Effect of #Treating #Parents Colonized With #Staphylococcus aureus on #Transmission to #Neonates in the #ICU – A #RCT (JAMA, abstract)

[Source: Journal of American Medical Association, full page: (LINK). Abstract, edited.]

Preliminary Communication / December 30, 2019

Effect of Treating Parents Colonized With Staphylococcus aureus on Transmission to Neonates in the Intensive Care Unit – A Randomized Clinical Trial

Aaron M. Milstone, MD, MHS1,2,3; Annie Voskertchian, MPH1; Danielle W. Koontz, MAA1; et al. Dina F. Khamash, MD1,4; Tracy Ross, BS5; Susan W. Aucott, MD6; Maureen M. Gilmore, MD6; Sara E. Cosgrove, MD, MS2,7; Karen C. Carroll, MD8; Elizabeth Colantuoni, PhD9

Author Affiliations: 1 Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland; 2 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; 3 Department of Hospital Epidemiology and Infection Control, The Johns Hopkins Hospital, Baltimore, Maryland; 4 Department of Pediatrics, Cooper University Health Care, Camden, New Jersey; 5 Division of Medical Microbiology, Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland; 6 Division of Neonatology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland; 7 Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; 8 Division of Medical Microbiology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland; 9 Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland

JAMA. Published online December 30, 2019. doi: https://doi.org/10.1001/jama.2019.20785


Key Points

  • Question  – Does treating parents with short-course intranasal mupirocin and topical chlorhexidine bathing compared with placebo reduce acquisition of Staphylococcus aureus colonization in neonates?
  • Findings  – In this randomized clinical trial that included 190 neonates with parents colonized with S aureus, treating parents with intranasal mupirocin and chlorhexidine-impregnated cloths compared with placebo significantly reduced the hazard of acquiring colonization with a parental S aureus strain (hazard ratio, 0.43).
  • Meaning  – Treating colonized parents may reduce risk of S aureus transmission to neonates, but these findings are preliminary and require further research for replication and to assess generalizability.




Staphylococcus aureus is a leading cause of health care–associated infections in the neonatal intensive care unit (NICU). Parents may expose neonates to S aureus colonization, a well-established predisposing factor to invasive S aureus disease.


To test whether treating parents with intranasal mupirocin and topical chlorhexidine compared with placebo would reduce transmission of S aureus from parents to neonates.

Design, Setting, and Participants  

Double-blinded randomized clinical trial in 2 tertiary NICUs in Baltimore, Maryland. Neonates (n = 236) with S aureus–colonized parent(s) were enrolled. The study period was November 7, 2014, through December 13, 2018.


Parents were assigned to intranasal mupirocin and 2% chlorhexidine–impregnated cloths (active treatment, n = 117) or petrolatum intranasal ointment and nonmedicated soap cloths (placebo, n = 119) for 5 days.

Main Outcomes and Measures  

The primary end point was concordant S aureus colonization by 90 days, defined as neonatal acquisition of an S aureus strain that was the same strain as a parental strain at time of screening. Secondary outcomes included neonatal acquisition of any S aureus strain and neonatal S aureus infections.


Among 236 randomized neonates, 208 were included in the analytic sample (55% male; 76% singleton births; mean birth weight, 1985 g [SD, 958 g]; 76% vaginal birth; mean parent age, 31 [SD, 7] years), of whom 18 were lost to follow-up. Among 190 neonates included in the analysis, 74 (38.9%) acquired S aureus colonization by 90 days, of which 42 (56.8%) had a strain concordant with a parental baseline strain. In the intervention and placebo groups, 13 of 89 neonates (14.6%) and 29 of 101 neonates (28.7%), respectively, acquired concordant S aureus colonization (risk difference, –14.1% [95% CI, –30.8% to –3.9%]; hazard ratio [HR], 0.43 [95.2% CI, 0.16 to 0.79]). A total of 28 of 89 neonates (31.4%) in the intervention group and 46 of 101 (45.5%) in the control group acquired any S aureus strain (HR, 0.57 [95% CI, 0.31 to 0.88]), and 1 neonate (1.1%) in the intervention group and 1 neonate (1.0%) in the control group developed an S aureus infection before colonization. Skin reactions in parents were common (4.8% intervention, 6.2% placebo).

Conclusions and Relevance  

In this preliminary trial of parents colonized with S aureus, treatment with intranasal mupirocin and chlorhexidine-impregnated cloths compared with placebo significantly reduced neonatal colonization with an S aureus strain concordant with a parental baseline strain. However, further research is needed to replicate these findings and to assess their generalizability.

Trial Registration  ClinicalTrials.gov Identifier: NCT02223520

Keywords: Intensive Care; Staphylococcus aureus; Pediatrics; Antibiotics; Mupirocin; Chlorhexidine.


#Chlorhexidine for #meatal #cleaning in reducing #catheter-associated #UTIs: a multicentre stepped-wedge randomised controlled trial (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Chlorhexidine for meatal cleaning in reducing catheter-associated urinary tract infections: a multicentre stepped-wedge randomised controlled trial

Oyebola Fasugba, PhD, Prof Allen C Cheng, PhD, Victoria Gregory, MSc, Prof Nicholas Graves, PhD, Jane Koerner, PhD, Prof Peter Collignon, PhD, Anne Gardner, PhD, Prof Brett G Mitchell, PhD

Published: April 12, 2019 / DOI: https://doi.org/10.1016/S1473-3099(18)30736-9




Evidence for the benefits of antiseptic meatal cleaning in reducing catheter-associated urinary tract infection (UTI) is inconclusive. We assessed the efficacy of 0·1% chlorhexidine solution compared with normal saline for meatal cleaning before urinary catheter insertion in reducing the incidence of catheter-associated asymptomatic bacteriuria and UTI.


A cross-sectional, stepped-wedge, open-label, randomised controlled trial was undertaken in Australian hospitals. Eligible hospitals were Australian public and private hospitals, with an intensive care unit and more than 30 000 hospital admissions per year. Hospitals were randomly assigned to an intervention crossover date using a computer-generated randomisation system. Crossover dates occurred every 8 weeks; during the first 8 weeks of the study, no hospitals were exposed to the intervention (control phase), after which each hospital sequentially crossed over from the control to the intervention every 8 weeks. Patients requiring a urinary cathetwer were potentially eligible for inclusion in this hospital-wide study. Participants were excluded if they were younger than 2 years, had a medical reason preventing the use of the chlorhexidine, had the catheter inserted in theatre, did not have the catheter insertion date documented, required in-and-out or suprapubic catheterisation, had symptoms and signs suggestive of UTI at the time of catheter insertion, or were currently undergoing treatment for UTI. The intervention was the use of 0·1% chlorhexidine solution for meatal cleaning before urinary catheterisation with 0·9% normal saline used in the control phase. Masking of hospitals was not possible because it was not feasible to mask staff administering the intervention. The co-primary outcomes were the number of cases of catheter-associated asymptomatic bacteriuria and UTI per 100 catheter-days and were assessed within 7 days of catheter insertion in the intention-to-treat population. This trial is registered with Australian New Zealand Clinical Trials Registry, number ACTRN12617000373370.


21 hospitals were assessed for eligibility between Jan 5, 2017, and May 1, 2017; of these, three were successfully enrolled and randomised to one of three intervention crossover dates. 1642 participants in these hospitals were included in the study between Aug 1, 2017, and March 12, 2018, 697 (42%) in the control phase and 945 (58%) in the intervention period. In the control period, 13 catheter-associated UTI and 29 catheter-associated asymptomatic bacteriuria events in 2889 catheter-days (0·45 catheter-associated UTI cases and 1·00 catheter-associated asymptomatic bacteriuria cases per 100 catheter-days) were recorded compared with four catheter-associated UTI and 16 catheter-associated asymptomatic bacteriuria events in 2338 catheter-days (0·17 catheter-associated UTI cases and 0·68 catheter-associated asymptomatic bacteriuria cases per 100 catheter-days) during the intervention period. The intervention was associated with a 74% reduction in the incidence of catheter-associated asymptomatic bacteriuria (incident rate ratio 0·26, 95% CI 0·08–0·86, p=0·026), and a 94% decrease in the incidence of catheter-associated UTI (0·06, 95% CI 0·01–0·32, p=0·00080). There were no reported adverse events.


The use of chlorhexidine solution for meatal cleaning before catheter insertion decreased the incidence of catheter-associated asymptomatic bacteriuria and UTI and has the potential to improve patient safety.


HCF Research Foundation.

Keywords: Chlorhexidine; UTIs; Bacteriuria.


#Chlorhexidine versus routine #bathing to prevent #MDR organisms and all-cause #bloodstream #infections in general medical and surgical units (#ABATE Infection trial)… (Lancet, abstract)

[Source: The Lancet, full page: (LINK). Abstract, edited.]

Chlorhexidine versus routine bathing to prevent multidrug-resistant organisms and all-cause bloodstream infections in general medical and surgical units (ABATE Infection trial): a cluster-randomised trial

Prof Susan S Huang, MD,  Prof Edward Septimus, MD, Ken Kleinman, ScD, Julia Moody, MS, Jason Hickok, MBA, Lauren Heim, MPH, Adrijana Gombosev, MS, Taliser R Avery, MS, Katherine Haffenreffer, BS, Lauren Shimelman, BA, Prof Mary K Hayden, MD, Prof Robert A Weinstein, MD, Caren Spencer-Smith, MIS, Rebecca E Kaganov, BA, Michael V Murphy, BA, Tyler Forehand, MBA, Julie Lankiewicz, MPH, Micaela H Coady, MS, Lena Portillo, BS, Jalpa Sarup-Patel, BS, John A Jernigan, MD, Jonathan B Perlin, MD, Prof Richard Platt, MD, for theABATE Infection trial team

Published: March 05, 2019 / DOI: https://doi.org/10.1016/S0140-6736(18)32593-5




Universal skin and nasal decolonisation reduces multidrug-resistant pathogens and bloodstream infections in intensive care units. The effect of universal decolonisation on pathogens and infections in non-critical-care units is unknown. The aim of the ABATE Infection trial was to evaluate the use of chlorhexidine bathing in non-critical-care units, with an intervention similar to one that was found to reduce multidrug-resistant organisms and bacteraemia in intensive care units.


The ABATE Infection (active bathing to eliminate infection) trial was a cluster-randomised trial of 53 hospitals comparing routine bathing to decolonisation with universal chlorhexidine and targeted nasal mupirocin in non-critical-care units. The trial was done in hospitals affiliated with HCA Healthcare and consisted of a 12-month baseline period from March 1, 2013, to Feb 28, 2014, a 2-month phase-in period from April 1, 2014, to May 31, 2014, and a 21-month intervention period from June 1, 2014, to Feb 29, 2016. Hospitals were randomised and their participating non-critical-care units assigned to either routine care or daily chlorhexidine bathing for all patients plus mupirocin for known methicillin-resistantStaphylococcus aureus (MRSA) carriers. The primary outcome was MRSA or vancomycin-resistant enterococcus clinical cultures attributed to participating units, measured in the unadjusted, intention-to-treat population as the HR for the intervention period versus the baseline period in the decolonisation group versus the HR in the routine care group. Proportional hazards models assessed differences in outcome reductions across groups, accounting for clustering within hospitals. This trial is registered withClinicalTrials.gov, number NCT02063867.


There were 189 081 patients in the baseline period and 339 902 patients (156 889 patients in the routine care group and 183 013 patients in the decolonisation group) in the intervention period across 194 non-critical-care units in 53 hospitals. For the primary outcome of unit-attributable MRSA-positive or VRE-positive clinical cultures ( figure 2), the HR for the intervention period versus the baseline period was 0·79 (0·73–0·87) in the decolonisation group versus 0·87 (95% CI 0·79–0·95) in the routine care group. No difference was seen in the relative HRs (p=0·17). There were 25 (<1%) adverse events, all involving chlorhexidine, among 183 013 patients in units assigned to chlorhexidine, and none were reported for mupirocin.


Decolonisation with universal chlorhexidine bathing and targeted mupirocin for MRSA carriers did not significantly reduce multidrug-resistant organisms in non-critical-care patients.


National Institutes of Health.

Keywords: Antibiotics; Drugs Resistance; Chlorhexidine; Mupirocin; MRSA; Bacteremia.


#Assessment of the #potential for inducing #resistance in #MDR organisms from exposure to #minocycline, #rifampin and #chlorhexidine used to treat intravascular #devices (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Assessment of the potential for inducing resistance in multidrug resistant organisms from exposure to minocycline, rifampin and chlorhexidine used to treat intravascular devices.

Joel Rosenblatt, Nylev Vargas-Cruz, Ruth A. Reitzel, Issam I Raad

DOI: 10.1128/AAC.00040-19



To assess the potential for induction of antimicrobial resistance following repeated sub-inhibitory exposures to the combination Minocycline (M), Rifampin (R), and Chlorhexidine (CH), a total of 29 clinical microbial pathogenic isolates were repeatedly exposed to sub-inhibitory concentrations of M, R and CH for 20 passages. Minimum inhibitory concentrations (MICs) of the M, R and CH combination were assessed at each passage to evaluate the potential for resistance to have been induced. The combination of M, R and CH showed significant antimicrobial efficacy and synergy against organisms resistant to all 3 individual components (MIC ≥16 μg/mL for M, or MIC ≥4 μg/mL for R or CH). Among the organisms originally resistant to 2 or more individual components and the organisms originally susceptible to 2 or more individual components, there was no evidence that organisms became resistant following 20 repeated sub-inhibitory exposure cycles to the triple combination. The risk of resistance developing to the triple combination is extremely low because microbes are inhibited or killed before resistances can simultaneously emerge to all three agents. Surveillance studies monitoring development of resistance should be conducted in a clinical setting.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Minocycline; Rifampin; Chlorhexidine.


Sequential #evolution of #virulence and #resistance during clonal spread of community-acquired #MRSA (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Sequential evolution of virulence and resistance during clonal spread of community-acquired methicillin-resistant Staphylococcus aureus

Richard Copin, William E. Sause, Yi Fulmer, Divya Balasubramanian, Sophie Dyzenhaus, Jamil M. Ahmed, Krishan Kumar, John Lees, Anna Stachel, Jason C. Fisher, Karl Drlica, Michael Phillips, Jeffrey N. Weiser, Paul J. Planet, Anne-Catrin Uhlemann, Deena R. Altman, Robert Sebra, Harm van Bakel, Jennifer Lighter, Victor J. Torres, and Bo Shopsin

PNAS published ahead of print January 11, 2019 / DOI: https://doi.org/10.1073/pnas.1814265116

Edited by Emil C. Gotschlich, The Rockefeller University, New York, NY, and approved December 6, 2018 (received for review August 17, 2018)



Epidemics of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) are of growing medical concern. To understand the emergence of virulence and antimicrobial resistance, both of which promote CA-MRSA spread, we examined an on-going disease cluster within an enclosed community by analyzing the genome sequences of CA-MRSA clones characterized by high prevalence and a profound persistence. Metabolic adaptation and a phage primed the clone for success, and then a fully optimized variant was created by selection of plasmid-mediated biocide resistance. The data provide mechanistic insight and indicate that high-risk populations are incubators for evolution of consequential phenotypes. Immediate interruption of this evolutionary pattern is essential for forestalling dissemination of resistance from high-risk communities to hospitals and the general population.



The past two decades have witnessed an alarming expansion of staphylococcal disease caused by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). The factors underlying the epidemic expansion of CA-MRSA lineages such as USA300, the predominant CA-MRSA clone in the United States, are largely unknown. Previously described virulence and antimicrobial resistance genes that promote the dissemination of CA-MRSA are carried by mobile genetic elements, including phages and plasmids. Here, we used high-resolution genomics and experimental infections to characterize the evolution of a USA300 variant plaguing a patient population at increased risk of infection to understand the mechanisms underlying the emergence of genetic elements that facilitate clonal spread of the pathogen. Genetic analyses provided conclusive evidence that fitness (manifest as emergence of a dominant clone) changed coincidently with the stepwise emergence of (i) a unique prophage and mutation of the regulator of the pyrimidine nucleotide biosynthetic operon that promoted abscess formation and colonization, respectively, thereby priming the clone for success; and (ii) a unique plasmid that conferred resistance to two topical microbiocides, mupirocin and chlorhexidine, frequently used for decolonization and infection prevention. The resistance plasmid evolved through successive incorporation of DNA elements from non-S. aureus spp. into an indigenous cryptic plasmid, suggesting a mechanism for interspecies genetic exchange that promotes antimicrobial resistance. Collectively, the data suggest that clonal spread in a vulnerable population resulted from extensive clinical intervention and intense selection pressure toward a pathogen lifestyle that involved the evolution of consequential mutations and mobile genetic elements.

MRSA – evolution – antimicrobial resistance – virulence



1 R.C. and W.E.S. contributed equally to this work.

2 To whom correspondence may be addressed. Email: Bo.Shopsin@nyumc.org, Victor.Torres@nyumc.org, or Jennifer.Lighter@nyumc.org.

Author contributions: R.C., W.E.S., J. Lighter, V.J.T., and B.S. designed research; R.C., W.E.S., Y.F., D.B., S.D., J.M.A., K.K., A.S., J.C.F., M.P., and D.R.A. performed research; R.C., J. Lees, P.J.P., A.-C.U., R.S., and H.v.B. contributed new reagents/analytic tools; R.C., W.E.S., D.B., and S.D. analyzed data; and R.C., W.E.S., K.D., J.N.W., V.J.T., and B.S. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

Data deposition: All genomic data reported in this paper have been deposited in the National Center for Biotechnology Information BioProject database (accession no. PRJNA497094).

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1814265116/-/DCSupplemental.

Published under the PNAS license.

Keywords: Antibiotics; Drugs Resistance; Mupirocin; Chlorhexidine; MRSA; CA-MRSA; Staphylococcus aureus.


Intracellular activity of #antimicrobial compounds used for #Staphylococcus aureus #nasal #decolonization (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Intracellular activity of antimicrobial compounds used for Staphylococcus aureus nasal decolonization

J Rigaill, M F Morgene, M Gavid, Y Lelonge, Z He, A Carricajo, F Grattard, B Pozzetto, P Berthelot, E Botelho-Nevers, P O Verhoeven

Journal of Antimicrobial Chemotherapy, dky318, https://doi.org/10.1093/jac/dky318

Published: 16 August 2018




Staphylococcus aureus is able to invade mammalian cells during infection and was recently observed inside nasal mucosa of healthy carriers.


To determine the intracellular activity of antimicrobial compounds used for decolonization procedures using a cell model mimicking S. aureus nasal epithelium invasion.

Patients and methods

HaCaT cells and human nasal epithelial cells (HNECs) recovered from nasal swabs of S. aureus carriers were visualized by confocal laser scanning microscopy to detect intracellular S. aureus cells. An HaCaT cell model, mimicking S. aureus internalization observed ex vivo in HNECs, was used to assess the intracellular activity against S. aureus of 21 antimicrobial compounds used for nasal decolonization, including mupirocin and chlorhexidine.


HaCaT cells and HNECs were found to internalize S. aureus with the same focal pattern. Most antimicrobial compounds tested on HaCaT cells were shown to have weak activity against intracellular S. aureus. Some systemic antimicrobials, including fusidic acid, clindamycin, linezolid, minocycline, ciprofloxacin, moxifloxacin, rifampicin and levofloxacin, reduced S. aureus intracellular loads by 0.43–1.66 log cfu/106 cells compared with the control (P < 0.001). By contrast, mupirocin and chlorhexidine reduced the S. aureus intracellular load by 0.19 and 0.23 log cfu/106 cells, respectively.


These data indicate that most of the antimicrobial compounds used for nasal decolonization, including mupirocin and chlorhexidine, exhibit weak activity against intracellular S. aureus using the HaCaT cell model. This work emphasizes the need to better understand the role of the S. aureus intracellular reservoir during nasal colonization in order to improve decolonization procedures.


© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Keywords: Antibiotics; Staphylococcus aureus; Mupirocin; Chlorhexidine.


#Mechanisms of increased #resistance to #chlorhexidine and cross-resistance to #colistin following exposure of #Klebsiella pneumoniae clinical isolates to chlorhexidine (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Mechanisms of increased resistance to chlorhexidine and cross-resistance to colistin following exposure of Klebsiella pneumoniae clinical isolates to chlorhexidine

Matthew E Wand*, Lucy J Bock, Laura C Bonney and J Mark Sutton*

Author Affiliations: Public Health England, National Infection Service, Porton Down, Salisbury, Wiltshire, SP4 0JG, UK.



Klebsiella pneumoniae is an opportunistic pathogen which is often difficult to treat due to its multidrug resistance (MDR). We have previously shown that K. pneumoniae strains are able to “adapt to” (become more resistant) to the widely used bisbiguanide antiseptic chlorhexidine. Here we investigated the mechanisms responsible and the phenotypic consequences for chlorhexidine adaptation with particular reference to antibiotic cross-resistance. In five of six strains adaptation to chlorhexidine also led to resistance to the last resort antibiotic colistin. Here we show that chlorhexidine adaptation is associated with mutations in the two component regulator phoPQ and a putative tet-repressor gene (smvR), adjacent to the MFS family efflux pump smvA. Up-regulation of smvA (10-27 fold) was confirmed in smvR mutant strains and this effect and the associated phenotype was suppressed when a wild type copy of smvR was introduced on plasmid pACYC. Up-regulation of phoPQ (5-15 fold) and phoPQ-regulated genes, pmrD (6-19 fold) and pmrK (18-64 fold), were confirmed in phoPQ mutant strains. In contrast, adaptation of K. pneumoniae to colistin did not result in increased chlorhexidine resistance despite the presence of mutations in phoQ and elevated phoPQ, pmrD and pmrK transcript levels. Insertion of a plasmid containing phoPQ from chlorhexidine adapted strains into wild-type K. pneumoniae resulted in elevated expression levels of phoPQ, pmrD and pmrK and increased resistance to colistin but not chlorhexidine. The potential risk of colistin resistance emerging in K. pneumoniae as a consequence of exposure to chlorhexidine has important clinical implications in infection prevention procedures.



*To whom correspondence should be addressed: Dr Mark Sutton or Dr Matthew Wand, Technology Development Group, Public Health England, Microbiology Services Division, Porton Down, Salisbury, Wiltshire, UK, SP4 0JG. Tel.: +44 (0) 1980 612316; Fax: +44 (0) 1980 612622; e-mail: mark.sutton@phe.gov.uk or matthew.wand@phe.gov.uk.

© Crown copyright 2016.

Keywords: Klebsiella Pneumoniae; Antibiotics; Drugs Resistance; Colistin; Chlorhexidine.