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Antimicrobial resistance in major pathogens of hospital-acquired pneumonia in Asian countries

  • Evelina N. Lagamayo
    Correspondence
    Address correspondence to Evelina N. Lagamayo, MD, Associate Professor, Department of Laboratory Medicine, University of Santo Tomas, Manila, Philippines.
    Affiliations
    Department of Laboratory Medicine, University of Santo Tomas, Espana, Manila; and St. Lukes Medical Center, E. Rodriguez Avenue, Quezon City, Philippines
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      Antimicrobial resistance is a worldwide problem. For patients with hospital-acquired or ventilator-associated pneumonia, resistant pathogens pose a significant challenge to successful treatment outcomes and to the cost-effective delivery of health care. In the developing world, antibiotic resistance may be relatively more prevalent compared with Western countries. Common resistant pathogens include methicillin-resistant Staphylococcus aureus, multidrug resistant Pseudomonas aeruginosa, multidrug resistant Acinetobacter species, and extended-spectrum β-lactamase-producing strains of Escherichia coli and Klebsiella pneumoniae. The emergence of these strains has provided a major impetus toward development of the present consensus treatment recommendations of the Asian HAP Working Group. The following review provides summary data regarding the incidence and prevalence of antibiotic-resistant pathogens in 10 Asian countries.
      The present consensus treatment recommendations represent the findings of an expert panel. The intent of the article is to provide useful, practical information to assist the clinician in the treatment of patients with hospital-acquired pneumonia (HAP) and ventilator-acquired pneumonia (VAP). It is hoped that this information will help in the development of effective treatment regimens for these patients.
      Nosocomial infection is an important cause of morbidity and mortality worldwide, a problem made worse when nosocomial pathogens acquire antibiotic resistance. The emergence of resistant microorganisms has a significant impact on treatment outcomes and also poses a challenge to the provision of health care and its cost-effectiveness. This is especially true in the developing world, where antibiotic-resistant pathogens may have a higher prevalence and incidence. In Asian countries, antimicrobial resistance for common pathogens of hospital-acquired pneumonia (HAP), including methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant (MDR) Pseudomonas aeruginosa, MDR Acinetobacter species, and extended-spectrum β-lactamase-producing (ESBL[+]) strains of Escherichia coli and Klebsiella pneumoniae has been documented.
      • Prashanth K.
      • Badrinath S.
      Epidemiological investigation of nosocomial Acinetobacter infections using arbitrarily primed PCR and pulse-field gel electrophoresis.
      • Lee K.
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      • Docquier J.D.
      • et al.
      Novel acquired metallo-β-lactamase gene, bla(SIM-1), in a class 1 integron from Acinetobacter baumannii clinical isolates from Korea.
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      • Hashim S.
      • Sarijo J.
      • et al.
      Prevalence of nosocomial infection and antibiotic use at a university medical center in Malaysia.
      • Lee H.J.
      • Suh J.T.
      • Kim Y.S.
      • Lenz W.
      • Bierbaum G.
      • Schaal K.P.
      Typing and antimicrobial susceptibilities of methicillin-resistant Staphylococcus aureus (MRSA) strains isolated in a hospital in Korea.
      • Thongpiyapoom S.
      • Narong M.N.
      • Suwalak N.
      • Jamulitrat S.
      • Intaraksa P.
      • Boonrat J.
      • et al.
      Device-associated infections and patterns of antimicrobial resistance in a medical-surgical intensive care unit in a university hospital in Thailand.
      In Singapore, it has been noted that antibiotic resistance is increasing among gram-negative bacilli and S aureus, both common pathogens in HAP.
      • Lim T.K.
      Emerging pathogens for pneumonia in Singapore.
      Very high rates of MRSA, at least 70% of all S aureus isolates, have also been reported in Hong Kong and Japan.
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      • Pfaller M.A.
      • Schmitz F.J.
      • Smayevsky J.
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      • Jones R.N.
      • et al.
      SENTRY Partcipants Group
      Survey of infections due to Staphylococcus species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, Latin America, Europe, and the Western Pacific region for the SENTRY Antimicrobial Surveillance Program, 1997-1999.
      Other common resistant pathogens include imipenem-resistant P aeruginosa, ceftazidime-resistant A baumannii, third-generation cephalosporin-resistant K pneumoniae, and fluoroquinolone-resistant E coli.
      • Thongpiyapoom S.
      • Narong M.N.
      • Suwalak N.
      • Jamulitrat S.
      • Intaraksa P.
      • Boonrat J.
      • et al.
      Device-associated infections and patterns of antimicrobial resistance in a medical-surgical intensive care unit in a university hospital in Thailand.
      The prevalence of drug-resistant organisms has been a major rationale for development of the present consensus treatment recommendations for HAP in Asia. The following summarizes the findings of clinical microbiologists representing 10 Asian countries, relevant to the emergence of antibiotic-resistant pathogens of HAP.

      Methods

      An expert panel (Appendix) was convened comprising clinical microbiologists representing 10 Asian countries. The panel members exchanged and critically analyzed information regarding the etiologic distribution and antimicrobial resistance patterns of nosocomial pathogens causing HAP and ventilator-acquired pneumonia (VAP) in Asian hospitals. National and local surveillance data, where available, were analyzed on an individual hospital or individual country basis. Areas of incomplete knowledge were identified, and this, it is hoped, will be useful to define the direction of future surveillance and microbiologic studies.

      Overall incidence of HAP by major resistant pathogens

      Methicillin-resistant S aureus

      For HAP, including data for VAP, the overall range of MRSA incidence was 1% to 78%. For early-onset HAP, the range was 6% to 30%, and, for late-onset HAP, an incidence of 12% to 60% was reported. For VAP cases, the incidence was 14.2% to 80% overall. No data were available regarding the incidence of MRSA in early- and late-onset VAP (Table 1).
      Table 1Overall incidence of HAP by major resistant pathogens methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter species, ESBL(+) Klebsiella pneumoniae, and ESBL(+) Escherichia coli
      Incidence (%) of HAP by specific pathogen
      HAP (including VAP)VAP
      PathogenOverallEarlyLateOverallEarlyLate
      MRSA1-786-3012-6014.2-80NRNR
      Ceftazidime-resistant P aeruginosa0-300-101.5-3012.9-35NRNR
      Imipenem-resistant P aeruginosa0-310-101.5-309.7-30NRNR
      Ciprofloxacin-resistant P aeruginosa0-391.2-300.8-409.7-40NRNR
      MDR
      MDR means resistance to ≥3 classes of antibiotics.
      P aeruginosa
      0-200-100-2016.1-25NRNR
      Ceftazidime-resistant Acinetobacter species0-76.30-152.7-4040-87.3NRNR
      Imipenem-resistant Acinetobacter species0.9-300-51.1-3014.5-70NRNR
      MDR Acinetobacter species1.2-870-101.5-4035-96.4NRNR
      ESBL(+) K pneumoniae0.9-401.2-101.1-4020-52.4NRNR
      ESBL(+) E coli2.3-401.2-102.7-4011-55NRNR
      MDR, multidrug resistant; NR, not reported.
      MDR means resistance to ≥3 classes of antibiotics.
      The proportion of all S aureus clinical isolates that were MRSA was 29% to 70%. Among nosocomial infections, MRSA represented 8% to 80% of all clinical infections by S aureus, and, among intensive care unit (ICU) infections, MRSA represented 41% to 100%. For HAP cases, including VAP, the incidence of MRSA was 10.8% to 78% and, for VAP cases, 14.2% to 15%. Among MRSA strains, <5% exhibited reduced susceptibility to vancomycin and none exhibited resistance to linezolid (Table 2).
      Table 2Resistance in Staphylococcus aureus: MRSA
      Incidence of MRSA%
      Per all clinical isolates of S aureus29-70
      Per nosocomial infections8-80
      Per ICU infections41-100
      Per HAP cases (including VAP)10.8-78
      Per VAP cases14.2-15
      MRSA with reduced susceptibility to vancomycin
      Frequency of MRSA strains among all clinical infections by S aureus.
      (VISA or VRSA)
      <5
      MRSA with linezolid resistance
      Frequency of MRSA strains among all clinical isolates of MRSA.
      0
      VISA, vancomycin-intermediate S aureus; VRSA, vancomycin-resistant S aureus.
      Frequency of MRSA strains among all clinical infections by S aureus.
      Frequency of MRSA strains among all clinical isolates of MRSA.

      P aeruginosa

      In cases of HAP, including VAP, strains of P aeruginosa resistant to ceftazidime were reported to cause 0% to 30% of overall cases, 0% to 10% of early-onset cases, and 1.5% to 30% of late-onset cases. P aeruginosa resistant to imipenem was reported to cause 0% to 31% of overall cases, 0% to 10% of early-onset cases, and 1.5% to 30% of late-onset cases. P aeruginosa resistant to ciprofloxacin was reported to cause 0% to 39% of overall cases, 1.2% to 30% of early-onset cases, and 0.8% to 40% of late-onset cases. MDR P aeruginosa was associated with 0% to 20% of overall cases, 0% to 10% of early-onset cases, and 0% to 20% of late-onset cases (Table 1).
      For VAP cases, the overall incidence of P aeruginosa resistance to ceftazidime was 12.9% to 35%, resistance to imipenem was 9.7% to 30%, resistance to ciprofloxacin was 9.7% to 40%, and resistance to multiple drugs was 16.1% to 25%. No data were available regarding the incidence of drug-resistant P aeruginosa in early- and late-onset VAP (Table 1).
      The proportion of all P aeruginosa clinical isolates that were resistant to ceftazidime ranged from 3% to 48%. For cases of HAP (including VAP), the proportion ranged from 0% to 52% and, for VAP cases, 12.9% to 30%. Imipenem resistance was reported in 3% to 35% of all isolates of P aeruginosa overall, 0% to 31% of HAP cases (including VAP) and 0% to 31% of VAP cases. Ciprofloxacin resistance was reported in 4% to 44% of all clinical isolates of P aeruginosa, 0% to 39% of HAP cases (including VAP) and 9.7% to 40% of VAP cases. Resistance to piperacillin/tazobactam was reported in 2% to 30% of all isolates of P aeruginosa, 9.3% to 30% of all HAP cases (including VAP) and 9.7% to 30% of all VAP cases. Strains of P aeruginosa resistant to multiple drugs represented 14% to 23% of all clinical isolates, 0% to 25% of HAP cases (including VAP) and 16.1% to 30% of VAP cases (Table 3).
      Table 3Resistance in Pseudomonas aeruginosa
      Resistance in PseudomonasIncidence%
      Ceftazidime resistancePer all isolates of P aeruginosa3-48
      Per HAP cases (including VAP)0-52
      Per VAP cases12.9-30
      Imipenem resistancePer all isolates of P aeruginosa3-35
      Per HAP cases (including VAP)0-31
      Per VAP cases9.7-30
      Ciprofloxacin resistancePer all isolates of P aeruginosa4-44
      Per HAP cases (including VAP)0-39
      Per VAP cases9.7-40
      Piperacillin-tazobactam resistancePer all isolates of P aeruginosa2-30
      Per HAP cases (including VAP)9.3-30
      Per VAP cases9.7-30
      MDR (≥3 classes)Per all isolates of P aeruginosa14-23
      Per HAP cases (including VAP)0-25
      Per VAP cases16.1-30

      Acinetobacter species

      Overall, ceftazidime-resistant Acinetobacter species accounted for 0% to 76.3% of HAP cases (including VAP), 0% to 15% of early-onset cases and 2.7% to 40% of late-onset cases. Imipenem-resistant strains of Acinetobacter species represented 0.9% to 30% of overall HAP cases (including VAP), 0% to 5% of early-onset cases and 1.1% to 30% of late-onset cases. Multiple-drug resistance was reported in 1.2% to 87% of overall HAP cases (including VAP), 0% to 10% of early-onset cases and 1.5% to 40% of late-onset cases (Table 1).
      Overall, VAP cases caused by ceftazidime-resistant Acinetobacter species ranged from 40% to 87.3%, those caused by imipenem-resistant strains ranged from 14.5% to 70%, and those caused by MDR Acinetobacter species ranged from 35% to 96.4%. No data were available regarding the incidence of drug-resistant Acinetobacter species in early- and late-onset VAP (Table 1).
      The percentage of all Acinetobacter species clinical isolates resistant to imipenem ranged from 2% to 77%. For cases of HAP (including VAP), the percentage ranged from 0% to 68% and, for VAP cases, 14.5% to 20%. Ciprofloxacin resistance was reported in 23.2% to 92% of all isolates of Acinetobacter species overall, 0% to 86% of HAP cases (including VAP) and 40% to 92.7% of VAP cases. MDR Acinetobacter species was found in 25% to 66% of all clinical isolates, 1.2% to 87% of HAP cases (including VAP) and 30% to 96.4% of VAP cases. Pan-drug resistance (resistance to all antibiotic classes) was found in 0% to 30% of all clinical isolates, 0% to 46% of HAP cases (including VAP) and 3.6% to 20% of VAP cases (Table 4).
      Table 4Resistance in Acinetobacter species
      Resistance in AcinetobacterIncidence%
      Imipenem resistancePer all isolates of Acinetobacter2-77
      Per HAP cases (including VAP)0-68
      Per VAP cases14.5-20
      Ciprofloxacin resistancePer all isolates of Acinetobacter23.2-92
      Per HAP cases (including VAP)0-86
      Per VAP cases40-92.7
      MDR (≥3 classes)Per all isolates of Acinetobacter25-66
      Per HAP cases (including VAP)1.2-87
      Per VAP cases30-96.4
      PDR (all antibiotic classes)Per all isolates of Acinetobacter0-30
      Per HAP cases (including VAP)0-46
      Per VAP cases3.6-20
      MDR, multidrug resistant; PDR, pan drug resistant.

      K pneumoniae

      The overall incidence of ESBL-producing K pneumoniae was 0.9% to 40% of cases of HAP (including VAP). The incidence ranged from 0% to 10% for early-onset cases and from 1.1% to 40% for late-onset cases. For VAP cases, the overall incidence of K pneumoniae producing ESBL was 20% to 52.4%. No data were available regarding the incidence of ESBL(+) K pneumoniae in early- and late-onset VAP (Table 1).
      The proportion of all K pneumoniae clinical isolates that were resistant to ceftriaxone ranged from 4% to 60%. For cases of HAP (including VAP), the proportion ranged from 0.3% to 40% and, for VAP cases, 50% to 60%. Imipenem resistance was reported in 0% to 24% of all isolates of K pneumoniae overall, 0% to 50.9% of HAP cases (including VAP) and 1% to 57.1% of VAP cases. Ciprofloxacin resistance was reported in 13% to 68% of all clinical isolates, 0.3% to 18% of HAP cases (including VAP) and 10% to 40% of VAP cases. Resistance to piperacillin/tazobactam was reported in 10% to 37% of all isolates of K pneumoniae, 0.3% to 8% of all HAP cases (including VAP) and 5% to 15% of all VAP cases. ESBL-producing K pneumoniae represented 11% to 45% of all clinical isolates, 0.9% to 35% of HAP cases (including VAP) and 20% to 52.4% of VAP cases (Table 5).
      Table 5Resistance in Klebsiella pneumoniae
      Resistance in K pneumoniaeIncidence%
      Cefriaxone resistancePer all isolates of K pneumoniae4-60
      Per HAP cases (including VAP)0.3-40
      Per VAP cases50-60
      Imipenem resistancePer all isolates of K pneumoniae0-24
      Per HAP cases (including VAP)0-50.9
      Per VAP cases1-57.1
      Ciprofloxacin resistancePer all isolates of K pneumoniae13-68
      Per HAP cases (including VAP)0.3-18
      Per VAP cases10-40
      Piperacillin-tazobactam resistancePer all isolates of K pneumoniae10-37
      Per HAP cases (including VAP)0.3-8
      Per VAP cases5-15
      ESBL (+)Per all isolates of K pneumoniae11-45
      Per HAP cases (including VAP)0.9-35
      Per VAP cases20-52.4

      E coli

      The overall incidence of ESBL-producing E coli was 2.3% to 40% of cases of HAP (including VAP). The incidence ranged from 1.2% to 10% for early-onset cases and from 2.7% to 40% for late-onset cases. For VAP cases, the overall incidence of E coli producing ESBL was 11% to 55%. No data were available regarding the incidence of ESBL(+) E coli in early- and late-onset VAP (Table 1).
      The proportion of all E coli clinical isolates resistant to ceftriaxone ranged from 10% to 60%. For cases of HAP (including VAP), the proportion ranged from 2.3% to 53% and, for VAP cases, 50% to 60%. Imipenem resistance was reported in 0% to 10% of all isolates of E coli overall and 0% to 10% of HAP cases (including VAP). No imipenem resistance was reported for VAP cases. Ciprofloxacin resistance was reported in 26% to 80% of all clinical isolates, 26% to 55% of HAP cases (including VAP) and 50% to 80% of VAP cases. Resistance to piperacillin/tazobactam was reported in 5% to 39% of all isolates of E coli, 0% to 13% of all HAP cases (including VAP) and 10% of all VAP cases. ESBL-producing E coli represented 8% to 50% of all clinical isolates, 2.3% to 40% of HAP cases (including VAP) and 50% to 60% of VAP cases (Table 6).
      Table 6Resistance in Escherichia coli
      Resistance in E coliIncidence%
      Cefriaxone resistancePer all isolates of E coli10-60
      Per HAP cases (including VAP)2.3-53
      Per VAP cases50-60
      Imipenem resistancePer all isolates of E coli0-10
      Per HAP cases (including VAP)0-10
      Per VAP cases0
      Ciprofloxacin resistancePer all isolates of E coli26-80
      Per HAP cases (including VAP)2.6-55
      Per VAP cases50-80
      Piperacillin-tazobactam resistancePer all isolates of E coli5-39
      Per HAP cases (including VAP)0-13
      Per VAP cases10
      ESBL (+)Per all isolates of E coli8-50
      Per HAP cases (including VAP)2.3-40
      Per VAP cases50-60

      Discussion

      In general, P aeruginosa, Acinetobacter species, MRSA, and ESBL(+) E coli and K pneumoniae are the most common pathogens of HAP and VAP in Asian countries. In the present analysis, the 2 most common drug-resistant pathogens causing HAP are methicillin-resistant S aureus and MDR Acinetobacter species. In Korea and Taiwan, MRSA was most common, representing 50% to 70% of all S aureus isolates in Korea
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      • et al.
      Multicenter surveillance of antimicrobial resistance of major bacterial pathogens in intensive care units in 2000 in Taiwan.
      Current estimates are that, in cases of HAP or VAP, approximately 80% of A baumannii isolates are resistant to ceftazidime or fluoroquinolone, and less than 15% are resistant to imipenem. In Singapore, data presented by the panel indicate that, among Acinetobacter species, approximately 50% was susceptible to aminoglycosides, yet only approximately 20% was susceptible to carbapenems. The overall rate of drug resistance in Acinetobacter species is 84%, whereas that in VAP cases is 60% to 70%. In Pakistan, the panel reported that there has also been a recent rise in the incidence of MDR Acinetobacter species. On the other hand, a multicenter study
      • Johnson D.M.
      • Biedenbach D.J.
      • Jones R.N.
      In vitro evaluation of broad-spectrum β-lactams in the Philippines medical centers: role of fourth-generation cephalosporins. The Philippines Antimicrobial Resistance Study Group.
      reported that Acinetobacter species in the Philippines were yet highly susceptible (87.5% each) to the fourth-generation cephalosporins cefepime and cefpirome.
      Gram-negative bacilli producing ESBL appear to be on the rise in some Asian countries and pose a serious problem in pulmonary infections. Often, these strains are cross-resistant to other classes of drugs, such as fluoroquinolones and aminoglycosides. The incidence of ESBL-producing bacilli appears to be highest in India. Published studies have reported that the proportion of Klebsiella species producing ESBL range from 71% to 87%,
      • Grover S.S.
      • Sharma M.
      • Pasha S.T.
      • Singh G.
      • Lal S.
      Antimicrobial susceptibility pattern and prevalence of extended spectrum β-lactamase (ESBLs) producing strains of Klebsiella pneumoniae from a major hospital in New Delhi.
      • Jain A.
      • Roy I.
      • Gupta M.K.
      • Kumar M.
      • Agarwal S.K.
      Prevalence of extended-spectrum β-lactamase-producing gram-negative bacteria in septicaemic neonates in a tertiary carehospital.
      and, for E coli strains, the proportion is 64%.
      • Jain A.
      • Roy I.
      • Gupta M.K.
      • Kumar M.
      • Agarwal S.K.
      Prevalence of extended-spectrum β-lactamase-producing gram-negative bacteria in septicaemic neonates in a tertiary carehospital.
      Studies from Thailand
      • Jitsurong S.
      • Yodsawat J.
      Prevalence of extended-spectrum β-lactamases (ESBLs) produced in blood isolates of gram-negative bacteria in a teaching hospital in southern Thailand.
      • Chayakulkeeree M.
      • Junsriwong P.
      • Keerasuntonpong A.
      • Tribuddharat C.
      • Thamlikitkul V.
      Epidemiology of extended-spectrum β-lactamase producing gram-negative bacilli in Siriraj Hyospital, Thailand, 2003.
      report that, overall, ESBL production among gram-negative bacilli is 30%. Among K pneumoniae, 44% to 57% are ESBL producers, and, among E coli strains, 5.1% are ESBL producers. Data presented from the panel report a higher incidence of ESBL-producing E coli in Thailand, 15% to 40%, and a higher incidence of quinolone resistance, approximately 50%, than reported in the literature. A multicenter study
      • Hsueh P.R.
      • Liu Y.C.
      • Yang D.
      • Yan J.J.
      • Wu T.L.
      • Huang W.K.
      • et al.
      Multicenter surveillance of antimicrobial resistance of major bacterial pathogens in intensive care units in 2000 in Taiwan.
      in Taiwan showed that 12% of E coli was ESBL producing, and 11% of Klebsiella was ESBL producing. In recent years, this percentage has been rising, increasing to 15% of E coli isolates and 29% of Klebsiella species isolates as of 2005. Data presented at this workshop, albeit representing 1 hospital, showed that ESBL-producing Klebsiella in Taiwan represents 15% of all clinical isolates, 25% of Klebsiella in HAP cases and 15% of Klebsiella in VAP cases. A limited number of HAP cases because of infection with E coli were available for analysis, and these indicated that approximately one third of isolates were ESBL producers. A Chinese multicenter study
      • Chen M.J.
      • Wang H.
      China Nosocomial Pathogens Resistance Surveillance Study Group
      Continuous surveillance of antimicrobial resistance among nosocomial gram-negative bacilli from intensive care units in China (article in Chinese).
      reported that the prevalence of ESBL production in E coli and K pneumoniae increased from 11% to 34% from 1994-2001. Studies from Hong Kong report that 11% to 14% of E coli and Klebsiella species were ESBL producers,
      • Ho P.L.
      • Tsang D.N.
      • Que T.L.
      • Ho M.
      • Yuen K.Y.
      Comparison of screening methods for detection of extended-spectrum β-lactamases and their prevalence among Escherichia coli and Klebsiella species in Hong Kong.
      • Hirakata Y.
      • Matsuda J.
      • Miyazaki Y.
      • Kamihira S.
      • Kawakami S.
      • Miyazawa Y.
      • et al.
      Regional variation in the prevalence of extended-spectrum β-lactamase-producing clinical isolates in the Asia-Pacific region (SENTRY 1998-2002).
      and data presented by the panel show that ESBL-producing E coli accounts for 2.3% of HAP cases, whereas Klebsiella species account for 0.9% of HAP cases. In Malaysia, the incidence of ESBL-producing E coli is estimated at 7% to 8%. From Pakistan, only general information was available. Studies in local Pakistani journals have shown that the proportion of ESBL-producing organisms among nosocomial gram-negative bacilli is currently 36% to 52% and continues to rise.
      • Jabeen K.
      • Zafar A.
      • Hasan R.
      Frequency and sensitivity pattern of extended spectrum β-lactamase-producing isolates in a tertiary care hospital laboratory of Pakistan.
      Resistance to multiple drugs among ESBL(+) gram-negative bacteria appears to be quite high in some Asian countries. A study
      • Grover S.S.
      • Sharma M.
      • Pasha S.T.
      • Singh G.
      • Lal S.
      Antimicrobial susceptibility pattern and prevalence of extended spectrum β-lactamase (ESBLs) producing strains of Klebsiella pneumoniae from a major hospital in New Delhi.
      from a major hospital in New Delhi found that 39% to 88% of K pneumoniae isolates were resistant to third- and fourth-generation cephalosporins, whereas 51% to 90% were resistant to aztreonam, piperacillin, chloramphenicol, or trimethoprim-sulfamethoxazole. In a multicenter Indian surveillance study,
      • Jones R.N.
      • Rhomberg P.R.
      • Varnam D.J.
      • Mathai D.
      A comparison of the antimicrobial activity of meropenem and selected broad-spectrum antimicrobials tested against multi-drug resistant gram-negative bacilli including bacteraemic Salmonella spp.: initial studies for the MYSTIC programme in India.
      resistance was reported to piperacillin/tazobactam (23%), ciprofloxacin (57%), aminoglycosides (60%-65%), and other β-lactam drugs (60%-70%). The indiscriminate use of third-generation cephalosporins has been proposed as a reason for the rise of ESBL-producing strains in India.
      • Jain A.
      • Roy I.
      • Gupta M.K.
      • Kumar M.
      • Agarwal S.K.
      Prevalence of extended-spectrum β-lactamase-producing gram-negative bacteria in septicaemic neonates in a tertiary carehospital.
      Increased antibiotic use may be related to the introduction, in 2003, of less expensive, more widely available generic formulations into the market.
      In Taiwan, published data show that 70% of ESBL(+) E coli strains and 63% of ESBL(+) Klebsiella species were resistant to ciprofloxacin.
      • Liao C.H.
      • Sheng W.H.
      • Want J.T.
      • Sun H.Y.
      • Wang H.K.
      • Hsueh P.R.
      • et al.
      In vitro activities of 16 antimicrobial agents against clinical isolates of extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae in two regional hospitals in Taiwan.
      Resistance to amikacin was 19% for E coli and 28% for Klebsiella. In a prospective study in Thailand
      • Thongpiyapoom S.
      • Narong M.N.
      • Suwalak N.
      • Jamulitrat S.
      • Intaraksa P.
      • Boonrat J.
      • et al.
      Device-associated infections and patterns of antimicrobial resistance in a medical-surgical intensive care unit in a university hospital in Thailand.
      of ICU patients (including VAP cases), 38% of E coli was resistant to quinolones, and 45% of K pneumoniae was resistant to third-generation cephalosporins. In Korea, KONSAR data
      • Lee K.
      • Park K.H.
      • Jeong S.H.
      • Lim H.S.
      • Shin J.H.
      • Yong D.
      • et al.
      Further increase of vancomycin-resistant Enterococcus faecium, amikacin- and fluoroquinolone-resistant Klebsiella pneumoniae, and imipenem-resistant Acinetobacter species in Korea: 2003 KONSAR surveillance.
      shows, similarly, that E coli (18.9% of all isolates) is resistant to cefotaxime (11%), cefoxitin (8%), fluoroquinolone (33%), and piperacillin-tazobactam (5%). K pneumoniae (8.6% of all isolates) was reported to be resistant to ceftazidime (25%), cefoxitin (23%), and piperacillin-tazobactam (14%). Based on data from Hong Kong in 2000,
      • Ho P.L.
      • Tsang D.N.
      • Que T.L.
      • Ho M.
      • Yuen K.Y.
      Comparison of screening methods for detection of extended-spectrum β-lactamases and their prevalence among Escherichia coli and Klebsiella species in Hong Kong.
      ESBL-producing bacilli were highly susceptible to third-generation cephalosporins (>98% to cefpodoxime and ceftriaxone), yet the panel noted that resistance has since increased markedly and estimated the rate at 25% for ceftriaxone versus E coli and 16% versus Klebsiella species. Resistance to ciprofloxacin was noted to be approximately 36% in E coli and 13% in Klebsiella species. Resistance to piperacillin/tazobactam in Klebsiella species was estimated to be 12%. A multicenter study
      • Johnson D.M.
      • Biedenbach D.J.
      • Jones R.N.
      In vitro evaluation of broad-spectrum β-lactams in the Philippines medical centers: role of fourth-generation cephalosporins. The Philippines Antimicrobial Resistance Study Group.
      in the Philippines reported that ceftazidime-resistant E coli and Klebsiella species occurred at rates of 13.3% and 31.1%, respectively. Cefepime and cefpirome were 97.8% to 100% active in vitro against these ESBL phenotypes.
      To date, resistance to imipenem among ESBL(+) bacilli has not been noted in the literature to an appreciable extent in Asian countries. In Korea, resistance to imipenem was reported in 0.1% of E coli isolates and 0.3% of K pneumoniae isolates.
      • Lee K.
      • Park K.H.
      • Jeong S.H.
      • Lim H.S.
      • Shin J.H.
      • Yong D.
      • et al.
      Further increase of vancomycin-resistant Enterococcus faecium, amikacin- and fluoroquinolone-resistant Klebsiella pneumoniae, and imipenem-resistant Acinetobacter species in Korea: 2003 KONSAR surveillance.
      In Hong Kong,
      • Ho P.L.
      • Tsang D.N.
      • Que T.L.
      • Ho M.
      • Yuen K.Y.
      Comparison of screening methods for detection of extended-spectrum β-lactamases and their prevalence among Escherichia coli and Klebsiella species in Hong Kong.
      no imipenem resistance was noted in E coli strains, but 1% of Klebsiella species strains was found to be resistant. An Indian multicenter surveillance study
      • Jones R.N.
      • Rhomberg P.R.
      • Varnam D.J.
      • Mathai D.
      A comparison of the antimicrobial activity of meropenem and selected broad-spectrum antimicrobials tested against multi-drug resistant gram-negative bacilli including bacteraemic Salmonella spp.: initial studies for the MYSTIC programme in India.
      reported that 99.1% of organisms was susceptible to meropenem. A Chinese multicenter study
      • Wang H.
      • Chen M.
      China Nosocomial Pathogens Resistance Surveillance Group
      Surveillance for antimicrobial resistance among clinical isolates of gram-negative bacteria from intensive care unit patients in China, 1996 to 2002.
      reported that susceptibility to imipenem was 95% to 100% for K pneumoniae and 99% to 100% for E coli. In Malaysia, resistance to imipenem is estimated at <1%. Resistance has not been observed in Thailand, Taiwan,
      • Liao C.H.
      • Sheng W.H.
      • Want J.T.
      • Sun H.Y.
      • Wang H.K.
      • Hsueh P.R.
      • et al.
      In vitro activities of 16 antimicrobial agents against clinical isolates of extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae in two regional hospitals in Taiwan.
      or the Philippines.
      • Johnson D.M.
      • Biedenbach D.J.
      • Jones R.N.
      In vitro evaluation of broad-spectrum β-lactams in the Philippines medical centers: role of fourth-generation cephalosporins. The Philippines Antimicrobial Resistance Study Group.
      In Pakistan, the panel reported that overall resistance to antibiotics is very high, especially as observed over the past 2 to 3 years. Overall, 12% to 13% of Klebsiella species were resistant to carbapenems and tazobactam; E coli strains were found to be resistant to ceftriaxone, imipenem, and ciprofloxacin.
      Resistance in P aeruginosa to 1 or more antimicrobial agent has been documented in the literature. Studies from Thailand,
      • Girlich D.
      • Naas T.
      • Leelaporn A.
      • Poirel L.
      • Fennewald M.
      • Nordmann P.
      Nosocomial spread of the integron-located veb-1-like cassette encoding an extended-spectrum β-lactamase in Pseudomonas aeruginosa in Thailand.
      Taiwan,
      • Hsueh P.R.
      • Liu Y.C.
      • Yang D.
      • Yan J.J.
      • Wu T.L.
      • Huang W.K.
      • et al.
      Multicenter surveillance of antimicrobial resistance of major bacterial pathogens in intensive care units in 2000 in Taiwan.
      and Korea
      • Lee K.
      • Park K.H.
      • Jeong S.H.
      • Lim H.S.
      • Shin J.H.
      • Yong D.
      • et al.
      Further increase of vancomycin-resistant Enterococcus faecium, amikacin- and fluoroquinolone-resistant Klebsiella pneumoniae, and imipenem-resistant Acinetobacter species in Korea: 2003 KONSAR surveillance.
      report that 19% to 24% of P aeruginosa isolates were resistant to ceftazidime and that 15% to 20% were resistant to imipenem
      • Hsueh P.R.
      • Liu Y.C.
      • Yang D.
      • Yan J.J.
      • Wu T.L.
      • Huang W.K.
      • et al.
      Multicenter surveillance of antimicrobial resistance of major bacterial pathogens in intensive care units in 2000 in Taiwan.
      • Lee K.
      • Park K.H.
      • Jeong S.H.
      • Lim H.S.
      • Shin J.H.
      • Yong D.
      • et al.
      Further increase of vancomycin-resistant Enterococcus faecium, amikacin- and fluoroquinolone-resistant Klebsiella pneumoniae, and imipenem-resistant Acinetobacter species in Korea: 2003 KONSAR surveillance.
      Members of the panel noted that, in Thailand, MDR P aeruginosa also demonstrates resistance to carbenem (approximately 30%), ciprofloxacin (20%-25%), and piperacillin-tazobactam (20%). In Hong Kong, the prevalence of MDR P aeruginosa was noted to vary between different medical centers. Overall drug resistance in P aeruginosa, as of 2005, was reported to be generally low, ranging from 0% to 4% for cefotaxime, ceftazidime, imipenem, piperacillin/tazobactam, or ciprofloxacin but may be higher in some hospitals. In one large hospital in Singapore, the susceptibility of clinical isolates of Pseudomonas species to carbapenem, ceftazidime, or amikacin ranged from approximately 60% to 70% and remained high (at least 30%) when evaluating total cases, ICU cases, or HAP cases. A multicenter study
      • Johnson D.M.
      • Biedenbach D.J.
      • Jones R.N.
      In vitro evaluation of broad-spectrum β-lactams in the Philippines medical centers: role of fourth-generation cephalosporins. The Philippines Antimicrobial Resistance Study Group.
      in the Philippines reported that piperacillin/tazobactam was most effective against P aeruginosa (80% susceptible). The panel reported that, recently, in the Philippines, resistance has arisen in P aeruginosa against cefoperazone when used as a single agent. In current practice, combination treatment with cefoperazone/sulbactam is preferred.
      Despite the importance of the findings presented in this study, there are several limitations that should be taken into consideration when assessing our conclusions. First, our results center around the findings of a collective expert panel, which can be very subjective, wherein the individually analyzed national and local surveillance data may not be free of bias. Without the reliance on formal or structured evaluation methods, the data gleaned from this exchange may not be uniformly measured.
      In addition, there are inherent difficulties in compiling and comparing different sources of data from individual hospitals and local and national surveillance across many nations. Because of the varied availability and nature of the data collected, the surveillance data between countries are not comparable, and the comparisons we make are not always justified, which creates problems with the reliability, homogeneity, and generalizability of the data. Future studies would benefit from collaboration networks in the Asian-Pacific region.
      Last, a discussion of antibiotic use patterns and antibiotic control programs is absent because such topics were not addressed by this panel. These key subjects are critical to our understanding of HAP/VAP epidemiology and etiology and should be included in future antimicrobial resistance studies in this region.

      Summary

      An informal survey of etiologic pathogens in Asian countries revealed that MRSA is most common in Korea and Taiwan, whereas Acinetobacter species are most common in Malaysia, Thailand, Pakistan, and India. National surveillance data are lacking in many countries, and very little data exist that are specific to nosocomially acquired pneumonia, be it HAP or VAP. Overall, MRSA, Acinetobacter species, ESBL-producing E coli and Klebsiella, and P aeruginosa were found to be the most common pathogens causing HAP and VAP in Asian countries. Better knowledge of local patterns of pathogen distribution can help facilitate treatment choices.

      Appendix

      Panel members of Asian HAP Working Group were (in alphabetical order) the folowing: Jae-Hoon Song, MD, PhD (organizer) Samsung Medical Center, Korea; Altaf Ahmed, MD, Liaquat National Hospital, Pakistan; Nor Liza Ariffin, MD, University Malaya, Malaysia; Rajesh Chawla, MD, Indraprastha Apollo Hospital, India; Manolito Chua, MD, Research Institute for Tropical Medicine, Philippines; Tulsi Chugh, MD, SGR Hospital, India; Renato Dantes, MD, University of Philippines, Philippine General Hospital, Philippines; Po-Ren Hsueh, MD, National Taiwan University Hospital, Taiwan, R. O. C.; Bi Jie Hu, MD, Zhongshan Hospital of Fudan University, Shanghai, China; Yhu-Chering Huang, MD, PhD, Chang Gung Children's Hospital, Taiwan R. O. C.; Muhammad Jawed, MB, BS, Liaquat National Hospital, Pakistan; Ki-Suck Jung, MD, PhD, Hallym University Sacred Heart Hospital, South Korea; Lalitha Kesavan, MD, Christian Medical College, India; Wen-Chien Ko, MD, National Cheng Kung University Hospital, Taiwan R. O. C.; KiTae Kwon, MD, Samsung Medical Center, Korea; Raymond Wai Man Lai, MB, ChB, FRCPA, FHKAM, Prince of Wales Hospital, Hong Kong; Kyungwon Lee, MD, PhD, Yonsei Univ College of Medicine Severance Hospital, South Korea; Amorn Leelarasamee, MD, Siriraj Hospital, Mahidol University, Thailand; Tzer Pin Raymond Lin, MD; Roslina Abdul Manap, MMED, MRCP, Hospital University Kebangsaa Malaysia, Malaysia; Naseem Salahuddin, ABMI, FACP, Liaquat National Hospital, Pakistan; Raman Sardana, MD, Indraprastha Apollo Hospital, India; Thomas So, FRCP, FHKAM, Princess Margaret Hospital, Hong Kong; Chusana Suankratay, MD, PhD, Chulalangkorn University, Thailand; Paul Tambyah, MD, National University of Singapore, Singapore; Hui Wang, PhD, Peking Union Medical College, China; Adisom Wongsa, MD, Yonghong Xiao, PhD, Institute of Clinical Pharmacology, Peking University, China; Rohani Yasin, MD, Institute of Medical Research, Malaysia.

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