To determine the duration of carbapenemase-producing Enterobacteriaceae (CPE) carriage, we studied 21 CPE carriers for &#xBB;1 year. Mean carriage duration was 86 days; probability of decolonization in 1 year was 98.5%, suggesting that CPE-carriers' status can be reviewed yearly. Prolonged carriage was associated with use of antimicrobial drugs

Barkham, T

Bertrand, D

Chen, SL

Cooper, BS

Fenlon, SN

Hernandez-Koutoucheva, A

Ling, ML

Lye, D

Marimuthu, K

Mo, Y

Musicha, P

Nagarajan, N

Ng, OT

Tang, WY

To determine the duration of carbapenemase-producing Enterobacteriaceae (CPE) carriage, we studied 21 CPE carriers for »1 year. Mean carriage duration was 86 days; probability of decolonization in 1 year was 98.5%, suggesting that CPE-carriers' status can be reviewed yearly. Prolonged carriage was associated with use of antimicrobial drugs

Mo, Yin

Hernandez Koutoucheva, Anastasia

Musicha, Patrick

Bertrand, Denis

Lye, David

Ng, Oon Tek

Fenlon, Shannon N

Chen, Swaine L

Ling, Moi Lin

Tang, Wen Ying

Barkham, Timothy

Nagarajan, Niranjan

Cooper, Ben

Marimuthu, Kalisvar

Oxford University Research Archive

Rapid global dissemination of carbapenemase-producing Enterobacteriaceae (CPE) poses a pub-lic health threat (1). To prevent the spread of CPE in healthcare settings, international guidelines advocate for early identification, isolation, and contact precau-tions (2,3). To provide information helpful for the design of rational infection control policies, we esti-mated CPE carriage duration in a hospital cohort and identified risk factors for prolonged carriage.The StudyDuring October 2016–February 2018, we conducted a prospective cohort study involving CPE carriers from 2 tertiary care centers in Singapore. CPE carriers were identified by routine collection of rectal swab samples in accordance with local infection control policies. We included patients who were >21 years of age and had the capacity to provide consent (Appendix Figure 1, https://wwwnc.cdc.gov/EID/article/26/9/19-0592-App1.pdf). We retrieved from medical records of enrolled patients the latest dates of CPE-negative rectal swab samples before the first positive sample. We collected fecal samples from participants at the time of enrollment, weekly for 4 weeks, monthly for 5 months, and bimonthly for 6 months. We recorded demographic characteristics, healthcare contact his-tory, and medication history.The fecal samples were inoculated onto selec-tive chromogenic agar (CHROMID CARBA SMART; bioMérieux, https://www.biomerieux-diagnostics.com), and species identification was performed with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (Bruker, https://www.bruker.com). Antimicrobial susceptibility testing was performed by using VITEK-2 (bioMérieux). All Enterobacteriaceae isolates with a MIC of >2 mg/L for meropenem or >1.0 mg/L for ertapenem underwent PCR to detect blaNDM-1, blaKPC, blaOXA-48, blaIMI-1, and blaIMP genes (4). All CPE isolates and fecal DNA underwent sequencing on an Illumina HiSeq 4000 sequencer (https://www.illumina.com). We used the Shan-non diversity index to measure α-diversity for fecal microbial communities (https://cran.r-project.org/web/packages/vegan/vegan.pdf).We analyzed data by using Bayesian multistate Markov models to account for interval censoring (Ap-pendix). First, we estimated the overall transmission rates by considering patients to be in either CPE colo-nized or noncolonized states. Second, we considered CPE colonization on the species level and included as separate states carbapenemase-producing (CP)–Esche-richia coli (CP-EC) colonized, CP–Klebsiella pneumoniae Duration of Carbapenemase- Producing Enterobacteriaceae  Carriage in Hospital PatientsYin Mo,1 Anastasia Hernandez-Koutoucheva,1 Patrick Musicha, Denis Bertrand,  David Lye, Oon Tek Ng, Shannon N. Fenlon, Swaine L. Chen, Moi Lin Ling, Wen Ying Tang,  Timothy Barkham, Niranjan Nagarajan, Ben S. Cooper, Kalisvar Marimuthu2182 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 26, No. 9, September 2020DISPATCHESAuthor affiliations: National University Hospital, Singapore (Y. Mo); Mahidol-Oxford Tropical Medicine Research Unit, Bangkok,  Thailand (Y. Mo, A. Hernandez-Koutoucheva, P. Musicha,  B.S. Cooper); National University of Singapore, Singapore (Y. Mo, D. Lye, S.L. Chen, N. Nagarajan, K. Marimuthu); Genome Institute of Singapore, Singapore (D. Bertrand, S.N. Fenlon, S.L. Chen,  N. Nagarajan); University of Oxford, Oxford, UK (P. Musicha,  B.S. Cooper); Nanyang Technological University (D. Lye, O.T. Ng); National Centre for Infectious Diseases, Singapore (D. Lye,  O.T. Ng, K. Marimuthu); Tan Tock Seng Hospital, Singapore (D. Lye, W.Y. Tang, T. Barkham, K. Marimuthu); Singapore General Hospital, Singapore (M.L. Ling)DOI: https://doi.org/10.3201/eid2609.190592 1These authors contributed equally to this article.To determine the duration of carbapenemase-producing Enterobacteriaceae (CPE) carriage, we studied 21 CPE carriers for ≈1 year. Mean carriage duration was 86 days; probability of decolonization in 1 year was 98.5%, suggesting that CPE-carriers’ status can be reviewed yearly. Prolonged carriage was associated with use of antimicrobial drugs. Carbapenemase-Producing Enterobacteriaceae Carriage(CP-KP) colonized, and CP-EC/KP co-colonized (Ap-pendix Figure 2). All analyses were performed by us-ing R version 3.4.4 (https://www.R-project.org) and RStan (http://mc-stan.org).We enrolled 21 patients (Table). Mean (± SD) fol-low-up period was 294 (± 77) days, and each partici-pant provided 12 (± 1.5) samples. Throughout follow-up, 15 (71.4%) participants carried >1 species of CPE, and only 3 (14.3%) carried >1 type of carbapenemase gene (χ2 of difference in proportions = 14.8, simulated p = 0.0005) (Appendix Table 1). The most common species carried were K. pneumoniae (18 [85.7%]) and E. coli (16 [76.2%]). The most frequently observed carbapenemase genes were blaOXA-48 (11 [52.4%]) and blaKPC (8 [38.1%]). We obtained 76 CP-KP isolates from the samples; the most common sequence type (25 [32.9%]) was 307. Among the 83 CP-EC isolates, the most common sequence type (22 [26.5%]) was 131. Sample positivity was continuous until clearance for most (17 [81.0%]) of the 21 participants. For 4 par-ticipants, negative samples were followed by positive samples; the longest period was 3 negative samples over 3 consecutive weeks (Appendix Figure 5).The estimated mean duration of CPE carriage was 86 (95% credible interval [CrI] 60– 122) days. The probability of decolonization in 1 year was 98.5% (95% CrI 95.0%–99.8%), assuming a constant decolo-nization rate within the time interval. The longest observed carriage duration was 387 days. We per-formed a sensitivity analysis that included 16 par-ticipants who became decolonized during follow-up (i.e., the last sample collected was negative for CPE). This analysis gave a mean carriage time of 77 (95% CrI 53–108) days and a 98.8% (95% CrI 96.5%–99.9%) probability of decolonization within 1 year.As time-fixed covariates, we analyzed age, co-col-onization with other multidrug-resistant organisms, presence of a urinary catheter, antimicrobial drug use during follow-up, Charlson Comorbidity Index score, and readmission; as a time-varying covariate, we used the Shannon Diversity Index score to ex-plore the covariates’ association with decolonization (Appendix Figure 3). The only factor associated with prolonged CPE carriage was antimicrobial drug use during the follow-up period (hazard ratio 0.48, 95% CrI 0.20–0.93). The rate of decolonization for CP-EC was lower than that for CP-KP (0.018 [95% CrI 0.007–0.031] per day vs. 0.030 [95% CrI 0.016–0.049] per day) (Appendix Table 2, Figure 4).ConclusionsCPE infections are typically preceded by asymptom-atic carriage, especially in vulnerable patients such as those who are immunocompromised and critically ill (5). To prevent transmission, active surveillance to identify CPE carriers is essential but may be associat-ed with a high cost:benefit ratio if implemented with-out knowledge of the natural history of CPE carriage.Previously reported CPE carriage durations vary widely; median durations range from 43 to 387 days (5–7). These variations probably result from differ-ences in follow-up schedules, microbiological and molecular methods used to identify CPE, and crite-ria to define clearance. Studies that reported longer carriage duration tended to adopt an opportunistic sampling strategy and considered both clinical and fecal samples to determine carriage (7). Opportunistic sampling may lead to selection bias because patients with more healthcare contacts would have more sam-ples collected. Infrequent and inconsistent sampling is more likely to misclassify recolonization from a new transmission event as continuous colonization, resulting in perceived longer duration of carriage.Of note, the participants carried more species of CPE than types of carbapenemase genes. Although this observation may be the result of new acquisition events, it is more parsimoniously explained by ac-tive interspecies horizontal gene transfer, especially  Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 26, No. 9, September 2020 2183 Table. Demographics for 21 participants in study of duration of carbapenemase-producing Enterobacteriaceae carriage in hospital patients, Singapore* Characteristic No. (%) Sex   M 15 (71.4)  F 6 (28.6) Ethnicity    Chinese 15 (71.4)  Malay 3 (14.3)  Indian 2 (9.5)  Other 1 (4.8) Ambulatory status   Independently performs ADL 12 (57.1)  Requires assistance in ADL 4 (19.0)  Wheelchair bound 3 (14.3)  Bed bound 2 (9.5) Recent surgery† 15 (71.4) Colonization or infection with another MDRO in the year preceding enrollment 4 (19.0) Hospitalization in past year 11 (52.4) Antibiotic intake during follow-up period 13 (61.9) Readmission during follow-up period 10 (47.6) Recent overseas travel  13 (61.9) *Median age (interquartile range) was 60.0 (50.0–69.0) y; median Charlson Morbidity Index (interquartile range) 3.0 (2.0–5.0). ADL, activities of daily living; MDRO, multidrug-resistant organisms, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, carbapenem-resistant Enterobacteriaceae, carbapenem-resistant Acinetobacter baumanii, and carbapenem-resistant Pseudomonas aeruginosa, recorded from surveillance and clinical cultures taken in the year before study enrollment. †Gastrointestinal surgeries (n = 7), skin and soft tissue surgeries (n = 4), neurosurgery (n = 2), removal of Tenckhoff catheter (n = 1), and urologic procedure (n = 1).  DISPATCHESin a low-transmission setting such as Singapore. Dif-ferential rates of clearance of CP-KP and CP-EC can be related to colonizing affinity of the species and fit-ness cost of carbapenemase genes, which vary widely among different species (8). Further studies incorpo-rating between-host and within-host transmission dynamics of resistance may shed light on the roles of bacterial clones and plasmids in spreading and main-taining resistance.Our study has limitations. First, because the par-ticipants were screened after hospital admission, the time of initial colonization could not be confidently determined. However, our multistate Markov mod-els assume a constant rate of decolonization. Our sen-sitivity analysis used the latest CPE-negative swab samples, so carriage duration estimates were similar to those calculated without the last known CPE-neg-ative swab samples, suggesting that our modeling as-sumptions were reasonable. Second, our sample size was small and drawn from a single population, and the extent to which our findings can be extrapolated to other populations is uncertain. However, our study was rigorously conducted in terms of frequency of fecal sample collection, duration of follow-up, and number of participants in a nonoutbreak setting. The use of multistate models has been shown to preserve power with modest sample size given more frequent follow-ups (9).Our systematic sampling and robust methods for identifying CPE enabled us to closely follow par-ticipants’ carriage status. Using combined detection methods of culture on carbapenem-resistance selec-tive media, antibiotic susceptibility testing, and PCR, we found that 4 (19.0%) patients had intervening neg-ative samples, 1–3 weeks apart. This finding suggests that a patient should have >2 negative samples 4–6 weeks apart before considering CPE to be eliminated. The finding that the probability of decolonization is 98.5% in 1 year suggests that a policy of review-ing CPE carrier status yearly may be appropriate for this population. Further health economics analysis is needed to make institution-specific recommendations for rescreening frequency. Given the finding that an-timicrobial drug use was the most important factor associated with prolonged CPE carriage, use of anti-microbial drugs in these patients should be avoided if not clinically indicated.The study is primarily supported by the Singapore  Biomedical Research Council–Economic Development Board Industry Alignment Fund (grant no. IAF311018). M.Y. is supported by the Singapore National Medical Research Council (NMRC) Research Fellowship (grant no. NMRC/Fellowship/0051/2017). B.S.C. is supported  by the UK Medical Research Council/Department for  International Development (grant no. MR/K006924/1). P.M. is supported by the Joint Programming Initiative on Antimicrobial Resistance (MODERN) (grant no. C-17-0014). A.H. is supported by Wellcome Trust (grant no. 212630/Z/18/Z). The Mahidol-Oxford Tropical Medicine Research Unit is part of the Wellcome-Trust Major Overseas Programme in Southeast Asia (grant no. 106698/Z/14/Z). Additional grant support was provided by the NMRC Clinician-Scientist Individual Research Grant (grant no. NMRC/CIRG/1463/2016 and NMRC/CIRG/1467/2017); the Singapore Ministry of Education Academic Research Fund Tier 2 grant, New Delhi  Metallo-Beta-Lactamase, a global multi-centre,  whole-genome study (grant no. MOE2015-T2-2-096); an NMRC collaborative grant, Collaborative Solutions  Targeting Antimicrobial Resistance Threats in Health Systems (grant no. NMRC CGAug16C005); and an NMRC Clinician Scientist Award (grant no. NMRC/ CSA-INV/0002/2016).About the AuthorDr. Mo is an infectious diseases physician and senior lecturer at the National University of Singapore. Her research interests are antimicrobial resistance and infection control. She is pursuing a PhD degree with the University of Oxford and leading a multicenter clinical trial in Asia on shortening duration of antimicrobial drug use for patients with ventilator-associated pneumonia.References  1. Logan LK, Weinstein RA. The Epidemiology of  carbapenem-resistant Enterobacteriaceae: the impact and  evolution of a global menace. J Infect Dis. 2017;215(suppl_1) :S28–36. https://doi.org/10.1093/infdis/jiw282  2. Magiorakos AP, Burns K, Rodríguez Baño J, Borg M,  Daikos G, Dumpis U, et al. Infection prevention and control measures and tools for the prevention of entry of  carbapenem-resistant Enterobacteriaceae into healthcare settings: guidance from the European Centre for Disease Prevention and Control. Antimicrob Resist Infect Control. 2017;6:113. https://doi.org/10.1186/s13756-017-0259-z  3. Centers for Disease Control and Prevention. Healthcare-associated infections [cited 2019 Mar 7]. https://www.cdc.gov/hai/organisms/cre/cre-toolkit/index.html  4. 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Commun Stat Simul Comput. 2017; 46:7040–61.  https://doi.org/10.1080/03610918.2016.1222425Address for correspondence: Mo Yin, National University Hospital, Division of Infectious Disease, 5 Lower Kent Ridge Rd, Singapore; email: yin_mo@nuhs.edu.sg Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 26, No. 9, September 2020 2185• Complexity of the Basic Reproduction Number (R0)  • Aeromedical Transfer of Patients with Viral Hemorrhagic Fever •  Clinical and Radiologic Characteristics of Human Metapneumovirus Infections in Adults, South Korea • Enterovirus A71 Infection and Neurologic Disease, Madrid, Spain, 2016• Epidemiology of Imported Infectious Diseases, China, 2005–2016   •  Risk Factors for Elizabethkingia Acquisition and Clinical Characteristics of Patients, South Korea •  Effects of Antibiotic Cycling Policy on Incidence of Healthcare-Associated MRSA and Clostridioides difficile Infection in Secondary Healthcare Settings •  Association of Increased Receptor-Binding Avidity of Influenza A(H9N2) Viruses with Escape from Antibody-Based Immunity and Enhanced Zoonotic Potential  • Variable Protease-Sensitive Prionopathy Transmission to Bank Voles  •  Zoonotic Source Attribution of Salmonella enterica Serotype Typhimurium Using Genomic Surveillance Data, United States  •  Multiple Introductions of Domestic Cat Feline Leukemia Virus in Endangered Florida Panthers   •  Prescription of Antibacterial Drugs for HIV-Exposed, Uninfected Infants, Malawi, 2004–2010   •  Influenza H5/H7 Virus Vaccination in Poultry and Reduction of Zoonotic Infections, Guangdong Province, China, 2017–18   •  Higher Viral Load of Emerging Norovirus GII.P16-GII.2 than Pandemic GII.4 and Epidemic GII.17, Hong Kong, China   •  Autochthonous Transmission of Coccidioides in Animals,  Washington, USA •  Avian Influenza A(H9N2) Virus in Poultry Worker, Pakistan, 2015  •  Meat and Fish as Sources of Extended-Spectrum β-Lactamase–Producing Escherichia coli, Cambodia   •  Oral Transmission of Trypanosoma cruzi, Brazilian Amazon  •  Puumala Hantavirus Genotypes in Humans, France, 2012–2016  •  New Multidrug-Resistant Salmonella enterica Serovar Anatum Clone, Taiwan, 2015–2017  •  Seroepidemiology of Parechovirus A3 Neutralizing Antibodies, Australia, the Netherlands, and United States•  Identification of Lonepinella sp. in Koala Bite Wound Infections, Queensland, Australia   •  Surgical Site Infections Caused by Highly Virulent Methicillin-Resistant Staphylococcus aureus Sequence Type 398, China   •  Canine Influenza Virus A(H3N2) Clade with Antigenic Variation,  China, 2016–2017  •  Isolation and Full-Genome Characterization of Nipah Viruses from Bats, Bangladesh •  Burdens of Invasive Methicillin-Susceptible and Methicillin-Resistant Staphylococcus aureus Disease, Minnesota, USA •  Dengue Virus IgM Serotyping by ELISA with Recombinant Mutant Envelope Proteins   •  Orogenital Transmission of Neisseria meningitidis Causing Acute Urethritis in Men Who Have Sex with Men  •  Trends in Azole Resistance in Aspergillus fumigatus, the Netherlands, 1994–2016   •  Using the Health Belief Model to Analyze Instagram Posts about Zika for Public Health Communications•  Zoonotic Endocarditis in a Man, the Netherlands •  Trachoma in 3 Amerindian Communities, Venezuelan Amazon, 2018 ®     January 2019AntimicrobialResistanceTo revisit the January 2019 issue, go to:https://wwwnc.cdc.gov/eid/articles/issue/25/1/table-of-contents

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Duration of carbapenemase-producing enterobacteriaceae carriage in hospital patients

Duration of carbapenemase-producing enterobacteriaceae carriage in hospital patients

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