Extreme drug resistance in Acinetobacter baumannii infections in intensive care units, South Korea.

To the Editor: Acinetobacter spp. have emerged as a cause of nosocomial infections, especially in intensive care units (ICUs). In South Korea, Acinetobacter spp. was ranked as the third most frequently found pathogen in ICUs (). With the emergence of multidrug-resistant (MDR) or pandrug-resistant (PDR) isolates, few drugs are now available to treat MDR or PDR Acinetobacter infections; polymyxins are the only therapeutic option in many cases (). Current polymyxin resistance rates among Acinetobacter isolates are low worldwide (). We report the emergence of extreme drug resistance (XDR) in A. baumannii isolates from patients in ICUs of Samsung Medical Center in Seoul, South Korea. These isolates were resistant to all tested antimicrobial drugs, including polymyxin B and colistin, to which PDR isolates are normally susceptible.

Sixty-three nonduplicate Acinetobacter spp. isolates were collected from the ICUs from April through November 2007. Species identification was performed based on partial RNA polymerase β-subunit gene sequences, amplified rDNA restriction analysis, and the gyrase B gene–based multiplex PCR method (). Forty-four isolates were identified as A. baumannii: 9 as genomic species 3, six as genomic species 13TU, 2 as A. baumannii-like species, and 1 each as A. junnii and genomic species 10.

In vitro susceptibility testing was performed and interpreted by using the broth microdilution method according to the Clinical and Laboratory Standards Institute guidelines (). Colistin and polymyxin B resistances were defined as MIC >4 mg/L (). MDR was defined as characterized by resistance to >3 classes of antimicrobial drugs, and PDR was defined as characterized by resistance to all antimicrobial drugs, regardless of colistin and polymyxin B susceptibility. XDR was defined as resistance to all antimicrobial drugs. Multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE) were performed for all PDR isolates according to previously described methods (,). Genes encoding oxacillinases, such as those classified as OXA-23-like, OXA-24/40-like, OXA-51-like, and OXA-58-like, were detected as previously described (). PCR and sequence analyses were performed to detect and characterize the other antimicrobial resistance genes, according to methods reported ().

Of 63 Acinetobacter isolates, 31.7% and 34.9% were resistant to imipenem and meropenem, respectively. Of the 63 isolates, 27.0% and 30.2% were resistant to polymyxin B and colistin, respectively. For the other antimicrobial drugs, Acinetobacter spp. isolates showed antimicrobial resistance rates >50%. Nineteen isolates (30.2%), all belonging to A. baumannii, were PDR. Most of these PDR isolates (16/19, 84.2%) were collected from endotracheal aspirate, and others were from peritoneal fluid and sputum. When characterized by PFGE and MLST, all PDR isolates belonged to a single clone, ST22, and all contained the blaOXA-23 and blaOXA-66 genes. ISAba1 was detected upstream of blaOXA-23 and blaOXA-66 in all PDR isolates. In addition, most PDR isolates contained blaTEM-116, blaPER-1, and blaADC-29 genes. TEM-116 is a point mutant derivative of TEM-1, Val84→Ile. All β-lactamase genes were located on a plasmid. Also, ISAba1 was located at the upstream of all the blaADC, which was shown by PCR. However, none of the isolates had blaCTX-M, blaVEB, blaIMP, blaVIM, or blaGIM.

Of the PDR isolates, 8 were resistant even to colistin and polymyxin B. These 8 isolates also showed resistance to tigecycline (MICs 4 mg/L). Thus, they were resistant to all antimicrobial drugs tested in this study and were considered to have XDR. The underlying diseases of the patients whose isolates were examined varied (Table). Although 2 isolates with XDR were colonizers, 6 caused infections. All but 1 patient was treated with mechanical ventilation before isolation of the pathogen. Number of hospital days before isolation of A. baumannii was 13–256 days, and the number of ICU days before isolation was 2–38 days. Four patients were immunocompromised, and 3 had bacteremia. Among the patients with infections characterized by XDR, the overall 30-day mortality rate was 66.7%, and the infection-related 30-day mortality rate was 50.0%. All 8 isolates with XDR showed common characteristics: ST22 containing OXA-23, OXA-66, TEM-116, PER-1, and ADC-29.

Table

Clinical characteristics of 8 patients infected with extremely drug-resistant Acinetobacter baumannii isolates, South Korea*

Strain no.	Patient age/sex	Underlying disease	Infection†	Days before isolation		Concurrent bacteremia	30-d outcome	Infection-related death
				Hospitalized	In ICU
07AC–052	60 y/F	Acute myeloid leukemia	Pneumonia	15	8	No	Died	Yes
07AC–159	79 y/M	Lymphoma	Pneumonia	35	9	No	Died	No
07AC–192	50 y/M	Status postliver transplantation	Pneumonia	256	2	Yes	Survived	NA
07AC–204	55 y/F	Steven-Johnson syndrome	Pneumonia	13	13	Yes	Survived	NA
07AC–336	16 mo/M	Medulloblastoma	Pneumonia	32	13	Yes	Died	Yes
07AC–347	17 mo/M	Hepatoblastoma	Pneumonia	135	28	No	Died	Yes
07AC–329	1 mo/F	Edward syndrome	Colonization‡	33	33	NA	NA	NA
07AC–063	56 y/M	Lung cancer	Colonization‡	26	21	NA	NA	NA

*ICU, intensive care unit; NA, not applicable. All but 1 patient (with strain 07AC–192) had mechanical ventilators. Four patients (with strains 07AC–159, 07AC–192, 07AC–336, and 07AC–063) were immunocompromised hosts who had daily administration of corticosteroid (>20 mg/d of prednisolone or an equivalent drug) during >2 wk and treatment with chemotherapy for an underlying malignancy during 1 month before hospital admission.
†Infection is defined as invasion of the body tissues by microorganisms resulting in disease.
‡Colonization occurs when an agent’s presence in a host does not cause a specific immune response or infection.

We report the emergence of XDR in PDR A. baumannii isolates in South Korea. Characteristics of PDR A. baumannii isolates suggest that they spread from a single clone. A single A. baumannii strain with XDR might evolve from the prevailing PDR A. baumannii and could disseminate in the ICU, probably after contamination of the hospital environment and by nosocomial transmission. In South Korea, a high resistance rate to imipenem and meropenem in Acinetobacter spp. isolates may lead to extensive use of polymyxins (). Thus, we can hypothesize that the most prevalent carbapenem-resistant, or MDR A. baumannii clone, became PDR and then evolved into clones with XDR by acquisition of polymyxin resistance caused by antimicrobial pressure. Our investigation showed a simultaneous emergence of resistance to all antimicrobial agents available, including colistin, polymyxin B, and tigecycline. XDR poses serious problems in the treatment of patients with A. baumannii infections, especially given the slow development of new antimicrobial agents.