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Controversies in infection: infection control or antibiotic stewardship to control healthcare-acquired infection?

      Summary

      Despite record resource being devoted to the control of healthcare-acquired infection (HCAI), rates have never been higher. Although the discovery of the contagiousness of puerperal sepsis by Alexander Gordon heralded the golden era of bacteriology and antibiotics, this led to a belief that infection was beaten. This in its turn may well have led us into a false sense of security and an over-reliance on antibiotics. Modern medicine has built many of its advances on a need for antibiotics, but their very success has led to huge over-use and resulting problems of resistance. Compounded by the absence of a good antibiotic pipeline we are now being forced to address the paradox of antibiotics; namely that they may actually be causing many HCAIs. Not only Clostridium difficile infection, but many others such as those caused by meticillin-resistant Staphylococcus aureus, are more or less completely contingent on antibiotic prescribing. Control of prescribing would probably be just as effective a measure in our fight against HCAI as conventional infection control measures. Arguably, traditional infection control is akin to fire-fighting and antibiotic stewardship to prevention.

      Keywords

      Introduction

      In a time of unparalleled resource devoted to infection control, and healthcare-acquired infection (HCAI) seemingly uncontrollable, it is pertinent to assess whether current strategies to contain HCAI are failing and, if so, why?
      Certainly, the public perception is of hospitals as the dangerous places of Florence Nightingale's time.
      • Williams K.
      Reappraising Florence Nightingale.
      Meticillin-resistant Staphylococcus aureus (MRSA) rates continue to rise in most countries, as do most of the multi-resistant Gram-negative bacteria (see the European Antimicrobial Resistance Surveillance System website) and in many countries Clostridium difficile seems to be an increasing problem, not withstanding its ascertainment difficulties.
      • Planche T.
      • Aghaizu A.
      • Holliman R.
      • et al.
      Diagnosis of Clostridium difficile infection by toxin detection kits: a systematic review.
      With MRSA and C. difficile, at least, it is quite clear that those infections are an additional burden, with rates of meticillin-susceptible S. aureus (MSSA) infection remaining stable or even increasing.
      • Gould I.M.
      Costs of hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) and its control.
      What is also notable is that the majority of day-to-day infection control problems in the hospital are due to increasingly resistant bacteria. In this bicentenary year of Charles Darwin's birth it is pertinent to reflect on the role that antibiotic use may have as a selecting force for evolution of these ‘superbugs’.
      In this short review I will reflect on our over-reliance on antibiotics in modern medicine and try to put antibiotic stewardship in historical perspective alongside infection control, at least as an equal partner in our fight against HCAI.

      Are infection control policies failing?

      Ignaz Semmelweis is often cited as the father of modern infection control, although such concepts are actually more than 2000 years older!
      • Dallas J.
      Little worms which propagate plague.
      Marcus Terentius Varro (116–27 bc), a Roman soldier and Director of the Imperial Library in Rome, warned against the building of homes near swamps ‘because there are bred certain minute creatures which cannot be seen by the eyes, which float in the air and enter the body through the mouth and nose and there cause serious diseases’.
      Girolamo Fracastoro (1478–1553) was perhaps the first to formulate a recognisable ‘modern theory’ of contagion. He stated that it could occur in three ways; by direct contact with the infected, by contact with their clothes, or through the air. He described the agents of contagion as germs or seeds, small imperceptible particles, each specific for a different disease.
      It took the invention of the microscope for theories to advance. Robert Hooke (1635–1703), Athanasius Kircher (1602–1680) and Antonie van Leeuwenhoek (1632–1723) described micro-organisms in numerous settings using microscopes. Hooke even described ‘little worms’ in the blood of victims of bubonic plague in 1656! By 1764, Sir John Pringle (1707–1782) had established the basic principles of sanitation and ventilation of hospital wards and military quarters. He uses the word ‘antiseptic’ in the context of Kircher's theory of contagion by microscopic germs (‘animalcula’).
      But it is to the obstetrician Alexander Gordon of Aberdeen (1752–1798) that we must look for the next big breakthrough.
      • Porter I.A.
      Alexander Gordon, M.D. of Aberdeen 1752–1799.
      Based on detailed diaries he kept of an outbreak of puerperal fever which ran its course from 1789–1793 in Aberdeen, Gordon deduced the relationship between erysipelas and puerperal fever, its cause as being transferred from the postmortem room to the lying-in room by midwives and its prevention by adequate hand hygiene and disinfection of clothes. His treatise, first published in 1795, predates Semmelweis by more than 50 years but despite being reprinted several times over the next century, in London and the USA, he has always been overshadowed by Semmelweis.

      Gordon A. Treatise on the epidemic puerperal fever of Aberdeen. London; 1795.

      Interestingly, like Semmelweis, Gordon made himself unpopular among his colleagues with his observations. Soon after, he left Aberdeen and died of tuberculosis. Gordon was cited by Oliver Wendell Holmes but not by Semmelweis, so it is interesting to speculate on whether Semmelweis was actually aware of Gordon's work.
      • Holmes O.W.
      The contagiousness of puerperal fever.
      Possibly he was and probably he should have been, as the treatise had been published so many times. Also, Scottish medicine was well renowned during that period and communication with and travel to Europe frequent. On the other hand, Semmelweis was said not to have a good grasp of the medical literature, unlike Gordon.
      • Loudon I.
      The tragedy of childbed fever.
      Further advance awaited Pasteur's refutation of spontaneous generation of life, Koch's recognition of the first pathogenic organism (anthrax), Lister's implementation of Pasteur's findings in the form of antiseptic surgery and its development into aseptic surgery.
      • Bulloch W.
      The history of bacteriology.
      In the meantime, Florence Nightingale had introduced better sanitation and hand washing at the Barrack hospital in Scutari, although her role in this has recently been debated.
      • Williams K.
      Reappraising Florence Nightingale.
      It is well documented that antiseptic and subsequently aseptic surgery and other procedures were rapidly taken up by virtually all informed medical practitioners over the following years and popular perception is that they were well adhered to, with the traditional matron overseeing good practice.
      • Bulloch W.
      The history of bacteriology.
      But does this still generally apply or has poor practice crept in, albeit perhaps just outside the operating theatre? Certainly this seems to be the case where hand hygiene adherence rates of 20–40% are considered normal.
      • Cepeda J.A.
      • Whitehouse T.
      • Cooper B.
      • et al.
      Isolation of patients in single rooms or cohorts to reduce spread of MRSA in intensive-care units: prospective two-centre study.
      If this be so, may it be due directly or indirectly to the great success of, and perhaps over-reliance on, antibiotics – with a belief that antibiotics can negate the need for good hygiene, asepsis and cleanliness? Furthermore, could antibiotic use actually be harmful in some instances, actually increasing the number of infections? Increasingly we hear calls for zero tolerance in failure to adhere to hand hygiene and other infection control policies. But perhaps some of the policies of recent years have been misplaced. Take universal precautions (UPs), for example. Such a blind faith in their broad applicability has, I believe, been one of the main reasons for the failure to control MRSA.
      • Gould I.M.
      Can we control MRSA?.
      Over-reliance on UPs to the exclusion of specific policies targeting the biology of problem organisms such as MRSA is counterproductive, even if UPs could be successfully implemented. A problem organism such as MRSA should be targeted specifically according to its method of spread and biological weaknesses.
      • Lindsay J.A.
      • Holden M.T.
      Understanding the rise of the superbug: investigation of the evolution and genomic variation of Staphylococcus aureus.
      In the case of MRSA this means active surveillance cultures, admission cultures, isolation, decolonisation and decontamination.
      • Gould I.M.
      • MacKenzie F.M.
      • MacLennan G.
      • Pacitti D.
      • Watson E.J.
      • Noble D.W.
      Topical antimicrobials in combination with admission screening and barrier precautions to control endemic methicillin-resistant Staphylococcus aureus in an intensive care unit.
      This has been clear for at least three decades but with a few exceptions, for example in Scandinavia and Holland, such policies have been very poorly implemented.

      The antibiotic era

      It is hard to imagine hospital medicine in the pre-antibiotic era, but contemporary reports of the difference that antibiotics made to individual cases well describe the fantastic advance that they were.
      • Jeffrey J.S.
      • Thomson S.
      Penicillin in battle casualties.
      Indeed it is the case that many of the great advances of modern medicine and surgery would not have been possible without the ability to rely on antibiotics to cure secondary infection. But at what cost? The average hospital now uses, on average, levels approaching 100 defined daily doses per 100 occupied bed-days, a value equivalent to ecological saturation.
      • MacKenzie F.M.
      • Bruce J.
      • Struelens M.J.
      • Goossens H.
      • Mollison J.
      • Gould I.M.
      • ARPAC Steering Group
      Antimicrobial drug use and infection control practices associated with the prevalence of methicillin-resistant Staphylococcus aureus in European hospitals.
      This is the equivalent of all patients receiving a full daily dose of antibiotic from the day of admission until discharge. Of course, on average, only less than half of inpatients will actually receive antibiotics at any one time, but those who do receive them are often on double doses or combination therapy. Many guidelines advocate prolonged antibiotic prophylaxis, particularly for the ever-increasing number of immunosuppressed patients, and often these uses are justified by a reasonable evidence base.
      • Gafter-Gvili A.
      • Paul M.
      • Fraser A.
      • Leibovici L.
      Effect of quinolone prophylaxis in afebrile neutropenic patients on microbial resistance: systemic review and meta-analysis.
      On many other occasions, however, prescribing is definitely inappropriate – ‘just in case’ or on the basis of a poor quality severity assessment or misdiagnosis. Current policies to shorten length of stay and curtail costs also encourage empiric use, often of unnecessarily broad-spectrum antibiotics. Combination therapy is often used for a number of reasons, good and bad, including broadening spectrum to accommodate increasing antibiotic resistance, thus completing the spiralling circle of therapeutic empiricism.
      • Kim J.H.
      • Gallis H.A.
      Observations on spiraling empiricism: its causes, allure, and perils, with particular reference to antibiotic therapy.
      Much antibiotic over-use may seem justifiable for the individual patient when viewed in isolation; nevertheless antibiotic use, unlike any other drug category, cannot be viewed in such isolation.

      Antibiotic use as a cause of HCAI

      Each antibiotic prescription has an environmental, ecological consequence.
      • Sarkar P.
      • Gould I.M.
      Antimicrobial agents are societal drugs: how should this influence prescribing?.
      Only over the past decade has this become widely accepted, although Fleming warned of this at an early stage. But the downside of antibiotics goes well beyond development of resistance as already mentioned with MRSA and C. difficile. Indeed, not only does antibiotic use select for and maintain antibiotic resistance, but it also enhances its spread.
      • Gould I.M.
      Antibiotic policies to control hospital-acquired infection.
      • Dancer S.J.
      The effect of antibiotics on methicillin-resistant Staphylococcus aureus.
      This latter point is crucial to the control of modern HCAI and illustrates how potentially critical antibiotic stewardship is in the control of most HCAIs. Possibly it also illustrates why traditional infection control policies have not been as successful as we would have hoped.
      Increased transmission of tetracycline-resistant organisms during tetracycline therapy was demonstrated as long ago as 1960.
      • Berntsen C.
      • McDermott W.
      Increased transmissibility of staphylococci to patients receiving an antimicrobial drug.
      In 2008 increased numbers of MRSA were demonstrated in the noses of carriers receiving quinolones or β-lactams (to which the MRSA strains were resistant) compared with controls.
      • Cheng V.C.C.
      • Li I.W.S.
      • Wu A.K.L.
      • et al.
      Effect of antibiotics on the bacterial load of meticillin-resistant Staphylococcus aureus colonization in anterior nares.
      Presumably this is due to the competitive advantage that was achieved by the antibiotic administration, ablating the normal protective commensal flora (including MSSA), allowing multiplication of the MRSA with increased potential for contaminating the environment. It is easy to imagine adjacent patients being more susceptible to acquisition of MRSA if they are also on an appropriate ‘MRSA selecting’ antibiotic. Furthermore, antibiotics such as the quinolones and cephalosporins are well known to increase expression of fibronectin adhesins, facilitating adherence and ability to colonise, and also many other virulence factors such as toxins which might cause colonisation to develop into infection.
      • Gould I.M.
      Antibiotic policies to control hospital-acquired infection.
      • Dancer S.J.
      The effect of antibiotics on methicillin-resistant Staphylococcus aureus.
      With the increasing trend to admission screening for MRSA, such knowledge should be put to good use by avoiding prescription of agents to which the MRSA is resistant, both in MRSA carriers and their contacts. This is not always an easy task when dealing with multiply resistant MRSA.
      In 1970 Sleigh et al. described inability to control an outbreak of multidrug-resistant (MDR) Klebsiella pneumoniae in a neurosurgery unit.
      • Price D.J.E.
      • Sleigh J.D.
      Control of infection due to Klebsiella aerogenes in a neurosurgical unit by withdrawal of all antibiotics.
      All conventional control measures had failed, so the authors took the unusual, and probably never to be repeated, step of banning prescription of all antibiotics. Not only did the outbreak strain disappear (actually it may have been declining anyway) but, more interestingly, the total number of infections decreased dramatically and no one died of uncontrolled infection during the period of embargo on antibiotic prescriptions.
      So we have to ask ourselves, could antibiotic use be increasing the incidence of most HCAIs due to MDR bacteria, and not just MRSA and C. difficile? Perhaps it is not just resistance that is caused by antibiotics but also HCAI? This is a frightening thought on one hand, as we have become so reliant on antibiotics. On the other hand, this reliance has probably become over-reliance, leading to poor quality infection control in the belief that infection has been beaten by antibiotics. But it is also a good time to take stock, as the antibiotic pipeline is dry and there are no significant developments expected for another 10–20 years.
      • Gould I.M.
      Antimicrobials: an endangered species?.
      So the sooner we are more cautious in our use of antibiotics the better, needing to preserve those that we have.
      Returning to MRSA as an example, there are many case–control studies demonstrating prior antibiotic exposure, particularly with cephalosporins and quinolones as a risk factor for both MRSA colonisation and infection.
      • Tacconelli E.
      Does antibiotic exposure increase the risk of methicillin-resistant Staphylococcus aureus (MRSA) isolation? A systematic review and meta-analysis.
      The same applies, of course, to many other MDR bacteria including most of the MDR Gram-negatives. For MRSA there are also numerous ecological studies demonstrating such a relationship at a community and hospital level.
      • Jeffrey J.S.
      • Thomson S.
      Penicillin in battle casualties.
      There are even a dozen or so studies in the literature suggesting that MRSA rates were decreased by antibiotic policies that reduced use of cephalosporins and quinolones.
      • Gould I.M.
      Comment on: Interventions to control MRSA: high time for time-series analysis?.
      Usually, however, such studies demonstrate the concept of ‘squeezing the balloon’ whereby reduction in use of one drug is mirrored by increasing use of another. Usually this will have its own resistance problems, although it may be that the cephalosporins and quinolones, in particular, are more prone to resistance developing than the penicillins, for example.

      Antibiotic stewardship

      Unfortunately, reducing total antibiotic use is even more difficult than modulating class use and there are very few robust studies in the literature that demonstrate a reversal of resistance.
      • Davey P.
      • Brown E.
      • Fenelon L.
      • et al.
      Systematic review of antimicrobial drug prescribing in hospitals.
      There are complex molecular reasons why this might be the case, particularly the mobile gene cassette that can integrate on chromosomes to encode multiple resistance determinents. Use of any one agent thus encoded can provide selection advantage for maintaining all such encoded resistance determinants. Also, any loss of fitness can often be compensated for by mutations in the bacteria. So it may be that proper stewardship can only halt the current development of resistance, although there are enough examples of reversals to give us some hope.
      • Gould I.M.
      The epidemiology of antibiotic resistance.
      One of the main problems is how to reduce overall antibiotic use, as modern medical developments seem to know no end to the immunosuppression of the patient. Currently, our efforts on stewardship (which mainly revolve around formularies and guidelines) achieve only uniformity of prescribing with adherence to policies, guidelines and formularies. Paradoxically this may actually be more harmful, as the best defence against resistance is probably diversity of prescribing.
      • Sandiumenge A.
      • Diaz E.
      • Rodriguez A.
      • et al.
      Impact of diversity of antibiotic use on the development of antimicrobial resistance.
      Little effort is actually put into reducing prescribing with the possible exception of shortening dose duration. What is really required is better diagnosis (of course including better diagnostics), better severity assessment and, where antibiotics are indicated, better knowledge of pharmacokinetic/pharmacodynamic dosing schedules to optimise outcome and delay development of resistance. These are difficult things to address in the middle of the night when relatively junior doctors are making the prescribing decision, often trying to protect themselves from the threat of under-treating (and perhaps of litigation) and trying to do their best for the patient. More is better or let's prescribe ‘just in case’!
      The example of recent guidelines from the British and American Thoracic Societies for treatment of community-acquired pneumonia (CAP) are a good case in point.
      • Anonymous
      Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia.
      • British Thoracic Society Standards of Care Committee
      BTS guidelines for the management of community acquired pneumonia in adults.
      They make recommendations for various severities of illness but the natural inclination of most clinicians is always to ‘cover’ themselves or their patients with the recommendation for treatment of severe cases. Arguably, such resulting over-use of cephalosporins, quinolones and macrolides may have triggered the MRSA outbreaks in North America and the UK.
      • Monnet D.L.
      • MacKenzie F.M.
      • López-Lozano J.M.
      • et al.
      Antimicrobial drug use and methicillin-resistant Staphylococcus aureus, Aberdeen, 1996–2000.
      The guidelines themselves are not without fault. While they purport to be evidence-based, the antibiotic recommendations are definitely not, leaning heavily to combination therapy and the perceived need to cover all aetiological agents. The Scandinavian countries, which by and large have retained penicillin monotherapy as their treatment of choice for CAP, have not published worse outcomes and have many fewer problems with antibiotic resistance.
      Gone are the days when we can aspire to ‘cover’ 100% in the empiric treatment of every severe infection.
      • Masterton R.G.
      The new treatment paradigm and the role of carbapenems.
      Paradoxically, this is at a time when it has never been clearer that immediate appropriate empiric therapy is beneficial to the septic patient. Difficult decisions have to be made. For instance, do we prescribe a carbapenem and glycopeptide for all septic patients if we have an ESBL and MRSA problem? At what ‘level’ is MRSA or ESBL a problem that should impact on empiric choice? What happens when carbapenem resistance or glycopeptide resistance become problematic, as they already have in some parts of the world? Colistin, tigecycline and fosfomycin are possible alternatives but not so universally applicable as carbapenems. Outcome with them or with glycopeptides, even in susceptible organisms, may be suboptimal, making decisions on empiric therapy even more difficult. While re-evaluation and possible step-down are often an option within the next 48 h, this will be too late for some patients and in the majority there will not be any positive cultures to guide follow-on therapy. Much more strategic thought needs to be given to these important issues in the absence of new antibiotics to help us out of this dilemma.
      In conclusion, new thinking is needed in our use of antibiotics, not only to delay the development of further antibiotic resistance but to help in the control of HCAI. This will require widespread consultation and the time just might be now.

      Conflict of interest statement

      None declared.

      Funding sources

      None.

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