MicrobiologyBytes

Methicillin-resistant Staphylococcus aureus (MRSA), first identified in the 1960s, was initially considered to be a nosocomial pathogen (hospital acquired infection). Beginning in the late 20th century, a specific clone of MRSA known as USA300 emerged as a leading cause of community-acquired infection, but doubts remain as to where many cases of MRSA infection originate, and how to break the transmission of this dangerous strain.

A new study finds that 8% of hospital outpatients carrying methicillin-resistant MRSA lived with an MRSA-positive pet. When faced with chronic and or recurrent MRSA cases, physicians should consider the possibility of household pets as MRSA source. Patients should be informed of this possibility. Unnecessary close contact should be avoided and heightened hygiene practices should be instituted. Sampling/swabbing of all the human and animals in a household seems appropriate to identify unrecognized sources and break potential cycles of reinfection especially in cases involving immunocompromised patients.

Transmission of MRSA between Companion Animals and Infected Human Patients Presenting to Outpatient Medical Care Facilities. PLoS ONE 6(11): e26978. doi:10.1371/journal.pone.0026978
Methicillin-resistant Staphylococcus aureus (MRSA) is a significant pathogen in both human and veterinary medicine. The importance of companion animals as reservoirs of human infections is currently unknown. The companion animals of 49 MRSA-infected outpatients (cases) were screened for MRSA carriage, and their bacterial isolates were compared with those of the infected patients using Pulsed-Field Gel Electrophoresis (PFGE). Rates of MRSA among the companion animals of MRSA-infected patients were compared to rates of MRSA among companion animals of pet guardians attending a “veterinary wellness clinic” (controls). MRSA was isolated from at least one companion animal in 4/49 (8.2%) households of MRSA-infected outpatients vs. none of the pets of the 50 uninfected human controls. Using PFGE, patient-pets MRSA isolates were identical for three pairs and discordant for one pair (suggested MRSA inter-specie transmission p-value = 0.1175). These results suggest that companion animals of MRSA-infected patients can be culture-positive for MRSA, representing a potential source of infection or re-infection for humans. Further studies are required to better understand the epidemiology of MRSA human-animal inter-specie transmission.

Tweet

Researchers have discovered a toxin – SElX – released by methicillin-resistant Staphylococcus aureus (MRSA) which leads the body’s immune system to go into overdrive and damage healthy cells. SElX is made by 95 per cent of S. aureus strains, making it a potential drug target to fight this hospital superbug. SElX belongs to a family of toxins known as superantigens that can invoke an extreme immune response. When it is released it triggers an over multiplication of immune cells, which can lead to high fever, toxic shock and potentially fatal lung infections looked at a strain of MRSA known as USA300 that can cause severe infections in otherwise healthy individuals. If we can find ways to target this toxin, we may be able to stop it from triggering an over-reaction of the body’s immune system and prevent severe infections.

A Novel Core Genome-Encoded Superantigen Contributes to Lethality of Community-Associated MRSA Necrotizing Pneumonia. (2011) PLoS Pathog 7(10): e1002271. doi:10.1371/journal.ppat.1002271

Other research has linked a naturally occurring mutation in the bacterium Clostridium difficile to severe and debilitating diarrhoea in hospital patients undergoing antibiotic therapy. These antibiotics destroy the “good” bacteria in the gut, which allows this “bad” bacterium to colonise the colon, where it causes bowel infections that are difficult to treat. The mutation wipes out an inbuilt disease regulator, called anti-sigma factor TcdC, producing hypervirulent strains of C. difficile that are resistant to antibiotics and which have been found to circulate in Canada, the US, UK, Europe and Australia. The results suggest that bacterial strains carrying this mutation have the potential to produce more of the harmful toxins that cause disease in susceptible individuals – commonly patients aged 65 years or over. As we now have a better understanding of these strains, we can design new strategies to prevent, control and treat these infections.

The Anti-Sigma Factor TcdC Modulates Hypervirulence in an Epidemic BI/NAP1/027 Clinical Isolate of Clostridium difficile. (2011) PLoS Pathog 7(10): e1002317. doi:10.1371/journal.ppat.1002317

Tweet

Staphylococcus aureus is an important human pathogen that is found in the nasal passages of approximately 1/3 of the population. The nose serves as a reservoir for spread of this pathogen and predisposes the host to potential infection. Factors contributing to S. aureus nasal colonization are only beginning to be understood. The collection and analysis of human nasal secretions provided evidence that the presence of haemoglobin in nasal secretions can promote S. aureus nasal colonization. Hemoglobin reduced expression of the S. aureus agr quorum sensing regulatory system known to be involved in surface colonization, and it was found that induction of the agr system reduced nasal colonization. These findings suggest that individuals experiencing frequent nosebleeds would be prone to S. aureus colonization and epidemiological data supports these findings. By understanding host factors and bacterial molecular mechanisms involved in nasal colonization we may one day be able to design novel decolonization strategies.

Hemoglobin Promotes Staphylococcus aureus Nasal Colonization. (2011) PLoS Pathog 7(7): e1002104. doi:10.1371/journal.ppat.1002104
Staphylococcus aureus nasal colonization is an important risk factor for community and nosocomial infection. Despite the importance of S. aureus to human health, molecular mechanisms and host factors influencing nasal colonization are not well understood. To identify host factors contributing to nasal colonization, we collected human nasal secretions and analyzed their ability to promote S. aureus surface colonization. Some individuals produced secretions possessing the ability to significantly promote S. aureus surface colonization. Nasal secretions pretreated with protease no longer promoted S. aureus surface colonization, suggesting the involvement of protein factors. The major protein components of secretions were identified and subsequent analysis revealed that hemoglobin possessed the ability to promote S. aureus surface colonization. Immunoprecipitation of hemoglobin from nasal secretions resulted in reduced S. aureus surface colonization. Furthermore, exogenously added hemoglobin significantly decreased the inoculum necessary for nasal colonization in a rodent model. Finally, we found that hemoglobin prevented expression of the agr quorum sensing system and that aberrant constitutive expression of the agr effector molecule, RNAIII, resulted in reduced nasal colonization of S. aureus. Collectively our results suggest that the presence of hemoglobin in nasal secretions contributes to S. aureus nasal colonization.

Tweet

It is eye-opening to search the internet for the term MRSA (methicillin-resistant Staphylococcus aureus) these days. Instead of epidemiological treatises from Morbidity and Mortality Weekly Report, or reports of decreasing surgical site infections attributed to the advent of active surveillance followed by decolonization and contact isolation procedures, one finds that the first items that are highlighted link to Michael Jackson’s nose infection following another of his minor rhinoplastic touch-ups; a web page devoted to the new best-seller wannabe, Maryn McKenna’s book Superbug, The Fatal Menace of MRSA; and recently World MRSA Day (October 2nd, in case your laboratory wishes to have an event) sponsored by the MRSA Survivors’ Network. Yes, MRSA has celebrity spokespersons, in the shape of actors Tanner Richie and Alicia Cole. How did this microbe, only a few years older than HIV, become so infamous? Actually, we have ourselves partly to blame…

MRSA: a case of pathogens, politics and penalties. Trends Microbiol. 23 Feb 2011
In the current era of public scientific ‘debate’ such as the scientific merit of climate change, it should come as no surprise that a bacterium would have its 15 minutes of political limelight. Furthermore, a few dedicated citizens can truly influence the lives of many by changing the law of the land. For microbiologists, who often complain that our contributions go unnoticed and that we have no political power, this story serves to prove otherwise.

Related:

• MRSA: Methicillin-resistant Staphylococcus aureus
• Clustering of MRSA strains across Europe
• Staphylococcus aureus: superbug

Antibiotics can have ecological effects that impact the efficacy of other antimicrobial agents or facilitate the development of secondary infections. When antibiotics are administered, particularly when they are overused or misused, they change the environment and the biome, which in turn can lead to the selection or development of bacterial strains resistant to a wide range of antibiotic agents, extending beyond the particular antibiotic or antibiotic class initially administered. Certain antibiotic agents also change the normal bacterial flora or environment within the gastrointestinal tract, which in turn can promote the colonization and overgrowth of particular bacteria (e.g. Clostridium difficile), and increase the risk of gastrointestinal infections associated with these bacteria. Antibiotic usage can also have an impact on skin and mucosa colonization (such as for methicillin-resistant Staphylococcus aureus) with significantly increased risk of subsequent infections. These forms of ‘collateral damage’ associated with antibiotic use are important considerations when deciding how best to use antibiotics to prevent or treat infections in the hospital (and community) setting. This review looks at some of the ecological effects of antibiotics used in the hospital and their potential for collateral damage of the nosocomial environment. Collateral damage is becoming an increasing problem due to the increasing severity of illness in hospitalized patients and the increasing use of broad-spectrum antibiotics. The ultimate goal is to understand how to better use antibiotics to optimize their beneficial effects, while minimizing risk of collateral damage, in other words, to improve antibiotic stewardship within hospitals and other institutions.

Beyond the target pathogen: ecological effects of the hospital formulary. (2011) Curr Opin Infect Dis. 24 Suppl 1: S21-31
Antibiotic therapy has the potential for intended as well as unintended consequences due to ecological effects that extend beyond the target pathogen. This review examines some of the collateral damage and collateral benefit that may occur when using antibiotic therapy. Antibiotics excreted in the gastrointestinal tract cause alterations of the indigenous flora. Such disruptions may increase the risk of colonization and overgrowth of pathogenic bacteria, including resistant species, with the potential for serious infection for an individual patient as well as possible hospital-wide dissemination resulting in local outbreaks of infection. For example, Clostridium difficile infection (CDI), and particularly associated diarrhea and colitis, is a potentially serious and growing problem in hospitals worldwide, and is associated with disruption of gut flora through use of broad-spectrum antibiotics, especially those with antianaerobic activity. Infection control measures and improved antibiotic stewardship are key measures for CDI prevention. Another example is the risk of intestinal colonization and overgrowth with resistant bacteria, which is heightened in surgical patients requiring antimicrobial therapy for intraabdominal infections. Results from two Optimizing Intra-Abdominal Surgery with Invanz studies (OASIS-I and OASIS-II) suggested emergence of resistant Enterobacteriaceae was less likely in these patients treated with ertapenem than in those treated with ceftriaxone/metronidazole or piperacillin/tazobactam. Finally, recent studies have reported that increased use of a nonpseudomonal carbapenem such as ertapenem does not reduce the susceptibility of Pseudomonas aeruginosa to pseudomonal carbapenems, for example, imipenem or meropenem. In fact, data from one study showed increased ertapenem/decreased imipenem use was associated with improved susceptibility of P. aeruginosa to imipenem, probably due to decreased selective pressure for resistant species. Improper antibiotic use can be associated with detrimental effects related to the ecological impacts of these drugs. Improved antibiotic stewardship and appropriate infection control measures are key to minimization of the collateral damage associated with antibiotic therapy and may even have collateral benefits.

The traditional route for identifying early hits in antibiotic research is to target multiplying bacteria. All current antibiotics have been generated this way. Activity of a potential antibiotic in such assays is predictive of an antimicrobial effect in humans (bearing in mind many compounds are not suitable due to undesirable characteristics such as toxicity). The disadvantage of this route is that the numbers of novel classes of non-toxic compounds which kill multiplying bacteria may have been almost exhausted and those that remain, may require substantial effort and expense to bring to market. Furthermore anti-multiplying agents are almost always either inactive or only partially active against non-multiplying or slowly multiplying or persister bacteria, which leads to the need for multiple doses of antibiotics in order to achieve cure of a bacterial infectious disease. This prolongs the duration of therapy and increases the emergence of resistance. Since bacterial resistance reduces the effectiveness of antibiotics, new ones are required at regular intervals, as the old ones lose their potency for most infections. However, the number of new antibiotics which reach the market each year is falling. Whilst at least 15 classes of antibiotics were introduced into the market between 1940 and 1962, only three new classes of antibiotics have been marketed since then. Together with their subsequent analogues, each class loses effectiveness, at least for some species of bacteria such as Gram-negatives, within 50 years after entry into the market. So, if we continue to use existing technologies for the next 50 years, it is unlikely that we will produce enough new classes to prevent the antibiotic era fading away. A fundamentally new route for antibiotic drug discovery is required if the antibiotic era is to continue. Bacterial molecules have been targeted, in order to create new drugs, but this has not produced any new classes of antibiotics which have reached the market. Another potential way to develop new antibacterials is to use bacteriophages. Although this method has been utilized for decades, no marketed bacteriophages are available in Western countries for licensed medicinal purposes.

In a clinical infection, multiplying and non-multiplying bacteria co-exist. Antibiotics kill multiplying bacteria, but they are very inefficient at killing non-multipliers which leads to slow or partial death of the total target population of microbes in an infected tissue. This prolongs the duration of therapy, increases the emergence of resistance and so contributes to the short life span of antibiotics after they reach the market. Targeting non-multiplying bacteria from the onset of an antibiotic development program is a new concept. This paper describes the proof of principle for this concept, which has resulted in the development of the first antibiotic using this approach. The antibiotic, called HT61, is a small quinolone-derived compound with a molecular mass of about 400 Daltons, and is active against non-multiplying bacteria, including methicillin sensitive and resistant, as well as Panton-Valentine leukocidin-carrying Staphylococcus aureus. It also kills mupirocin resistant MRSA. The mechanism of action of the drug is depolarisation of the cell membrane and destruction of the cell wall. The speed of kill is within two hours. In comparison to the conventional antibiotics, HT61 kills non-multiplying cells more effectively, 6 logs versus less than one log for major marketed antibiotics. HT61 kills methicillin sensitive and resistant S. aureus in the murine skin bacterial colonization and infection models. No resistant phenotype was produced during 50 serial cultures over a one year period. The antibiotic caused no adverse affects after application to the skin of minipigs. Targeting non-multiplying bacteria using this method should be able to yield many new classes of antibiotic. These antibiotics may be able to reduce the rate of emergence of resistance, shorten the duration of therapy, and reduce relapse rates.

A New Approach for the Discovery of Antibiotics by Targeting Non-Multiplying Bacteria: A Novel Topical Antibiotic for Staphylococcal Infections. 2010 PLoS ONE 5(7): e11818. doi:10.1371/journal.pone.0011818

Related:

• MRSA: Methicillin-resistant Staphylococcus aureus
• Evolution and pathogenesis of Staphylococcus aureus
• How antibiotics kill bacteria
• The cost of antibiotic resistance

Staphylococcus aureus is an invasive human pathogen with increasing incidence and morbidity in hospitals and the community. Both healthy persons and those with underlying illness are at risk for diverse skin and soft tissue infections, endocarditis, osteomyelitis, meningitis, bacteremia, and pneumonia (including pneumonia arising as a complication of influenza), with mortality rates ranging from 6–40%. The high frequency of poorly responsive and recurrent S. aureus disease in apparently immunocompetent hosts is a challenging feature of these infections. Groups that are particularly susceptible include children in daycare, sports teams, jailed inmates and military personnel. Moreover, the emergence and rapid spread of methicillin-resistant S. aureus (MRSA) has placed substantial burden on the healthcare system.

Colonization of the nares (nostrils) is a potent and increasingly prevalent risk factor for subsequent S. aureus infection. In at least 80% of S. aureus bacteremia cases in colonized subjects, the infecting strain is identical to a nasal colonizing strain detected prior to onset of bacteremia. Followed longitudinally, approximately 20–30% of persons are colonized persistently with S. aureus, 30% are colonized intermittently, and 50% never, or rarely, are colonized. Why some individuals apparently are resistant to colonization, and thus at lower risk of infection, remains an open question. Understanding the biology of this pathogen, especially its ecological niche in humans and the initial step in infection, colonization, may therefore provide new methods of limiting disease.

The Human Nasal Microbiota and Staphylococcus aureus Carriage. 2010 PLoS ONE 5(5): e10598. doi:10.1371/journal.pone.0010598
Nasal specimens were collected longitudinally from five healthy adults and a cross-section of hospitalized patients (26 S. aureus carriers and 16 non-carriers). Culture-independent analysis of 16S rRNA sequences revealed that the nasal microbiota of healthy subjects consists primarily of members of the phylum Actinobacteria (e.g., Propionibacterium spp. and Corynebacterium spp.), with proportionally less representation of other phyla, including Firmicutes (e.g., Staphylococcus spp.) and Proteobacteria (e.g. Enterobacter spp). In contrast, inpatient nasal microbiotas were enriched in S. aureus or Staphylococcus epidermidis and diminished in several actinobacterial groups, most notably Propionibacterium acnes. Moreover, within the inpatient population S. aureus colonization was negatively correlated with the abundances of several microbial groups, including S. epidermidis. The nares environment is colonized by a temporally stable microbiota that is distinct from other regions of the integument. Negative association between S. aureus, S. epidermidis, and other groups suggests microbial competition during colonization of the nares, a finding that could be exploited to limit S. aureus colonization.

Related:

• Staphylococcus aureus: superbug
• MRSA: Methicillin-resistant Staphylococcus aureus
• Evolution and pathogenesis of Staphylococcus aureus

Staphylococcus aureus is the main cause of purulent infection in humans. S. aureus has the potential for local as well as disseminated infection and can cause lesions in all tissues and anatomical sites. Infections can be either acquired in the community or in association with health care. The position of S. aureus as one of the most important human pathogens is largely due to its virulence potential and ubiquitous occurrence as a coloniser in humans, domestic animals, and livestock. Between 25% and 35% of healthy human individuals carry S. aureus on the skin or mucous membranes. Any injury that compromises epithelial integrity, trauma, medical or surgical interventions, as well as viral infections, can lead to tissue invasion. It is assumed that severity and outcome depend largely on the virulence of the introduced strain and the immune repertoire of the host. Occasionally, S. aureus acquires enhanced virulence and antimicrobial resistance through horizontal DNA transfer and maintains these mobile genetic elements in a predominantly clonal genomic background. Thus, clones of S. aureus are relatively stable and mainly diversify by the accumulation of single nucleotide substitutions in the absence of frequent interstrain recombination. It is therefore possible to discern different clones and clonal lineages by molecular typing. This method allows several important observations to be made regarding the evolution, epidemiology, and spread of clones with particular public health importance, such as hospital-, community- , and livestock-associated methicillin-resistant S. aureus (MRSA).

A new study finds that methicillin-resistant S. aureus (MRSA), responsible for several difficult-to-treat infections including blood poisoning and pneumonia and a particular problem in hospitals, occurs in distinct geographical clusters across Europe, indicating that MRSA is being diffused by patients moving between hospitals rather than spreading freely in the community. The study used an interactive Web tool to map different strains of the Staphylococcus aureus bacterium across the continent. MRSA infections have become more prevalent in hospitals over the past ten years, and information about its geographical distribution could help us to understand how it spreads and how to control it.

Since 2006 a large group of collaborators in 450 European hospitals located in 26 different countries collected both MRSA and methicillin-sensitive S. aureus (MSSA) isolates from infected patients. National laboratories identified specific strains of S. aureus by molecular typing and entered this information into a Web-based mapping application which is publicly available. The results show that strains of MRSA tend to cluster within regional borders and, in several instances, were associated with individual hospitals. This suggests that MRSA is mainly spread by patients who are repeatedly admitted to different hospitals. Control efforts aimed at interrupting the spread within and between health care institutions may not only be feasible but ultimately successful.

Geographic Distribution of Staphylococcus aureus Causing Invasive Infections in Europe: A Molecular-Epidemiological Analysis. PLoS Med 7(1): e1000215 doi:10.1371/journal.pmed.1000215:
Staphylococcus aureus is one of the most important human pathogens and methicillin-resistant variants (MRSAs) are a major cause of hospital and community-acquired infection. We aimed to map the geographic distribution of the dominant clones that cause invasive infections in Europe. In each country, staphylococcal reference laboratories secured the participation of a sufficient number of hospital laboratories to achieve national geo-demographic representation. Participating laboratories collected successive methicillin-susceptible (MSSA) and MRSA isolates from patients with invasive S. aureus infection using an agreed protocol. All isolates were sent to the respective national reference laboratories and characterised by quality-controlled sequence typing of the variable region of the staphylococcal spa gene (spa typing), and data were uploaded to a central database. Relevant genetic and phenotypic information was assembled for interactive interrogation by a purpose-built Web-based mapping application. Between September 2006 and February 2007, 357 laboratories serving 450 hospitals in 26 countries collected 2,890 MSSA and MRSA isolates from patients with invasive S. aureus infection. A wide geographical distribution of spa types was found with some prevalent in all European countries. MSSA were more diverse than MRSA. Genetic diversity of MRSA differed considerably between countries with dominant MRSA spa types forming distinctive geographical clusters. We provide evidence that a network approach consisting of decentralised typing and visualisation of aggregated data using an interactive mapping tool can provide important information on the dynamics of MRSA populations such as early signalling of emerging strains, cross border spread, and importation by travel. In contrast to MSSA, MRSA spa types have a predominantly regional distribution in Europe. This finding is indicative of the selection and spread of a limited number of clones within health care networks, suggesting that control efforts aimed at interrupting the spread within and between health care institutions may not only be feasible but ultimately successful and should therefore be strongly encouraged.

Related:

• MRSA: Methicillin-resistant Staphylococcus aureus
• Staphylococcus aureus: superbug
• Evolution and pathogenesis of Staphylococcus aureus

On MicrobiologyBytes I’ve often discussed dangerous antibiotic-resistant superbugs such as Staphylococcus aureus MRSA and Clostridium difficile, and what can be done about them. Manuka honey is gathered in New Zealand and Australia from bees which have fed on the manuka bush, Leptospermum scoparium. Recent research has shown that this particular honey has antibacterial activity due primarily to the presence of methylglyoxal (Identification and quantification of methylglyoxal as the dominant antibacterial constituent of Manuka (Leptospermum scoparium) honeys from New Zealand. Mol Nutr Food Res. 2008 Apr;52(4):483-9). This substance originates from dihydroxyacetone, which is present in the nectar of manuka flowers in varying amounts (The origin of methylglyoxal in New Zealand manuka (Leptospermum scoparium) honey. Carbohydr Res. 2009 May 26;344(8):1050-3). Nectar washed from manuka flowers contained high levels of dihydroxyacetone and no detectable methylglyoxal. Storage of manuka honey at 37°C leads to a decrease in the dihydroxyacetone content and a related increase in methylglyoxal. Addition of dihydroxyacetone to clover honey followed by incubation results in methylglyoxal levels similar to those found in manuka honey.

So why the fuss? Dressings containing manuka honey have been shown to be clinically effective against a wide range of bacteria which cause skin ulcers and chronic wound infections, a big problem in hospitals (PubMed: latest research). But manuka honey is in relatively short supply, and so expensive. Manuka honey is now being made in the UK from bushes brought to the Tregothnan Estate near Truro, Cornwall, in 1888. It goes well with a Cornish cream tea, but at £55 a pot, it’s still not cheap.

Subscribe to podcasts (free):
[iTunes] Enhanced podcasts & videos
[RSS] mp3 podcasts (audio only)
Play this episode: Enhanced version | Audio only

Related:

• Honey, I killed the superbug
• Flesh Eating Bacteria
• Staphylococcus aureus: superbug