Author: Jon Otter (@jonotter)

‘Crapsules’ spell the end for recurrent Clostridium difficile infection

Jon Otter (@jonotter) C. difficile , , , ,

Faecal microbiota transplantation (FMT) has shown remarkable efficacy for treating recurrent C. difficile infection (CDI). In fact, the randomized controlled trial to evaluate the effectiveness of FMT for recurrent CDI versus treatment with vancomycin was terminated early because FMT was so obviously superior, with a cure rate of more than 90% (see Figure 1, below).

Figure 1: Faecal microbiota transplant for recurrent CDI. Patients with recurrent CDI randomised to FMT (n=16), vancomycin (n=12) or vancomycin + bowel lavage (n=13). Colour scheme chosen carefully.van nood_blog

FMT is crude in every sense. You take donor stool, put it in a blender, sieve it, and deliver it to the recipient’s gut. I had the pleasure of watching a colleague prepare a dose of FMT in our laboratory in London last week. It really is a simple preparation. The delivery of the FMT to the recipient’s gut isn’t so much tricky as it is unpleasant for the recipient, with a tube required for the procedure.

So, could you deliver FMT orally? The answer according to a recent JAMA study is yes. The team from Boston in the US developed specially formulated capsules (aka ‘crapsules’) designed to deliver the FMT to the correct part of the gut. Of the 20 patients with recurrent CDI given a short 2 day course of ‘crapsules’, 14 (70%) resolved. The 6 non-responders were given a second course and 4 of these resolved, resulting in an overall resoluation rate of 90% (18/20). The quality of life benefits are obvious, and spelled out in the reduction in number of daily bowel movements (Figure 2, below). Although this wasn’t an RCT, so the patients knew they were getting the FMT and there could have been a placebo effect, the similarity in the rate of resolution between this study and the van Nood study (Figure 1) is striking.

Figure 2: Median number of bowel movements for 20 patients suffering from recurrent CDI treated with ‘crapsules’.Youngster blog

Oral FMT via ‘crapsules’ takes away the unpleasantness of the delivery for the recipient (if they can get over the ‘gross’ factor). But it doesn’t solve the lingering safety concerns associated with the procedure. We simply don’t have the tools to screen donor stool for problems we don’t yet know about. The experience from delivering hepatitis C virus to haemophiliacs in the 1980s in contaminated blood products from donors is salutary, and close to my heart since one of my good friends is still suffering the consequences of this. But, this risk has to be balanced against the urgent need of patients becoming increasingly desperate with recurrent CDI. If I had recurrent CDI, I’d be joining the queue for FMT.

The real solution to this problem is synthetic FMT. Lots of people are working on this at the moment – check our some of the work by Trevor Lawley on this. I am pretty certain that a simple bacterial cocktail will not make an effective synthetic FMT. There’s huge microbial and non-microbial diversity in the gut contents which will need to be replicated somehow. Clearly, some of this will be redundant, but it will take quite some time to pick through the constituent parts to derive an effective synthetic FMT. But I’m certain it will happen, and probably over the next decade.

Until then, ‘crapsules’ offer an alternative, effective way to deliver FMT, which is remarkably effective for resolving recurrent CDI. But recurrent CDI is just the start. There’s a host of other conditions that could potentially benefit from FMT. It may even be that ‘crapsules’ become a ‘new statin’: “a crapsule a day keeps the bad bugs away”?

Article citation: Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, Capsulized, Frozen Fecal Microbiota Transplantation for Relapsing Clostridium difficile Infection. JAMA 2014; in press.

Does chlorhexidine bathing work for Gram-negative bacteria?

Jon Otter (@jonotter) Acinetobacter, CRE , , ,

CHGThe idea of “source control” – using chlorhexidine to reduce the amount of bacteria on a patient’s skin – makes a lot of sense. There’s mounting evidence that chlorhexidine daily bathing works for Gram-positive pathogens, especially in the ICU.1 For example, one of the first thorough studies of chlorhexidine gluconate (CHG) daily bathing showed that the amount of VRE on the skin, in the environment and transmitted to others were all reduced by implementing CHG daily bathing.2 A number of more recent high-quality studies have provided evidence that CHG daily bathing in the ICU setting helps to prevent the transmission of Gram-positive bacteria (see Table below – although note that studies have not been universally positive for CHG).

Table: Studies evaluating the impact of chlorhexidine daily bathing (with or without other interventions) including data on Gram-negative bacteria.

Study Setting Design Intervention Results
Noto 2015 3 ICU Cluster RCT Daily CHG No significant reduction in HCAI (composite measure including CLABSI, CAUTI, VAP and CDI)
Derde 2014 4 ICU Time series analysis Daily CHG plus hand hygiene Reduction in all MDROs and MRSA (but not VRE or ESBLs)
Seyman 2014 5 ICU Before-after Weekly CHG ‘douche’ Reduction in BSI but not CLABSI; slight reduction in Gram-negative BSI (n too small for statistical analysis)
Hayden 2014 6 LTAC Before-after Bundle (including daily CHG) Acquisition of CRE fell from 4 to 2 per 100 patient weeks
Martínez-Reséndez 2014 7 ICU Before-after Daily CHG plus hand hygiene Reductions in all infections, and in A. baumannii VAP rate
Apisarnthanarak 2014 8 ICU Before-after Bundle (including daily CHG) Reductions in a. baumannii infection and colonization
Climo 2013 9 ICU Cluster RCT Daily CHG Reductions in MRSA / VRE acquisition and all BSI; BSI mainly CoNS (no significant reduction in Gram-negative BSI or CLABSI)
Milstone 2013 10 Paed ICU Cluster RCT Daily CHG BSI reduced; mainly CoNS (no significant reduction in Gram-negative BSI or CLABSI)
Munoz-Price 2010 11 LTAC Before-after Bundle (including daily CHG) CRE carriage prevalence fell from 21% to 0%
Evans 2010 12 ICU Before-after Daily CHG Rate of CLABSI reduced; A. baumannii colonisation reduced but not significantly
Popovich 2009 13 ICU Before-after Daily CHG Rate of CLABSI reduced; A. baumannii infection rate reduced but not significantly
Bleasdale 2007 14 ICU Cross-over Daily CHG Number of Gram-negative BSI in each arm too small for analysis
Gould 2007 15 ICU Before-after Daily CHG + mupirocin Number of Gram-negatives too small for analysis
Camus 2005 16 ICU RCT Daily CHG + mupirocin Number of Gram-negative acquisitions similar in intervention vs. control groups

The question of whether CHG is effective for the prevention and control of Gram-negative bacteria is rather more complicated. The main issue is that Gram-negative bacteria are less susceptible to CHG than Gram-positive bacteria.17 In theory, this shouldn’t be a problem because the amount of CHG applied to skin (10,000 mg/L) is much higher than the minimum inhibitory concentration (MIC) of most Gram-negative bacteria.17 However, it’s worth noting that the concentration of CHG measured on the skin of patients being treated with CHG in one study was considerably lower than the amount applied (15-312 mg/L before the daily bath and 78-1250 mg/L after the daily bath).18 Nonetheless, in this same study, CHG was found to be effective in reducing the skin burden of CRE on patients in a long-term acute care hospital (see Figure, below).18 So, should CHG bathing be applied to combat MDR-GNR?

Figure: Impact of chlorhexidine gluconate (CHG) daily bathing on skin colonization with KPC-producing K. pneumoniae in 64 long-term acute care patients (difference is statistically significant, p=0.01).Lin CHG

A number of studies have implemented CHG as part of a bundle of interventions to control various MDR-GNR. For example, a team from Thailand found that an intervention aimed at improving environmental hygiene combined with CHG brought an outbreak of A. baumannii under control.8 The National Institute of Health Clinical Center19 has included CHG bathing as a component of a successful CRE control bundle, and the same goes for long-term acute care hospitals.6,11 Meanwhile, a Dutch study found that implementing CHG bathing combined with improving hand hygiene failed to reduce the acquisition rate of ESBL Enterobacteriaceae.4 A Mexican study implemented CHG bathing combined with improved hand hygiene and reported a significant reduction in VAP due to A. baumannii.7 However, in all of these studies, it is not possible to tell whether it was the CHG or another element of the bundle that made the difference (or not, in the case of the Dutch study).

No study has been designed specifically to evaluate the impact of CHG daily bathing alone on the rate of Gram-negative bacteria infection or colonization, although rate of Gram-negative bacterial infection or colonization has been reported in several studies of CHG. A small number of high-quality studies that have evaluated CHG as a single intervention including randomization have failed to demonstrate a reduction on Gram-negative BSIs and CLABSIs (see the Climo9, Mlistone10 and Camus16 data from the Table above). Also, a non-randomised before-after study in a trauma ICU reported a non-significant reduction in Acinetobacter species colonization.12 Several other studies mention the rate of Gram-negative infection or colonization in passing, but the numbers are too small for meaningful statistical analysis (see Seyman,5 Popovich13, Bleasdale,14 and Gould15). Although these studies do not provide convincing evidence that CHG works for Gram-negative bacteria, it’s important to remember that they were not powered to evaluate the impact of CHG on Gram-negative bacteria.

One final point to consider is the potential for the development of CHG resistance. Units using CHG universally have reported an increase in the presence of bacteria with reduced CHG susceptibility.20-22 However, the actual degree of reduced susceptibility is moderate, meaning that the clinical importance of this reduced susceptibility is debatable. It is true to say, though, that the potential for meaningful reduced susceptibility is greater in Gram-negative bacteria than in Gram-positive bacteria due to their higher baseline MIC and manifold mechanisms of resistance to biocides and antibiotics.17

So, does CHG bathing work for Gram-negative bacteria? Based on current data, we simply don’t know.

References:

  1. Derde LP, Dautzenberg MJ, Bonten MJ. Chlorhexidine body washing to control antimicrobial-resistant bacteria in intensive care units: a systematic review. Intensive Care Med 2012; 38: 931-939.
  2. Vernon MO, Hayden MK, Trick WE et al. Chlorhexidine gluconate to cleanse patients in a medical intensive care unit: the effectiveness of source control to reduce the bioburden of vancomycin-resistant enterococci. Arch Intern Med 2006; 166: 306-312.
  3. Noto MJ, Domenico HJ, Byrne DW et al. Chlorhexidine Bathing and Health Care-Associated Infections: A Randomized Clinical Trial. JAMA 2015 in press.
  4. Derde LP, Cooper BS, Goossens H et al. Interventions to reduce colonisation and transmission of antimicrobial-resistant bacteria in intensive care units: an interrupted time series study and cluster randomised trial. Lancet Infect Dis 2014; 14: 31-39.
  5. Seyman D, Oztoprak N, Berk H, Kizilates F, Emek M. Weekly chlorhexidine douche: does it reduce healthcare-associated bloodstream infections? Scand J Infect Dis 2014; 46: 697-703.
  6. Hayden MK, Lin MY, Lolans K et al. Prevention of Colonization and Infection by Klebsiella pneumoniae Carbapenemase-Producing Enterobacteriaceae in Long Term Acute Care Hospitals. Clin Infect Dis 2014 in press.
  7. Martinez-Resendez MF, Garza-Gonzalez E, Mendoza-Olazaran S et al. Impact of daily chlorhexidine baths and hand hygiene compliance on nosocomial infection rates in critically ill patients. Am J Infect Control 2014; 42: 713-717.
  8. Apisarnthanarak A, Pinitchai U, Warachan B, Warren DK, Khawcharoenporn T, Hayden MK. Effectiveness of infection prevention measures featuring advanced source control and environmental cleaning to limit transmission of extremely-drug resistant Acinetobacter baumannii in a Thai intensive care unit: An analysis before and after extensive flooding. Am J Infect Control 2014; 42: 116-121.
  9. Climo MW, Yokoe DS, Warren DK et al. Effect of daily chlorhexidine bathing on hospital-acquired infection. N Engl J Med 2013; 368: 533-542.
  10. Milstone AM, Elward A, Song X et al. Daily chlorhexidine bathing to reduce bacteraemia in critically ill children: a multicentre, cluster-randomised, crossover trial. Lancet 2013; 381: 1099-1106.
  11. Munoz-Price LS, Hayden MK, Lolans K et al. Successful control of an outbreak of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae at a long-term acute care hospital. Infect Control Hosp Epidemiol 2010; 31: 341-347.
  12. Evans HL, Dellit TH, Chan J, Nathens AB, Maier RV, Cuschieri J. Effect of chlorhexidine whole-body bathing on hospital-acquired infections among trauma patients. Arch Surg 2010; 145: 240-246.
  13. Popovich KJ, Hota B, Hayes R, Weinstein RA, Hayden MK. Effectiveness of routine patient cleansing with chlorhexidine gluconate for infection prevention in the medical intensive care unit. Infect Control Hosp Epidemiol 2009; 30: 959-963.
  14. Bleasdale SC, Trick WE, Gonzalez IM, Lyles RD, Hayden MK, Weinstein RA. Effectiveness of chlorhexidine bathing to reduce catheter-associated bloodstream infections in medical intensive care unit patients. Arch Intern Med 2007; 167: 2073-2079.
  15. Gould IM, MacKenzie FM, MacLennan G, Pacitti D, Watson EJ, Noble DW. Topical antimicrobials in combination with admission screening and barrier precautions to control endemic methicillin-resistant Staphylococcus aureus in an Intensive Care Unit. Int J Antimicrob Agents 2007; 29: 536-543.
  16. Camus C, Bellissant E, Sebille V et al. Prevention of acquired infections in intubated patients with the combination of two decontamination regimens. Crit Care Med 2005; 33: 307-314.
  17. Stickler DJ. Susceptibility of antibiotic-resistant Gram-negative bacteria to biocides: a perspective from the study of catheter biofilms. J Appl Microbiol 2002; 92 Suppl: 163S-170S.
  18. Lin MY, Lolans K, Blom DW et al. The effectiveness of routine daily chlorhexidine gluconate bathing in reducing Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae skin burden among long-term acute care hospital patients. Infect Control Hosp Epidemiol 2014; 35: 440-442.
  19. Palmore TN, Henderson DK. Managing Transmission of Carbapenem-Resistant Enterobacteriaceae in Healthcare Settings: A View From the Trenches. Clin Infect Dis 2013; 57: 1593-1599.
  20. Horner C, Mawer D, Wilcox M. Reduced susceptibility to chlorhexidine in staphylococci: is it increasing and does it matter? J Antimicrob Chemother 2012; 67: 2547-2559.
  21. Otter JA, Patel A, Cliff PR, Halligan EP, Tosas O, Edgeworth JD. Selection for qacA carriage in CC22 but not CC30 MRSA bloodstream infection isolates during a successful institutional infection control programme. J Antimicrob Chemother 2013; 68: 992-999.
  22. Suwantarat N, Carroll KC, Tekle T et al. High prevalence of reduced chlorhexidine susceptibility in organisms causing central line-associated bloodstream infections. Infect Control Hosp Epidemiol 2014; 35: 1183-1186.

Image: John Loo.

Asthma and the "Hygiene Hypothesis": Does cleanliness matter? New study says “No”

Jon Otter (@jonotter) Contamination, Disinfection , , , ,

Guest Blogger Prof Sally Bloomfield (bio below) writes…In proposing the hygiene hypothesis in 1989, Dr David Strachan suggested that lower incidence of early childhood infections could explain the 20th century rise in allergic diseases. This was based on data showing that larger family size appears to protect against hay fever.  Strachan suggested that smaller families provided insufficient infection exposure because of less person to person spread of infections – but also because of “improved household amenities and higher standards of personal cleanliness”.  From this the notion that “we have become too clean for our own good” has arisen.

Most experts now agree that the “hygiene hypothesis” is a misnomer. Although the basic concept is still seen as correct, the link to infectious disease and hygiene is now largely discounted. A number of refinements to the hypothesis offer a more plausible explanation. The Old Friends (OF) Mechanism was proposed by Graham Rook in 2003. He proposed that the required exposures are not childhood diseases such as colds, flu, measles, norovirus, which have evolved only over the last 10,000 years, but the microbes we co-evolved with in hunter-gatherer times when the human immune system was developing. These Old Friends include largely non-harmful organisms such as helminths, commensal microbiota and environmental saprophytes.

Although these microbes are still there, through lifestyle changes we have gradually lost our exposure to them. Improved water, sanitation and food quality, although protective against infections, have also inadvertently reduced exposure to Old Friends which occupy the same habitats. The decline in natural childbirth in favour of caesarean section, and bottle instead of breast feeding is another likely factor. Reduced exposure to our outdoor environment has also occurred – we  now spend up to  80% of our time indoors.  Also, antibiotics may alter our interaction with microbes leading to reduced diversity of human gut microbiota.

Despite a shift in scientific thinking, the so-called “hygiene hypothesis” is still widely accepted in the public domain and  still discussed in terms of concepts such as ‘eat dirt’, ‘too clean is bad’, or ‘sterile homes’.   The lay audience, and even the U.S. FDA attribute the problem to ‘the extremely clean household environments often found in the developed world’.” (See headlines below!)

Bloomfield Public misconceptions re hygiene

What is overlooked is the fact that the relationship between household or personal cleanliness and development of allergies has never been properly investigated. At last – just this week, we have seen publication of the first study to directly evaluate this issue. From the study, Erika von Mutius, a highly respected researcher in this field, concludes – No. “Development of allergies and asthma was not related to cleaning activities”.

Methods: The study involved a birth cohort of 399 participant families recruited in urban and suburban regions of Munich, Germany, between Oct 1999 and Dec 2001. A telephone questionnaire interview comprising 31 questions was carried out to assess cleaning habits and cleaning frequencies in the homes, the use of detergents and the personal cleanliness of the child. In addition, 13 lifestyle factors and home characteristics were obtained from a self-administered questionnaire.  Questions about the child’s health focused on respiratory and allergic problems. Bacterial markers of home cleanliness were assessed in samples of floor and mattress dust.

Results and conclusions: As found by other workers, bacterial exposure in house dust was found to be associated with reduced risk of childhood allergies.  In turn, personal cleanliness, such as washing hands, and home cleanliness were objectively reflected by dust parameters. However, neither personal nor home cleanliness were associated with protection from asthma and allergies (see flow chart, below).

Bloomfield asthma blog flow chart

Note: In this study, cleanliness was substantiated by rather unspecific dust measurements. The findings however suggest that allergy protection operates through as yet unknown exposures, not assessed by unspecific markers. Future studies will require more detailed microbial analysis. Whether these microbes are affected by cleaning remains to be elucidated, but findings with unspecific markers suggest that normal cleaning does not affect permanent microbial colonization of indoor environments.

If, as now seems, allergies are not the price we have to pay for protection from infection, two fundamental questions need to be addressed:

  • “How can we develop an approach to hygiene, which helps to reconnect us with the necessary microbial exposures, whilst also protecting us against infectious diseases? “
  • How do we change public understanding about the difference between “cleanliness” (absence of visible dirt) and “hygiene” (protecting against infectious diseases)?

The answer to the first question is a return to basics, which means promoting “targeted hygiene”.  This means identifying the critical points in the chain of infection transmission and applying effective hygiene procedures at the appropriate times to prevent further spread.  Appropriate times are those associated with activities such as food and water hygiene, respiratory hygiene, toilet hygiene, laundry hygiene and so on.

Dispelling the misconceptions is a real challenge, made more difficult by the fact that people tend to think that hygiene and cleanliness is the same thing (i.e “if it looks clean it must be germ free”). It is possible that this is best done by promoting a more constructive approach i.e . stressing that getting dirty is healthy, but hygiene is vital in the times and places that matter.

Further Reading: Bloomfield SF, Stanwell-Smith R, Rook GA. 2013. The hygiene hypothesis and its implications for home hygiene, lifestyle and public health: summary.

The study can be found at: Am J Respir Crit Care Med. 2015 Jan 13. [Epub ahead of print] Asthma and the Hygiene Hypothesis – Does Cleanliness Matter? Weber J, Illi S, Nowak D, Schierl R, Holst O, von Mutius E, Ege MJ.

Guest blogger bio:

 bloomfield presenting

Dr Sally Bloomfield is an Honorary Professor at the London School of Hygiene and Tropical Medicine. She is also is the Chairman and Member of the Scientific Advisory Board of the International Scientific Forum on Home Hygiene (IFH). Through these roles Professor Bloomfield continues to develop her work in raising awareness of the importance of home hygiene in preventing the transmission of infectious disease, and developing and promoting home hygiene practice based on sound scientific principles. She is also working to develop understanding of “hygiene issues” such as the “hygiene hypothesis” and “antimicrobial resistance”.

Professor Bloomfield’s background is in healthcare and infectious disease. She has a degree in Pharmacy, and PhD in Pharmaceutical Microbiology from the University of Nottingham. Sally was previously a Senior Lecturer in Pharmaceutical Microbiology at Kings College London (1995 – 1997) and a Hygiene Liaison manager at Unilever Research Port Sunlight UK (1997 – 2001). She has published 100 research and review papers on the subject of home hygiene and the action and mode of action role of antimicrobial agents.

CRE “trafficking” plasmids through hospital surfaces

Jon Otter (@jonotter) Contamination, CRE , , ,

A team from the NIH Clinical Center in the US present a fascinating study, exploring the transmission of carbapenemase-encoding plasmids in unprecedented detail. The intro does a good job of introducing the ‘triple threat’ from CRE: pan-drug resistance, sharply increasing prevalence, and the potential for the horizontal transfer of carbapenemase genes between Enterobacteriaceae species. They introduce the idea of “plasmid trafficking”, which evokes images of shady bacteria dealing in antibiotic resistance genes (a la the infamous cartoon below):

File written by Adobe Photoshop? 4.0

NIH is a hospital that takes CRE seriously, after being stung by an outbreak in 2011. A quick look at who they screen for CRE illustrates just how seriously they take the threat:

  • ICU / high-risk patients screened twice weekly.
  • All patients screened monthly.
  • Admissions from other hospitals screened for CRE…twice (and given pre-emptive contact precautions until negative cultures are confirmed, for good measure).

They also performed some environmental sampling and recovered several CRE from the hospital environment. This will surprise some, but Enterobacteriaceae do have the potential to survive on surfaces for longer than you may expect.

Surveillance cultures identified 10 patients with KPC-producing Enterobacteriaceae and environmental surveillance identified 6 KPC-producing Enterobacteriaceae. They combined these with several historic isolates from the 2011 outbreak, and a couple of imported isolates to give a sample size of 20 isolates. They wanted to dig deeper into these isolates to explore whether or not they shared any plasmids. And here’s where it gets rather complicated. Conventional whole genome sequencing produces many short reads (100-500 bp) but these cannot distinguish between plasmids and chromosome-encoded genes. Therefore, the authors used a technique called single-molecule, real-time (SMRT) to generate longer reads (around 1000 bp) that make it possible to distinguish between plasmids and chromosome-encoded genes. [I know that I’ve over-simplified this clever genomics massively – but I’ll quickly get out of my depth otherwise!]

The report presents a picture of rare patient-to-patient nosocomial transmission (only 1 of 10 patients were thought to be in-hospital acquisitions), continual importation of diverse CRE, and a complex network of even more diverse plasmids. To illustrate the diversity, one strain of CRE contained no fewer than three distinct KPC-encoding plasmids!

The authors find some evidence of environmental spread of carbapenemase-encoding plasmids, with the carbapenemase-encoding plasmid from a patient matching plasmids recovered from different species of Enterobacteriaceae found in the patient’s environment. What the authors did not demonstrate is transmission of carbapenemase-encoding plasmids from the environment to patients – but I wouldn’t want to be admitted to a room with CRE lurking in the hospital environment!

There’s quite a bit of science around the horizontal transmission of plasmids within biofilms. Combine this with the recent finding of biofilms on dry hospital surfaces, and you have a concerning new angle on how CRE may be transmitted in hospitals.

Image credit. Nick Kim, with permission.

Article citation: Conlan S, Thomas PJ, Deming C et al. Single-molecule sequencing to track plasmid diversity of hospital-associated carbapenemase-producing Enterobacteriaceae. Sci Transl Med 2014; 6: 254ra126.

We need new antibiotics for Gram-negative, not Gram-positive bacteria

Jon Otter (@jonotter) Antibiotic resistance, CRE , ,

gram stain pos and neg

The threat from antibiotic resistance is more pink than purple. You probably need to be a microbiologist to get this: Gram-positive bacteria (such as MRSA and C. difficile) stain purple in the Gram stain, whereas Gram-negative bacteria (such as Klebsiella pneumoniae and Acinetobacter baumannii*) stain pink. All of the international concern surrounding antibiotic resistance from the WHO, CDC, PHE and others have focused our mind on one threat in particular: carbapenem-resistant Enterobacteriaceae (CRE). The Enterobacteriaceae family of bacteria are all Gram-negative, so we need to focus our drug discovery towards the Gram-negatives rather than the Gram-positives.

I blogged last week on the fanfare surrounding the discovery of Teixobactin. Whilst it looks promising, it’s still a long way from the pharmacy shelves, is most certainly not “resistance-proof” and, most importantly, only active against Gram-positive bacteria. I’ve received some useful comments in response to the blog pointing me in the direction of another novel antibiotic, Brilacidin.

Brilacidin is a novel antibiotic class that is in many ways more promising than Teixobactin, not least due to its activity against both Gram-positive and Gram-negative bacteria. Furthermore, it’s much closer to the pharmacy shelves, having undergone promising Phase 2b clinical trials (showing broadly comparable efficacy to daptomycin for the treatment of acute bacterial skin and skin structure infections).

Brilacidin is not without its problems though. Firstly, it is not active against A. baumannii. This is important, since multidrug-resistant – especially carbapenem-resistant – A. baumannii is a serious problem in ICUs around the world. Secondly, although the antibiotic is truly novel (working on the principle of ‘defensin-mimetics’), manufacturer claims that resistance is ‘unlikely’ are as fanciful as the “resistance-proof” claims associated with Teixobactin. Every class of antibiotics was novel once. And resistance has developed to them all!

There are some other emerging options for the antimicrobial therapy of multidrug-resistant Gram-negative bacteria. A number of beta-lactamase inhibitors combined with existing antibiotics are currently at various phases of the clinical trials process (for example, avibactam and MK-7655). Again though, although promising, beta-lactamase inhibitors have limitations, the most important being their specificity. For example, these inhibitors are effective against only some beta-lactamases (and have a blind spot for the metallo beta-lactamases such as NDM-1).

So, there is no silver bullet coming through the pipeline. And there will be no silver bullet. However clever we are in discovering or designing new antibiotics, some bacteria will always find a way to become resistant. It would be naive to think otherwise. Drug discovery is one part of our response to the rising threat of antibiotic resistance, but we ultimately need to focus on prevention over cure.

* Actually, A. baumannii is a bit “Gram-variable” so is somewhat pinky-purpley – but let’s not get too hung up on that. 

Image credit and caption: Marc Perkins. ‘Gram stain demonstration slide. A slide demonstrating the gram stain. On the slide are two species of bacteria, one of which is a gram positive coccus (Staphylococcus aureus, stained dark purple) and the other a gram-negative bacillus (Escherichia coli, stained pink). Seen at approximately 1,000x magnification.’

Teixobactin: a “resistance proof” antibiotic? No chance!

Jon Otter (@jonotter) Antibiotic resistance , , ,

It’s not often that I feature a mighty Nature paper on this ‘lil old blog, but this is a big one. A team from Northeastern University in Boston and a small company called NovoBiotic Pharmaceuticals have discovered a truly novel antibiotic, called ‘teixobactin’.

The finding stems from the fact that 99% of microbes in the external environment cannot be cultured in the laboratory. In order to overcome this problem, the authors ingeniously brought the laboratory to the soil by using the iChip (pictured below). The iChip is a way of capturing the growth of a microbe in its natural environment. Curiously, once grown in the iChip, most of the colonies could then be sub-cultured in the laboratory. When using the iChip, around 50% of the microbes in the soil can be cultured (compared with 1% using conventional methods).

ichip

The authors then screened extracts from an awful lot of isolates (10,000) for antimicrobial activity, and found one that stood out: ‘teixobactin’. It’s a novel cell wall inhibitor that interrupts peptidoglycan synthesis not by targeting proteins (such as the enzymes targeted by β-lactams), but by targeting lipids.

Teixobactin has impressive activity against a range of Gram-positive pathogens of importance to healthcare including S. aureus, E. faecium / faecalis, various streptococci, M. tuberculosis and, importantly, C. difficile. The authors found that teixobactin had equivalent activity to oxacillin (methicillin) in vitro, and superior activity to vancomycin both in vitro and in an animal model.

However, there are some problems:

  • Firstly, and most importantly, there is no activity against Gram-negative bacteria. Since the source microbe, the newly described Elftheria terrae, is a Gram-negative bacterium, this is no surprise, otherwise it would inhibit itself in the soil!
  • Secondly, the antibiotic is still a long way from the clinic, and has to undergo a series of rigorous human clinical trials before reaching the pharmacy shelves.
  • Thirdly, the authors made the promising discovery that they did not identify reduced susceptibility to teixobactin despite serial passage to sub-inhibitory doses for 27 days. The press have had a field day with this, and are talking in terms of “resistance resistant” antibiotics. But this is too much: the authors parallel the potential for resistance to teixobactin with the potential for resistance to vancomycin – and we are increasingly seeing clinically meaningful reduced susceptibility to vancomycin. There’s a rather obscure and quite frightening study showing that vancomycin resistance could be just around the corner: the study found that S. aureus exposed to sub-lethal doses of chlorhexidine as a surface biofilm became resistant to vancomycin after 48 hours (MIC >128 mg/L). So, bacteria will become resistant to whatever we throw at them, to a lesser or greater degree, given time and sub-lethal exposure.

So, teixobactin represents and exciting and huge leap forward in the process of antibiotic drug discovery – and we can expect more novel antibiotics to follow. However, we’d be foolish to think that resistance to teixobactin will not emerge in time.

Citation: Ling LL, Schneider T, Peoples AJ et al. A new antibiotic kills pathogens without detectable resistance. Nature 2015.

Image: NBC news.

Christmas 2014 Update

Jon Otter (@jonotter) Updates , , , , ,

Christmas lights

Now that you have digested your Christmas turkey, I thought that it would be a good time to send out an update. These articles have been posted since the last update:

I’m in a rather reflective mood, so time to remind you of some of the key themes from 2014: Ebola, MERS-CoV, universal vs. targeted interventions, faecal microbiota transplantation (FMT), whole genome sequencing (WGS), carbapenem-resistant Enterobacteriaceae (CRE), and some interesting developments in environmental science. And what will we be still talking about come Christmas 2015? Let’s hope it won’t be Ebola, and I think that WGS will be a lab technique akin to a Vitek machine rather than subject matter for NEJM. But I think we still have ground to cover on whether to go for universal or targeted interventions, FMT, and improving our study designs in infection prevention and control. I can also foresee important studies on the comparative and cost-effectiveness of the various tools at our disposal.

And finally, before I sign off for 2014, a classic BMJ study on why Rudolf’s nose is red (it’s to do with the richly vascularised nasal microcirculation of the reindeer nose, apparently).

Image: Christmas #27.

Who's harbouring CRE?

Jon Otter (@jonotter) CRE , , ,

carbapenemase

Many of us are in the process of developing policies of who to screen for CRE carriage. I’ve recently reviewed the literature for studies of CRE carriage (Table, summarising studies evaluating faecal carriage rate of CRE, below).

Author Year Location Setting n patients n carriers % carriers
Adler1 2015 Israel CRE carriage in post-acute hospitals, 2008 1147 184 16.0
– – – CRE carriage in post-acute hospitals, 2013 1287 127 9.9
Mack 2014 London ‘High-risk’ inpatients and admissions. 2077 7 0.3
Rai2 2014 East Delhi, India Outpatients 242 24 9.9
Zhao3 2014 Fujian, China Stool samples from hospitalized patients 303 20 6.6
Birgand4 2014 Paris, France Patients repatriated or recently hospitalized in a foreign country 132 9 6.8
Kim5 2014 Seoul, Korea ICU admissions 347 1 0.3
Girlich6 2014 Morocco Hospitalized patients 77 10 13.0
Lin7 2013 Chicago, USA Long term acute care hospitals 391 119 30.4
– – – Short stay hospital ICU 910 30 3.3
Villar8 2013 Buenos Aires, Argentina Non-hospitalized individuals 164 8 4.9
Kothari9 2013 New Delhi, India. Healthy neonates 75 1 1.3
Day10 2013 Pakistan Patients attending a military hospital 175 32 18.3
Swaminathan11 2013 New York All admissions to 7 units, including ICU, of 2 hospitals 5676 306 5.4
Nüesch-Inderbinen12 2013 Zurich, Switzerland Healthy community residents and outpatients 605 0 0.0
Armand-Lefèvre13 2013 Paris, France ICU patients 50 6 12.0
Wiener-Well14 2010 Jerusalem, Israel Hospitalized patients 298 16 5.4
The most important question to consider when reviewing these data are whether these are CRE or CPE? The rate of carriage of Enterobacteriaceae that are resistant to some carbapenemens by mechanisms that don’t involve carbapenemase will be higher than CPE. Some studies did not report whether they checked for carbapenemase production, and those that did reported a much lower rate of CPE. For example, Armand-Lefèvre et al.13 reported a 12% carriage rate of imipemen-resistant (i.e. carbapenem-resistant) Enterobacteriaceae in ICU patients but none of these carried a carbapenemase.A number of studies report shockingly high rates of carriage. A point-prevalence study of long-term acute care hospitals in Chicago found that 30% of patients carried CRE.7 High rates of carriage were also found in long-term acute care hospitals in Israel, but a national intervention reduced the rate of carriage from 16% in 2008 to 10% in 2013.1 Perhaps even more concerning are signs that there is a substantial community burden of carriage in the Indian Subcontinent. For example, 18% of patients attending a military hospital in Pakistan carried NDM-1 producing Enterobacteriaceae,10 and 10% of Enterobacteriaceae in stool specimens from 123 outpatients in East Delhi produced a carbapenemase.2

In contrast, most studies from Europe report very low rates of carriage, particular in community residents. For example, a Swiss study failed to identify a single carbapenemase producer in a sample of 605 community residents and outpatients.12 Similarly, data published from the Royal Free in London found that only 0.3% of 2077 ‘high-risk’ patients carried CRE.

So, where does this leave us in developing our CRE screening policies? These data mean that your approach will depend where you are. If you are in the middle of New Delhi, then your approach will be different to those of us in London. It seems that CRE is currently rare in most parts of Europe but the surprisingly high CRE carriage rates in some parts of the US are particularly troubling, and should serve to keep us all on our toes.

Image: ‘OXA-48 like carbapenemase.’

References

  1. Adler A, Hussein O, Ben-David D et al. Persistence of Klebsiella pneumoniae ST258 as the predominant clone of carbapenemase-producing Enterobacteriaceae in post-acute-care hospitals in Israel, 2008-13. J Antimicrob Chemother 2015; 70: 89-92.
  2. Rai S, Das D, Niranjan DK, Singh NP, Kaur IR. Carriage prevalence of carbapenem-resistant Enterobacteriaceae in stool samples: A surveillance study. Australas Med J 2014; 7: 64-67.
  3. Zhao ZC, Xu XH, Liu MB, Wu J, Lin J, Li B. Fecal carriage of carbapenem-resistant Enterobacteriaceae in a Chinese university hospital. Am J Infect Control 2014; 42: e61-64.
  4. Birgand G, Armand-Lefevre L, Lepainteur M et al. Introduction of highly resistant bacteria into a hospital via patients repatriated or recently hospitalized in a foreign country. Clin Microbiol Infect 2014; 20: O887-890.
  5. Kim J, Lee JY, Kim SI et al. Rates of fecal transmission of extended-spectrum beta-lactamase-producing and carbapenem-resistant Enterobacteriaceae among patients in intensive care units in Korea. Ann Lab Med 2014; 34: 20-25.
  6. Girlich D, Bouihat N, Poirel L, Benouda A, Nordmann P. High rate of faecal carriage of extended-spectrum beta-lactamase and OXA-48 carbapenemase-producing Enterobacteriaceae at a university hospital in Morocco. Clin Microbiol Infect 2014; 20: 350-354.
  7. Lin MY, Lyles-Banks RD, Lolans K et al. The importance of long-term acute care hospitals in the regional epidemiology of Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae. Clin Infect Dis 2013; 57: 1246-1252.
  8. Villar HE, Baserni MN, Jugo MB. Faecal carriage of ESBL-producing Enterobacteriaceae and carbapenem-resistant Gram-negative bacilli in community settings. J Infect Dev Ctries 2013; 7: 630-634.
  9. Kothari C, Gaind R, Singh LC et al. Community acquisition of beta-lactamase producing Enterobacteriaceae in neonatal gut. BMC Microbiol 2013; 13: 136.
  10. Day KM, Ali S, Mirza IA et al. Prevalence and molecular characterization of Enterobacteriaceae producing NDM-1 carbapenemase at a military hospital in Pakistan and evaluation of two chromogenic media. Diagn Microbiol Infect Dis 2013; 75: 187-191.
  11. Swaminathan M, Sharma S, Poliansky Blash S et al. Prevalence and risk factors for acquisition of carbapenem-resistant Enterobacteriaceae in the setting of endemicity. Infect Control Hosp Epidemiol 2013; 34: 809-817.
  12. Nuesch-Inderbinen M, Zurfluh K, Hachler H, Stephan R. No evidence so far for the dissemination of carbapenemase-producing Enterobactericeae in the community in Switzerland. Antimicrob Resist Infect Control 2013; 2: 23.
  13. Armand-Lefevre L, Angebault C, Barbier F et al. Emergence of imipenem-resistant gram-negative bacilli in intestinal flora of intensive care patients. Antimicrob Agents Chemother 2013; 57: 1488-1495.
  14. Wiener-Well Y, Rudensky B, Yinnon AM et al. Carriage rate of carbapenem-resistant Klebsiella pneumoniae in hospitalised patients during a national outbreak. J Hosp Infect 2010; 74: 344-349.

ECDC data shows progressive, depressing increase in antibiotic resistance in Europe

Jon Otter (@jonotter) Antibiotic resistance , , , ,

The ECDC recently released their 2013 report, which includes 2013 data. The data are on the whole fairly depressing for more parts of Europe, with high and increasing rates of resistance to important antibiotics in common bacteria. So it was not surprising to see ECDC issue a corresponding press release focusing on worrying resistance to last-line antibiotics.

I’ve chosen a few illustrative countries from this useful interactive database. Carbapenem resistance in Enterobacteriaceae (i.e. CRE) is one of the most concerning challenges facing us right now. So it’s not good to see continued high rates of carbapenem resistance in K. pneumoniae in Greece, and the seemingly inexorable increase in Italy (Figure 1). It’s worth noting that these are invasive isolates, the majority of which would be bloodstream infections. And the mortality rate for a CRE bloodstream infection is around 50%…

Figure 1: Susceptibility of Klebsiella pneumoniae invasive isolates to carbapenemsEARS-Net 2014 CRE

In some ways, the steady increase in multidrug-resistant K. pneumoniae from many parts of Europe, illustrated in Figure 2, is even more concerning than the sharp increases in CRE in some parts of Europe. If you draw a mental trend line for Italy and Portugal, it doesn’t look good.

Figure 2: Multidrug-resistant Klebsiella pneumoniae invasive isolates (resistant to third-generation cephalosporins, fluoroquinolones and aminoglycosides)EARS-Net MDR Kleb

The picture for P. aeruginosa (and I suspect the other non-fermenters like A. baumannii, which isn’t included in EARS-Net) in terms of carbapenem resistance is different to the Enterobacteriaceae (Figure 3). Rates are high in Greece, intermediate in Italy and Portugal, and low in the UK. But the trend is stable.

Figure 3: Susceptibility of Pseudomonas aeruginosa invasive isolates to carbapenemsEARS-Net 2014 CRPA

And let’s not forget about MRSA (Figure 4). The UK and some other European countries have done a tremendous job in reducing the transmission of MRSA. This has had an interesting and somewhat unexpected effect on the rate of methicillin-resistance in S. aureus, which has also reduced considerably. I suspect this is a consequence of interrupting the transmission of MRSA, but failing to prevent the spread of MSSA. Put another way, if MRSA and MSSA fell in tandem, the rate of methicillin-resistance in S. aureus would remain constant. The impressive reductions of MRSA reported in the UK have not been replicated everywhere in Europe. Portugal in particular increased from less than the UK in the early 2000s to more than the UK today. There is some evidence that the national campaign in Portugal to reduce healthcare-associated MRSA is making some impact, with a notable reduction in MRSA rate in 2013.

Figure 4: Susceptibility of Staphylococcus aureus invasive isolates to methicillin (i.e. MRSA rate)EARS-Net 2014 MRSA

In summary, it’s not all doom and gloom. The reductions in MRSA in the UK and elsewhere show that reducing the transmission of these antibiotic resistant bacteria can be done. But it takes considerable investment and national focus. Without this, it’s difficult to see the trends in antibiotic resistance, including to last-line agents, continuing to increase in some parts of Europe.

Is deliberately seeding hospital rooms with Bacillus spores a good idea? No, I don’t think so either!

Jon Otter (@jonotter) Contamination , ,

A fascinating Italian/Belgian multicentre study introduces us to the idea of “biocontrol” for problematic surface contamination. They test using “live” cleaning products that deliberately seed hospital surfaces with Bacillus species spores in an attempt to reduce the ecological space for pathogenic microbes through a “competitive exclusion” approach. Ridiculous as it sounds, there’s some logic to this idea. We’re just beginning to understand the potential of complementing a depleted microbiome in human health, so perhaps the same theory goes for the “environmentome”?

The study design is on the one hand impressive and ambitious, with more than 20,000 surfaces samples collected from the three hospitals. However, it is also messy and confusing, with different intervention and sampling protocols in the three hospitals. In particular, it’s a real shame that areas were not randomized to receive the “live” vs. conventional cleaning agents. It seems clear that this was not a carefully planned multicentre study using a standardized protocol – it reads more like three separate studies shoe-horned together.

That said, the results are impressive. Areas treated with the “live” cleaning agents were significantly less likely to be contaminated with coliforms, S. aureus, Candida albicans, with a more moderate impact on C. difficile. However, it’s difficult to determine the scale of the reduction since the relative rather than actual load reductions are reported.

A neat sub-experiment at one of the hospitals is perhaps the most convincing part of the study, where conventional and “live” cleaning agents were alternated (Figure). You can clearly see that the microbial load tracked downwards when the “live” agent was used, and rebounded when the conventional agent was reinstated.

vandini bacillus sporesFigure: Bacterial load of coliforms (black circles) and S. aureus (white circles). Black arrow = beginning of the “live” cleaning agent; black dotted arrow = conventional cleaning agent.

Notwithstanding the impressive reductions, this approach is ringing some alarm bells:

  • Do we really know what we’re doing by deliberately seeding the hospital environment with bacterial spores? Almost all microbes can be pathogenic to immuno-compromised patients. Plus, whilst you know what you’re putting down, you don’t know what it will become when exposed to the selective pressure of hospitals. The authors did take a look at this, using antibiotic susceptibility testing and a PCR assay to show that Bacillus species identified from the original cleaning agents and from hospitals surfaces during study did not differ in their carriage of antibiotic resistance genes. However, this is only scratching the surface of a complex risk.
  • Where do all the pathogens go? Having an environment that is full of Bacillus spores does not make a scrap of difference to the amount of pathogens that are shed into the environment. So, either the Bacillus spores somehow reduce the amount of time that these pathogens survive on surfaces, or offer them a more complex hiding place. I suspect the latter is more likely.
  • Related to this, recent work has identified established biofilms on dry hospital surfaces with important implications. Won’t a daily dose of Bacillus spores only serve to promote the buildup of this biofilm?
  • The authors proffer some potential reasons for the lower bacterial counts, including competition for nutrients and quorum sensing to destabilize biofilms. I think these are very unlikely, because they rely on the Bacillus spores germinating on the surfaces. I suspect that the spores remain firmly as spores, and the reductions are explained by occlusion and competition for space.
  • Ethics can be a pain, but it’s there for a reason – to prevent our patients from unnecessary harm. The outcome of their ethical submission was surprising: “The two Ethics Committees stated that a formal authorization was not necessary because the probiotic products would not be directly administered to patients but exploited for cleaning of hospital surfaces only.” Applying a soup of Bacillus species spores to a patient’s room is pretty much the same thing as applying the soup directly to their skin. Personally, I’d like to choose whether or not I’m admitted to a room deliberately seeded with Bacillus spores!
  • The authors insist on calling the “live” cleaning agents ‘probiotics’, which seems misplaced. To me, ‘xxx-biotics’ implies something that is administered to a patient.

The use of “live” cleaning agents provides an interesting alternative approach to antimicrobial surfaces, or chemicals with residual biocidal activity. However, I am not sure I accept the authors stark choice as their final conclusion: ‘When it comes down to risk management, one has to decide whether a patient should stay in an environment dominated by food grade microorganisms or in an environment harboring an elevated level of increasingly resistant pathogens.’ Personally, I’d prefer to be cared for in an environment with minimal levels of bacterial contamination, and free from contamination with pathogens. Is that too much to ask?

Article citation: Vandini et al. Hard Surface Biocontrol in Hospitals Using Microbial-Based Cleaning Products. PLoS One 2014;9:e108598.