MicrobiologyBytes

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.

Staphylococcus epidermidis frequently causes chronic infections, indicating pronounced capacity to evade host defenses. However, S. epidermidis is in general much less aggressive than its close relative, S. aureus. This paper looks at the molecular reasons for that discrepancy by showing that S. epidermidis immune evasion mechanisms are limited to those involving molecules that protect against or eliminate antimicrobial agents secreted by white blood cells, while immune evasion mechanisms of virulent S. aureus include the production of destructive toxins. This is especially noteworthy, because we demonstrate here for the first time that S. epidermidis has the capacity to produce a toxin with great potential to destroy white blood cells, but keeps its production at a very limited level. This study shows that two closely related human pathogens have adapted specific molecular mechanisms to evade host defenses, reflecting the unique approach used by each to cause human disease.

Staphylococcus epidermidis Strategies to Avoid Killing by Human Neutrophils. (2010) PLoS Pathog 6(10): e1001133. doi:10.1371/journal.ppat.1001133
Staphylococcus epidermidis is a leading nosocomial pathogen. In contrast to its more aggressive relative S. aureus, it causes chronic rather than acute infections. In highly virulent S. aureus, phenol-soluble modulins (PSMs) contribute significantly to immune evasion and aggressive virulence by their strong ability to lyse human neutrophils. Members of the PSM family are also produced by S. epidermidis, but their role in immune evasion is not known. Notably, strong cytolytic capacity of S. epidermidis PSMs would be at odds with the notion that S. epidermidis is a less aggressive pathogen than S. aureus, prompting us to examine the biological activities of S. epidermidis PSMs. Surprisingly, we found that S. epidermidis has the capacity to produce PSMδ, a potent leukocyte toxin, representing the first potent cytolysin to be identified in that pathogen. However, production of strongly cytolytic PSMs was low in S. epidermidis, explaining its low cytolytic potency. Interestingly, the different approaches of S. epidermidis and S. aureus to causing human disease are thus reflected by the adaptation of biological activities within one family of virulence determinants, the PSMs. Nevertheless, S. epidermidis has the capacity to evade neutrophil killing, a phenomenon we found is partly mediated by resistance mechanisms to antimicrobial peptides (AMPs), including the protease SepA, which degrades AMPs, and the AMP sensor/resistance regulator, Aps (GraRS). These findings establish a significant function of SepA and Aps in S. epidermidis immune evasion and explain in part why S. epidermidis may evade elimination by innate host defense despite the lack of cytolytic toxin expression. Our study shows that the strategy of S. epidermidis to evade elimination by human neutrophils is characterized by a passive defense approach and provides molecular evidence to support the notion that S. epidermidis is a less aggressive pathogen than S. aureus.

Related:

• Microbes on the skin: disease or defence?
• What gets up your nose?
• Staphylococcus aureus: superbug
• Evolution and pathogenesis of Staphylococcus aureus

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

Globalization and the trend toward the integration of trade of crops and livestock could have a major impact on the emergence and dissemination of pathogens. Shifts in agricultural practice result in opportunities for pathogens to expand into new host species and to spread rapidly to new territories. For example, the epidemics of bovine spongiform encephalitis (BSE) and the foot and mouth disease epidemic were caused by changing agricultural practices providing new opportunities for transmission, including the use of meat and bone meal in cattle feed, and the long-distance transport of livestock, respectively. The broiler poultry industry has been transformed within the last 50 years from a market dominated by smallholder chicken farms to a multibillion dollar industry controlled by a handful of multinational companies who supply a limited number of breeding lines to a global market. Infectious diseases of chicken flocks are a major economic burden on the industry. In particular, Staphylococcus aureus is associated with several infections of poultry including septic arthritis, subdermal abscesses (“bumble foot”), and gangrenous dermatitis. The impact of globalization on the emergence and spread of pathogens is an important veterinary and public health issue. S. aureus is a notorious human pathogen associated with serious nosocomial and community-acquired infections. In addition, S. aureus is a major cause of animal diseases including skeletal infections of poultry, which are a large economic burden on the global broiler chicken industry.

This new article provides evidence that the majority of S. aureus isolates from broiler chickens are the descendants of a single human-to-poultry host jump that occurred approximately 38 years ago (range, 30 to 63 years ago) by a subtype of the worldwide human ST5 clonal lineage unique to Poland. In contrast to human subtypes of the ST5 radiation, which demonstrate strong geographic clustering, the poultry ST5 clade was distributed in different continents, consistent with wide dissemination via the global poultry industry distribution network. The poultry ST5 clade has undergone genetic diversification from its human progenitor strain by acquisition of novel mobile genetic elements from an avian-specific accessory gene pool, and by the inactivation of several proteins important for human disease pathogenesis. These genetic events have resulted in enhanced resistance to killing by chicken heterophils, reflecting avian host-adaptive evolution.

This work shows the evolutionary history of a major new animal pathogen that has undergone rapid avian host adaptation and intercontinental dissemination. These data provide a new paradigm for the impact of human activities on the emergence of animal pathogens.

Recent human-to-poultry host jump, adaptation, and pandemic spread of Staphylococcus aureus. PNAS USA November 2, 2009. doi: 10.1073/pnas.0909285106

Related:

• Evolution and pathogenesis of Staphylococcus aureus
• Staphylococcus aureus: superbug
• Is that chicken bugged?