital transfers, travelers who are hospitalized for emergency medical careand subsequently repatriated, and the phenomenon of medical tourism have alsocontributed to the spread of drug-resistant bacteria. The situation is less well docu-mented for AB than for CP-CRE, especially in South and Southeast Asia, except perhapsfor CRAB causing infections in military personnel who have returned from Afghanistan(and Iraq) (6, 22, 173). Investigators from Edmonton, Canada, reported the spread ofOXA-23-positive AB and NDM-1-positive K. pneumoniae from a patient recently hospi-talized in India to five other patients in the same hospital in Edmonton, resulting in adeath in 2012 (174). Another outbreak of OXA-23-positive AB in a German hospital in2006 was attributed to a patient repatriated from a Thai hospital (175).

Multiple reports describe the exportation of CP-CRE, especially NDM-positive Enterobac-teriaceae, from South and Southeast Asian hospitals via former inpatients to hospitalsaround the world, including in Africa, Europe, the United States, and other parts of Asia(6, 174, 176–184). It is plausible that KPC and OXA carbapenemase-positive Enterobac-teriaceae were imported into South and Southeast Asia, as these enzymes were firstdiscovered in North America and the Middle East, respectively, but this cannot beconclusively proven for the most part and the question is at best academic at this time(13, 28). As an example, based purely on molecular data (identical Tn3-based trans-posons in the plasmids), it is plausible that some of Singapore’s KPC-positive K.pneumoniae isolates originated from China (185). Exportation of OXA carbapenemase-positive Enterobacteriaceae from the hospitals of South and Southeast Asian countriescontinues to be documented (179–181), but exportation of KPC-positive Enterobacte-riaceae appears to be far rarer at present.

CP-CRE have also been isolated from the community and environment in several Southand Southeast Asian countries, including India, Pakistan, and Vietnam (14, 85, 87, 153). Inthe first of these studies done in India, Walsh and coworkers showed that NDM-positiveEnterobacteriaceae could be isolated from seepage and even tap water throughout NewDelhi (14). One study from Pakistan documented 8.6% CP-CRE recovery rates from thediarrheal stools submitted for culture throughout multiple regions in the country, but it isunclear what fraction were true community-associated cases (85). A second study basicallyreplicated the New Delhi study by Walsh et al. in Pakistan, finding NDM-positive bacteria injust under 5% of water samples, although the results may be questionable given that 2 of12 isolates positive for NDM were Enterococcus spp. (87). Finally, a similar study in Hanoifound NDM-positive K. pneumoniae from 3 of 20 sites sampled (153).

It is plausible that poor environmental hygiene and sanitation have contributed tothe “escape” of CRE from the hospital setting (14, 85, 87, 153), or alternatively, thesemay represent the spillover from antimicrobial resistance in agriculture, which is evenmore poorly characterized in the region. Coriander that might have been exported fromeither Thailand or Vietnam was found to be positive for OXA-181-positive Klebsiellavariicola in Switzerland in 2015 (16), corresponding with reports of OXA-48-positiveEnterobacteriaceae from seafood originating from South Korea or China (186).

DISCUSSION

This review has highlighted the challenges faced by many South and Southeast Asiancountries with regard to the spread of CRAB and CRE. These countries are important to therest of the world, as they house more than a third of the world’s population and are majormedical tourism destinations as well as venues for vacationers and militaries from aroundthe world. There are, however, significant data gaps; countries such as Bhutan, Mal-

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dives, Myanmar, Laos, East Timor, and Brunei have not published any data oncarbapenem-resistant Gram-negative bacteria in the public domain, but it is conceiv-able that this may be a rising problem in those countries as well. Even in the remainingcountries, with the exception perhaps of Singapore, which is a small city-state, the lackof comprehensive surveillance programs that include molecular epidemiologic testinghas made it difficult to understand the origins and extent of the Gram-negativeantimicrobial resistance problem in depth. It is probably unwise to extrapolate thepublished findings from tertiary hospitals in large cities to all parts of the country.

Nonetheless, it seems clear that CRAB is a major cause of health care-associatedinfections in large referral hospitals throughout South and Southeast Asia, with mostinstitutions registering carbapenem resistance rates of �50% for AB, especially in theICU setting (53–60, 75–80, 98–100, 106, 107, 113, 114, 120, 121, 129, 134, 142–147, 157,158). The prevalence of CRE, including CP-CRE, is high in the tertiary hospitals of thelarger South Asian countries (10, 53, 62–71, 75, 82, 83, 99, 101, 102) but much lower insimilar hospitals in Southeast Asia (74, 114, 120, 121, 129, 134, 142, 147, 149, 150, 157,161). As seen by the numerous reports of CP-CRE exportation from South and SoutheastAsia (6, 174, 176–184), international dissemination of CP-CRE appears to be a far greaterproblem than that of CRAB, and it will conceivably be more difficult for other countriesto control CP-CRE within their own borders if this is also not tackled at its root in Southand Southeast Asia. The problem of CP-CRE is exacerbated by the parallel spread of themcr gene, conferring colistin resistance (17–19). As mentioned above, carbapenemase-producing mcr-positive Enterobacteriaceae have already been isolated (19–21), furtherdissemination of which will result in the rise of untreatable Gram-negative infections.

Crucially, the problem of carbapenem-resistant Gram-negative bacteria specificallyand antimicrobial resistance in general has been recognized by both the medicalcommunity and governments of many South and Southeast Asian countries. Therehave been several ground-up initiatives, including the Chennai Declaration, a series ofwide-ranging recommendations for tackling antimicrobial resistance from the Indianperspective resulting from a joint meeting of representatives of Indian medical societiesand professional councils, policymakers, researchers, and WHO representatives on 24August 2012 in Chennai, India, that resulted in a great deal of media and publicattention to the issue of antimicrobial resistance in India (50). SEARO has also played arole in coordinating governmental responses, resulting in the Jaipur Declaration (189).Health ministers of member states of SEARO made the declaration on 6 September2011, acknowledging the major public health issue of antimicrobial resistance andpledging a variety of efforts at both the national and regional levels in an attempt tocontrol it (189).

Other efforts to address the problem include strengthening microbiology laboratorydiagnostic capabilities in countries such as Timor-Leste and Bhutan, as well as in themore rural parts of South and Southeast Asian countries. The government of the UnitedKingdom has put in place the Fleming Fund, which may help to address criticallaboratory infrastructure gaps in Asia as it is rolled out over the next 5 years (187). Morecomprehensive antimicrobial resistance surveillance programs within each country aswell as on a regional level will help to plug current data gaps and keep tabs on anevolving situation with CRE. WHO’s global antimicrobial resistance surveillance system(GLASS), which promotes antimicrobial resistance surveillance in member states andprovides a platform for global data sharing, is a step in the right direction (188),although the impact will depend on its actual implementation. The Fleming Fund islikely to be complementary to this effort, as good microbiology laboratories are aprerequisite to surveillance (187).

Coupled with political will and an educated public, greater efforts at antimicrobialstewardship and infection prevention within health care settings, as well as betterhealth service delivery and environmental engineering, may help with curbing the riseand spread of carbapenem-resistant Gram-negative bacteria. Finally, focusing researchefforts on carbapenem-resistant Gram-negative bacteria, especially in terms of diag-nostics and new therapeutics, is well within the capability of several countries in these

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regions and will contribute to the global effort at combating these pathogens anddelaying the much-publicized “antibiotic apocalypse.”

ACKNOWLEDGMENTSWe thank Long Pang from the Saw Swee Hock School of Public Health for creating

the two map figures and also Patrick Lane of ScEYEnce Studios for the enhancement ofthese figures.

The authors have no conflicts of interest to declare with respect to the work herein.P.A.T. and L.-Y.H. conceived the study and reviewed the methodology. All authors

did literature review, drafted the manuscript, reviewed the work critically, and ap-proved the final draft of the manuscript for submission.

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Li-Yang Hsu is an infectious diseases physicianwho holds concurrent research and clinical ap-pointments as an adjunct associate professor inthe Yong Loo Lin School of Medicine and SawSwee Hock School of Public Health, NationalUniversity Health System, Singapore. He is alsoa visiting consultant to the Central TuberculosisLaboratory at the Singapore General Hospitaland an adjunct clinician-scientist at the Insti-tute of Bioengineering & Nanotechnology. Hisareas of research include the epidemiology ofmethicillin-resistant Staphylococcus aureus as well as the clinical and socio-economic impacts of antimicrobial resistance. He is the current director ofthe Singapore Infectious Diseases Initiative, a program funded by the Min-istry of Health Singapore to promote collaborative research on infectiousdiseases in Singapore.

Anucha Apisarnthanarak finished training ininfectious diseases and hospital epidemiology atWashington University School of Medicine. Heis currently an Associate Professor at Tham-masat University Hospital and Chief of the In-fectious Diseases Division at the same institu-tion. He also serves as adjunct visiting professorat the Division of Infectious Diseases, Washing-ton University School of Medicine, USA. Beingin a relatively resource-limited country, overthe past 15 years Dr. Apisarnthanarak’s researchhas focused on infection control in resource-limited settings, including con-trol of multidrug-resistant pathogens, antimicrobial stewardship, epi-demiology and control of emerging infectious diseases, and outbreakinvestigation.

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Erum Khan is a consultant clinical microbiolo-gist and associate professor at the Departmentof Pathology & Microbiology at the Aga KhanUniversity, Karachi, Pakistan. She has wonmultiple awards and honors, including theASM-UNESCO Leadership Award in 2009.Her research interests include emergence ofmultidrug- and pandrug-resistant organisms,which is one of the leading problems in Pakistanas well as in other parts of the world. Her workinvolves the advancement of the field of bacte-riology at the Clinical Microbiology Section of Aga Khan University Hospi-tal, developing and optimizing protocols of molecular techniques that cananswer important questions about antimicrobial resistance and its spread inthe hospital.

Nuntra Suwantarat, M.D., D(ABMM), re-ceived her M.D. from the Faculty of Medicine,Siriraj Hospital, Mahidol University, Salaya,Thailand. She completed a residency in internalmedicine at the University of Hawaii, Hono-lulu, HI. Following a clinical fellowship in infec-tious diseases at the Case Western ReserveUniversity Program in Cleveland, OH, Dr. Su-wantarat did a second fellowship in medical mi-crobiology at the Johns Hopkins University,Baltimore, MD, under the supervision of KarenC. Carroll. Upon completion of her fellowship training, Dr. Suwantaratjoined the faculty at Chulabhorn International College of Medicine, Tham-masat University, Pathum Thani, Thailand. She is currently a lecturer andinfectious diseases and microbiology consultant at Thammasat UniversityHospital. Dr. Suwantarat’s focused area of research is on antimicrobial-resistant bacteria and clinical microbiology in resource-limited settings.

Abdul Ghafur is the primary author and coor-dinator of the “Chennai Declaration,” a docu-ment and initiative by medical societies in Indiato tackle the challenge of antimicrobial resis-tance from an Indian perspective. He is a con-sultant and adjunct professor in infectious dis-eases and clinical microbiology at the ApolloHospitals, Chennai, India. He is a core commit-tee member for national antibiotic policy andguidelines of the Indian Ministry of Health.

Paul Anantharajah Tambyah is currently Pro-fessor of Medicine at the National University ofSingapore and Senior Consultant InfectiousDiseases Physician at the National UniversityHealth System. After completing medicalschool at the National University of Singaporeand military service in the Singapore ArmedForces Medical Corps, he trained in infectiousdiseases at the University of Wisconsin underDr. Dennis Maki. Since returning to Singapore,he has served on a number of national and in-ternational committees, including the Board of the Society of HealthcareEpidemiology in the United States and as Assistant Dean of the Yong Loo LinSchool of Medicine, National University of Singapore. He is currently anEXCO member of the International Society of Infectious Diseases and Sec-retary General of the Asia Pacific Society for Clinical Microbiology. His mainresearch interests are in device-associated infections and emerging infectiousdiseases, including Gram-negative resistant bacteria and pandemicinfluenza.

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