Effective antimicrobial agents are essential for the management of some bacterial infections in human and veterinary medicine and the increased prevalence of resistance is of major concern to health professionals and UK governments. The threat is particularly acute due to a lack of new antibiotics in development and the spread of multidrug resistant (MDR) organisms. Four recent high level reports document the extent of the issue: ESPAUR — English surveillance programme for antimicrobial utilisation and resistance (2014) (ESPAUR, 2015); Antimicrobial Resistance Empirical and Statistical Evidence-Base — Department of Health Antimicrobial Resistance Strategy Analytical Working group (2015) (Charlett et al, 2015); One Health Report (2015) (Hopkins and Muller-Pebody, 2015); and Tackling Drug-Resistant Infections Globally: final report and recommendations (O'Neill, 2016).
Antimicrobial resistance (AMR) is either inherent or acquired. Inherent or intrinsic resistance is the ability of all members of a bacterial species to resist the action of an antimicrobial agent because of structural or functional characteristics. Generally this is associated with an inability of the drug to bind to a target or to enter bacteria, efficient export of a drug out of bacteria, or the presence of enzymes that inactivate the drug (Table 1). Acquired resistance refers to the development of resistance in bacteria through spontaneous gene mutations or acquisition of plasmids carrying resistance genes from other bacteria. A recent study of 1000 year old Incan mummies identified antibiotic resistance genes, including beta-lactamases, penicillin-binding proteins, and resistance to fosfomycin, chloramphenicol, aminoglycosides, macrolides, quinolones, tetracycline and vancomycin demonstrating resistance genes were present long before antibiotics were discovered (Santiago-Rodriguez et al, 2015). The use of antimicrobial agents selects for these naturally occurring resistant bacteria.
| Bacteria | Antimicrobial | Mechanism |
|---|---|---|
| Anaerobic bacteria | Aminoglycosides | Unable to take up the drug |
| Aerobic bacteria | Metronidazole | Cannot reduce the drug to active form |
| Klebsiella spp. | Ampicillin | Beta-lactamase destroys the antibiotic |
| Pseudomonas aeruginosa | Trimethoprim-sulphonamide, tetracycline and chloramphenicol | Unable to uptake the antibiotic |
| Gram-negative bacteria | Glycopeptides | Drug cannot penetrate their wall |
| Enterococcus spp. | Cephalosporins | Lack penicillin binding proteins |
Generally antibiotics are safe and relatively inexpensive drugs, but this relative safety has led to their over-use for self-limiting or non-bacterial infections, and in prophylaxis (treatment to prevent disease) and metaphylaxis (medication of a group of animals to manage an expected disease outbreak). Prophylactic use should be restricted to cases where development of a bacterial infection is considered highly likely and where the establishment of an infection would be expected to cause severe morbidity, e.g. in an immunosuppressed oncology case, while metaphylaxis has no place in companion animal medicine. Inappropriate uses including poor penetration of the target area, incorrect route of administration, incorrect dose and use of broad spectrum rather than narrow spectrum antimicrobial drugs, are also a concern. Data are lacking for the level of inappropriate use in animals, but in human medicine it has been reported at 50% (Weese et al, 2013). In companion animal medicine β-lactamase–resistant penicillins, cephalosporins (e.g. cefovecin), and fluoroquinolones (e.g. enrofloxacin, marbofloxacin, pradofloxacin) are important drugs for the management of serious potentially life-threatening infections such as pneumonia, severe cellulitis and urinary tract infections. However, they are often used as first-line agents for relatively innocuous infections and thus are the most used but least preserved antibiotics. Three areas are of particular concern:
| No (%) of bacteria resistant to: | ||
|---|---|---|
| Organism | ≥3 antibiotic classes | ≥4 antibiotic classes |
| Corynebacterium spp. n= 138 | 45 (33%) | 26 (19%) |
| Enterococcus spp. n =235 | 184 (78%) | 128 (54%) |
| Escherichia coli n=1231 | 554 (45%) | 284 (23%) |
| Pasteurella spp. n=149 | 35 (24%) | 14 (9%) |
| Staphylococcus pseudintermedius n=1541 | 220 (14%) | 93 (6%) |
| No. (%) of all bacteria isolated from companion animals that are non-susceptible to: | |
|---|---|
| Framycetin (CIA) | 124/3469 (3.6%) |
| Cefovecin (CIA) | 781/5283 (15%) |
| Enrofloxacin (CIA) | 1102/7208 (15%) |
| Clarithromycin (CIA) | 503/1578 (32%) |
| Gentamicin (CIA) | 877/3496 (25%) |
| Ampicillin (CIA) | 1138/3551 (32%) |
| Amoxicillin/clavulanate (CIA) | 1339/7226 (19%) |
| Polymyxin B (CIA) | 1491/3482 (43%) |
| Cefalexin (HIA) | 2349/3989 (59%) |
| Lincomycin (HIA) | 4294/7196 (60%) |
| Fusidic acid (HIA) | 996/2011 (51%) |
| Trimethoprim-sulphonamide (HIA) | 1431/7220 (20%) |
| Tetracycline (HIA) | 3411/7213 (47%) |
The potential consequences of AMR are summarised in Table 4 with the most significant clinical effects being reduced treatment options, prolonged recovery and treatment failure. These effects were illustrated in a no-socomial outbreak of meticillin-resistant Staphylococcus pseudintermedius (MRSP) at the Veterinary Teaching Hospital of the University of Helsinki (Grönthal et al, 2014). Over 14 months 63 dogs and cats acquired MRSP infection while hospitalised, with many patients requiring prolonged hospital treatment or surgical procedures to combat the infection. Interestingly the majority of infections were treated successfully without the use of systemic antimicrobial agents. Risk factors for infection identified in this outbreak were the presence of skin lesions, recent antimicrobial use and prolonged hospitalisation. To avoid outbreaks, a search-and-isolate policy was implemented targeting at-risk patients on admission to identify carriers. Mortality rates associated with resistant bacteria in veterinary medicine have not been quantified, but in humans the World Health Organisation (WHO) state the death rate for patients with serious infections caused by common bacteria to be up to twice that of patients with infections caused by the same non-resistant bacteria, and that patients with meticillin-resistant Staphylococcus aureus (MRSA) are estimated to be 64% more likely to die than those with meticillin-sensitive Staphylococcus aureus (MSSA) (WHO, 2015).
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Infection, systemic inflammatory response syndrome (SIRS) and approaches to antibiosis
Infection may be defined as infiltration of sterile tissue by microorganisms or invasion of sites normally colonised by commensal bacteria by potentially pathogenic bacteria. Inflammation is the body's response to injury and is a complex process that has been summarised as a three stage process by Bone et al (1992). Stage I is characterised by the local production of humoural inflammatory mediators at the site of an injury. Leucocytes attracted to the damaged area may result in local tissue destruction and/or cellular injury with associated local pain and dis-comfort, but the effects are self limiting and a systemic inflammatory response does not develop. Stage II develops when cytokines leak into the circulation resulting in the recruitment of macrophages and platelets, and the development of an acute phase response. As healing progresses this response is ameliorated by a gradual reduction in pro-inflammatory mediators and the production of endogenous antagonists. Systemic signs such as lethargy and pyrexia may develop and empirical antibiosis may be required. Stage III develops when there is loss of regulation of the normal inflammatory response with proinflammatory cytokines continuing to be released into the systemic circulation in excess of anti-inflammatory cytokines. This systemic inflammatory response results in severe pathophysiological changes (cellular destruction, circulatory collapse and multiorgan dysfunction (MOD)), and if identified is an indication for broad spectrum antibiosis where a bacterial cause is considered likely.
Sepsis is deemed present when a systemic inflammatory response develops in response to a microbial infection and it has been referred to as a ‘silent killer’ because it can be difficult to identify. The initial localised infection (stage 1) is a priming event that on its own may not be a significant cause of disease. However, with the onset of sepsis and with each additional step in the cascade of dysregulated immune-responses, the illness can progress rapidly over hours in some cases to MOD and death. Common sites of infection that may progress to sepsis include the respiratory tract, oral cavity, skin and urinary tract. Prevention of MOD requires early identification and management of the systemic inflammatory response and sepsis.
Nurses play a vital role in identifying the early signs of sepsis. Early recognition allows for appropriate treatment to begin sooner, decreasing the likelihood of septic shock and the associated cascade of life-threatening organ failure. SIRS is suggested when abnormalities in temperature, heart rate, respiratory rate or arterial carbon dioxide tension (PaCO2) and the presence of a leucocytosis or leucopenia with immature neutrophils are evident (Table 5). It has been suggested for dogs and cats that for SIRS to be diagnosed two or more abnormalities must be present (DeClue et al, 2011; Babyak and Sharp, 2016). Change in oxygenation is an early sign suggesting patient deterioration and may be evident in declining pulse oximetry values. Increased respiratory and/or cardiac rates compensate for reduced tissue oxygenation, but ultimately these increase the metabolic demand and cannot be maintained resulting in further deterioration of the animal's oxygenation status; further compensation at this time is not possible. As the condition deteriorates towards severe sepsis and MOD, the animal's mental state may change, acute oliguria develops reflecting reduced renal perfusion, stress hyperglycaemia may be recognised, hypoxaemia deteriorates and a coagulopathy may be evident. Be aware that blood pressure readings are not always useful due to compensatory processes present. Frank hypotension associated with SIRS is uncommon, but as the condition progresses and compensatory processes become ineffective, persistent hypotension may be recognised even with adequate fluid resuscitation; this indicates acute circulatory failure. If blood pressure monitoring is unavailable, assessment of capillary refill time may be an approximate proxy.
| Species | Temp. | HR | RR | White cell count x 109/l |
|---|---|---|---|---|
| Dog (Declue et al, 2011) | >39.7°C or <37.84°C | >140 bpm | >40bpm or PaCO2 <30 mmHg | Total neutrophil count of >18 or <5, or band neutrophil >5% |
| Cat (Babayak and Sharp, 2016) | >39.7°C or <37.8°C | >225 bpm or <140 bpm | >40 bpm | Total neutrophil count of >19.5 or <5, or band neutrophil >5% |
When assessing for signs of SIRS it is important to recognise other influences on the clinical criteria, which may provide confounding information. The very young and older patients may not show a typical response and so the clinical suspicion will carry more weight in any decision making. Animals receiving a β-blocker or calcium channel blocker may be unable to increase their heart rate and, thus, tachycardia may not be identified. Nursing staff should be aware of co-morbidities and risk factors for the development of sepsis including diabetes mellitus, immunocompromised states, trauma, chronic diseases haematological problems and indwelling catheters. If these are identified monitoring should be carried out more frequently. Note that factors such as stress, anxiety and exertion may lead to a false diagnosis of SIRS.
In patients with SIRS, confirming a bacterial infection as the cause can be challenging. It is essential that samples for culture are taken as aseptically as possible and prior to antimicrobials being prescribed. Antimicrobial drug therapy must be justifiable and optimised to minimise the risk of resistance developing. Systemic administration of an antimicrobial should be avoided unless sepsis is suspected and empirical antibiosis is judged to be unavoidable (e.g. urinary tract infection, pneumonia, cellulitis); this does not preclude the prophylactic use of antimicrobials in immunosuppressed animals. Human studies have shown that early administration of an appropriate antimicrobial to cases of sepsis is associated with a significant reduction in the mortality rate (Kumar et al, 2006) and therefore each case must be assessed carefully and regularly for the development of SIRS. The choice of drug requires familiarity with the bacteria that commonly cause infections in different organ systems (Table 6) and their probable resistance patterns and can be guided by cytology, the practice's local antibiotic policy (see below) and guidelines such as the MINDME mnemonic (Table 7) and the BSAVA PROTECT message. Some bacteria have predictable sensitivities, e.g. Pasteurella multocida and Streptococcus canis to narrow spectrum penicillins, intracellular bacteria to tetracyclines and some anaerobes to penicillin. Where the species of bacteria is unknown broad-spectrum antibiosis active against Gram-positive and Gram-negative bacteria can be considered. However, only if Gram-negative organisms are identified in a Gram smear should empiric prescribing of a 3rd generation cephalosporin or fluoroquinolone be an option. Be aware that recent antibiotic administration within the past 3 months not only increases the risk of resistant bacteria being present, but has been associated with increased mortality in humans (Johnson et al, 2011). In such cases consider prescribing an alternative class of antibiotic. With regard to combination therapy, various human studies have shown that the use of two classes of antimicrobials provides no clinical advantage over monotherapy (Leibovici et al, 1997; Paul et al, 2003). Generally a broad spectrum beta-lactam antibiotic is the antibacterial of choice for empirical treatment, but once culture and sensitivity results are available the choice of antibacterial should be reviewed and antibiosis directed by the susceptibility results, even if there has been improvement on the initial treatment.
| Organ/tissue | Bacteria |
|---|---|
| Skin/wounds | Staphylococcus pseudintermedius, Staphylococcus felis, Streptococcus canis, Escherichia coli, Pseudomonas aeruginosa |
| Ear | Pseudomonas aeruginosa, Proteus spp, Staphylococcus pseudintermedius, Streptococcus canis, Enterococcus spp., Corynebacterium auriscanis |
| Urinary tract | Escherichia coli, Streptococcus canis, Enterococcus spp, Staphylococcus aureus, Staphylococcus pseudintermedius, Klebsiella spp., Pseudomonas aeruginosa |
| Respiratory tract | Pasteurella multocida, Bordetella bronchiseptica, Streptococcus equi ssp. zooepidemicus |
| Gastrointestinal tract | Salmonella spp., Campylobacter spp., Yersinia spp. |
| M Microbiology guides therapy wherever possible |
| I Indications should be evidence based |
| N Narrowest spectrum required |
| D Dosage appropriate to the site and type of infection |
| M Minimise duration of therapy |
| E Ensure monotherapy in most cases |
Antimicrobial stewardship
Antimicrobial stewardship is an area that nurses can and should be involved in. As the development of new drugs is slow it is of major importance to preserve the efficacy of the available veterinary antimicrobial medicines and the term ‘antimicrobial stewardship’ emphasises the obligation for those using antibiotics to ensure that they remain effective for future generations. For each clinical situation an antimicrobial stewardship plan (ASP) specifies appropriate antimicrobials, with their doses, recommended routes of administration and duration of use, that are most likely to achieve the best clinical outcome, while minimising toxic effects, the potential for resistance development and the spread of MDR infections. It may contain other recommendations such as combination therapies and antimicrobial drug cycling. The programme links veterinary practitioners and nurses with microbiologists, owners, regulators and pharmaceutical companies, and is a key strategy in combating the development of AMR.
A successful ASP requires:
ASP strategies used in human medicine generally fall into one of two types.
Application of these strategies to companion animal practice is feasible although they may be time-consuming to initially set up. In the first instance a simpler ASP strategy may be more feasible which would involve the preparation of a local antimicrobial policy (LAP) (Table 8). The LAP should be informed by an antibiogram possibly available from the supplier of the practice's bacteriology service. An antibiogram is an annual summary of the organisms isolated from samples submitted by a practice and their resistance patterns at the practice and national level. As the prevalence of antibiotic resistance varies between different areas knowledge of the local resistance pattern is helpful in guiding empirical antibiotic choice. Table 9 shows the variation in antimicrobial resistance for Staphylococcus pseudintermedius across four postcode areas. Regular sampling for culture and sensitivity testing is required to ensure the antibiogram remains up to date and valid. It is important to stress that the antibiogram is not provided as an alternative to culture and sensitivity testing, but as an adjunct to guide empirical antibiosis and to benchmark local resistance rates against national rates. Ultimately the choice of antimicrobial agent must be driven by sensitivity testing.
| The name of the practice's Antimicrobial Stewardship (ASP) coordinator |
| A recommendation to carry out cultures before antimicrobial administration and define for which clinical scenarios antibacterials may be used empirically, and when it is usually safe to wait for culture results |
| List first-choice antibiotics that can be prescribed without any restrictions |
| List restricted drugs that may be prescribed for specific indications defined by the LAP |
| List reserve drugs that can only be prescribed following permission from the antibacterial stewardship coordinator or an external expert |
| Build a relationship with the supplier of your bacteriology service who should provide advice on sample collection, transportation and rejection criteria and antibiograms summarising the organisms isolated and their resistance patterns at the practice and national level |
| Regularly re-appraise antibacterial use in the practice |
| No (%) resistant in postcode area | ||||
|---|---|---|---|---|
| Antibiotic | EH | G | PH | AB |
| Cefovecin | 21/429 (5%) | 0/93 (0%) | 3/82 (4%) | 1/139 (0.7%) |
| Trimethoprim sulphonamide | 64/501 (13%) | 10/105 (10%) | 5/116(4%) | 13/199 (7%) |
| Cephalexin | 20/162 (12%) | 3/28 (11%) | 1/45 (2%) | 2/76 (3%) |
| Enrofloxacin | 28/499 (6%) | 4/106 (4%) | 1/114 (0.8%) | 2/199 (1%) |
Conclusion
In conclusion, AMR is a significant threat to animal health and the approach advocated to reduce its prevalence requires optimisation of use of antimicrobial agents, appropriate biosecurity to prevent transmission of organisms to susceptible animals and ensuring adequate environmental decontamination. The latter two are not the subject of this article but they are areas that nurses should be heavily involved in. Antimicrobial drug use should be evidence based (culture and sensitivity), underpinned by knowledge of the predominant bacteria and their likely susceptibility profile combined with up to date information on local resistance patterns.