Phenotypic changes of methicillin-resistant Staphylococcus aureus during vancomycin therapy for persistent bacteraemia and related clinical outcome.
Persistent bacteraemia (PB) due to methicillin-resistant Staphylococcus aureus (MRSA) that fails to respond to glycopeptide therapy is a well-documented clinical problem. There are limited data on changes in agr functionality, vancomycin susceptibility and heteroresistance during MRSA PB. Thus, the frequency of these changes and their clinical significance remain unclear. Only patients with MRSA PB (≥7 days) from a prospective cohort of S. aureus bacteraemia were included. We collected isogenic paired strains and compared vancomycin MIC, vancomycin heteroresistance, and agr functionality between initial and final blood isolates. We also assessed the clinical outcome. A total of 49 patients had MRSA PB over 22 months. Bacteraemia persisted for a median of 13 days and most patients (98%) received glycopeptide as initial therapy. Among 49 isogenic pairs, only one pair showed a vancomycin MIC increase ≥2-fold by broth microdilution method, and only seven (14%) by E-test. Significant portions of initial isolates had vancomycin heteroresistance (49%) and agr dysfunction (76%). Development of vancomycin heteroresistance during PB occurred in four (16%) among 25 initial vancomycin-susceptible isolates, and acquisition of agr dysfunction occurred in two (16%) among 12 initial agr-functional isolates. Changes in the opposite direction occasionally occurred. These phenotypic changes during PB were not associated with mortality, whereas agr dysfunction of the initial isolates was significantly associated with mortality. During MRSA PB, phenotypic changes of MRSA isolates occurred occasionally under prolonged vancomycin exposure but were not significantly associated with clinical outcome. In contrast, initial agr dysfunction could be a predictor for mortality in MRSA PB.
Division of Infectious Diseases, Department of Internal Medicine, Gyeongsang National University Hospital, 79, Gangnam-ro, Jinju, Gyeongsangnam-do, 52727, Republic of Korea.
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Kim
Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro43-gil, Songpa-gu, Seoul, 138-736, Republic of Korea.
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ES
Kim
Division of Infectious Diseases, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Republic of Korea.
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SY
Park
Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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H
Sung
Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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MN
Kim
Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro43-gil, Songpa-gu, Seoul, 138-736, Republic of Korea.
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SH
Kim
Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro43-gil, Songpa-gu, Seoul, 138-736, Republic of Korea.
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SO
Lee
Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro43-gil, Songpa-gu, Seoul, 138-736, Republic of Korea.
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SH
Choi
Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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JY
Jeong
Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro43-gil, Songpa-gu, Seoul, 138-736, Republic of Korea.
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JH
Woo
Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro43-gil, Songpa-gu, Seoul, 138-736, Republic of Korea. drchong@amc.seoul.kr.
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http://orcid.org/0000-0003-1672-3185
YP
Chong
Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro43-gil, Songpa-gu, Seoul, 138-736, Republic of Korea. yskim@amc.seoul.kr.
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YS
Kim
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D016470:Bacteremia / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D001426:Bacterial Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000145:classification / Q000187:drug effects* / Q000302:isolation & purification / Q000502:physiology*; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010641:Phenotype; D011446:Prospective Studies; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D016019:Survival Analysis; D015534:Trans-Activators / Q000378:metabolism; D016896:Treatment Outcome; D014640:Vancomycin / Q000627:therapeutic use*; D055815:Young Adult
C095698:Agr protein, Staphylococcus aureus; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D015534:Trans-Activators; D014640:Vancomycin
MRSA; Persistent bacteraemia; Vancomycin; agr dysfunction; hVISA