Your Patient Has a Blood Culture Positive for Staphylococcus Aureus – What Do You Do?

taking thebloodculture. Return tothepatientandunderstand thereason for WHAT SHOULD YOU DO? SCENARIO CASE and Wyeth Pharmaceuticals. Chiron Pharmaceuticals, Pfizer Pharmaceuticals, DECLARATION OFINTERESTS whitebloodcellcount(WCC) transthoracic echocardiogram (TTE), Staphylococcus aureus methicillin-sensitive (MRSA), methicillin-resistant mental statusquestionnaire (MSQ), imaging (MRI), magneticresonance intravenous (IV), infective endocarditis (IE), bypass graft(CABG), artery coronary (CI), confidenceinterval computerised tomography (CT), (CNS), coagulase-negative staphylococcus C-reactive protein (CRP), Chemotherapy (BSAC), LIST OF ABBREVIATIONS KEYWORDS culture tothemanagementofMRSAendocarditis. to themanagementofapatientfrom firstisolationofstaphylococci inablood This overview takes theform ofaclinicalcasescenariowithstep-wiseapproach diseases consultants. local antibioticpolicyalongsideadvicefrom microbiology and/orinfectious Treatment shouldbeguidedby antibiotic therapy inapatientwithsignsofsepsis. Thisassessmentshouldnotdelay urgenttreatment withIV being endocarditis. ofthe ormetastaticcomplication, complication withthemostimportant bacteraemia must besuspectedandsought, Adeep-seatedsource, must beassessed. Thelevel ofriskyour patienthaving MRSA significance oftheorganismisolated. beginning withassessmentofthepatienttodeterminesignssepsisandlikely Detection ofstaphylococci inbloodculture shouldtriggerachainofevents of thestrain andprognosis oftheinfection thevirulence depend onamultitude offactorsincludingunderlying patientfactors, rateofcomplications, Theseverity, resources. rateandasignificantburden onhealthcareassociated withahighmortality ABSTRACT Staphylococcus aureus Your patienthasabloodculture positive for nimr,Mnhse,England Manchester, Infirmary, 1 1 P P Specialist Registrar, AMarwick, CA and renal dysfunction secondary toischaemicheart and renal dysfunctionsecondary failurewith anexacerbationofhis congestive heart wasadmitted23days ago 68years old, Mr Smith, cannot besure untiltomorrow. Staphylococcus aureus Thestaphylococci are likely tobe yesterday. staphylococci inboththebloodculture bottlestaken MrSmithon Ward Xhasgrown Youmicrobiologist. getacallfrom theduty St Elsewhere. You are thedutydoctorcovering Medical Ward Xof APER APER Staphylococcus aureus atrei,edcrii,MRSA, endocarditis, bacteraemia, .aureus, S. 2 3 MZiglam, HM oslatPyiin neto nt ieel optl ude Scotland, Dundee, NinewellsHospital, InfectionUnit, Consultant Physician, atrei SB,transoesophagealechocardiogram (TOE), bacteraemia (SAB), although themicrobiologist and thetimelinessofappropriate antibiotictherapy. lo rsue(P,BritishSocietyfor Antimicrobial Blood pressure (BP), .aureus S. D Nathwanihasacurrent personalinterest with 3 Nathwani D bacteraemia is an important clinicalproblembacteraemia isanimportant MS) polymerase chainreaction (PCR), (MSSA), Staphylococcus aureus – whatdoyou do? aews2 rah/iue His WCC was13x10 rate was22breaths/minute. He waslucidwithaMSQof9/10andhisrespiratory andhisBPwas110/62mmHg. regular, beats/minute, the bloodculture MrSmith’s pulsewas110 Atthe timeof grade fever over thepastthree days. infection atthetimebutnotedanintermittentlow- The resident hadnotfound any localisingsignsof Yesterday hehad ‘spiked’ afever (38°C)withrigors. his centralvenous pressure andfluidbalance. acute medicalemergencyadmissionfor monitoring furosemide through a duringhis ‘neck line’inserted Hehadreceived IV disease andtypeIIdiabetes. and CRPwas245. .aureus S. 2 Consultant Physician, Manchester Royal Manchester Consultant Physician, © 2006Royal CollegeofPhysicians ofEdinburgh Published online Published Correspondence to to Correspondence Infection Unit, East Block, Ninewells Block, East Unit, Infection J RCollPhysicians Edinb Hospital, Dundee, DD1 9SY 9SY DD1 Dundee, Hospital, tel. tel. fax. fax. e-mail [email protected] +44 (0)1382 496459 (0)1382 +44 +44 (0)1382 496547 (0)1382 +44 April 2006 April C A Marwick, A C 2006; 36: 350–355 350 9 /L CME CA Marwick, HM Ziglam, D Nathwani

TABLE 1 Risk factors associated with MRSA colonisation. TABLE 2 Predicted likelihood of methicillin resistance in a patient with Staphylococcus aureus bacteraemia.7 Recent hospitalisation. Risk Community-onset Hospital-onset Recent (3–6months) antimicrobial use. factors* Invasive lines or tube (IV, urinary catheters). Prior antibiotic Prior antibiotic Recent surgery. exposure exposure Nursing home resident. Advanced age. No Yes No Yes Underlying severe disease. 0 15% 62% 36% 84% Exposure to colonised or infected patient. 1 31% 81% 58% 94% Morbid obesity. Orthopaedic implant surgery. 2 53% 91% 77% 97% *History of hospitalisation or decubitus ulcer.

WHAT IS THE LIKELY SIGNIFICANCE OF THIS the acute receiving ward will have at least one of these CULTURE RESULT? COULD IT BE A risk factors. In addition, risk factors that appear to CONTAMINANT? promote the development of nosocomial SAB are the presence of a central venous catheter,hyponatraemia, and In determining the significance of this isolate, a number of anaemia. To advise prudent use of broad-spectrum factors are likely to tell us whether this is a true antibiotics, the predicted likelihood of MRSA in a bacteraemia as apposed to a contaminant: particular patient with SAB has recently been estimated and quantified in a clinical decision rule by Lodise et al.7 1 The presence of local and/or systemic signs of (see Table 2). The presence of hospitalisation, recent long infection and sepsis; duration of hospital stay, recent course of antibiotics, and 2 The detection of bacteria in both blood culture the presence of a decubitus ulcer, increase the likelihood bottles; of the infection being MRSA. 3 The occurrence of early detection of bacteria in the laboratory (time to positivity of the blood culture <14 WHAT IS THE LIKELY SOURCE OF INFECTION hours); AND WHAT SHOULD YOU DO? 4 If the patient has a coagulase-negative staphylococcus CME (CNS) it is more likely to be a contaminant, although The aetiology of SAB is as follows: primary bacteraemia, this is not always the case. Two positive blood cultures for which no source is identified (about 20% of cases), and for CNS within five days, or one positive culture plus secondary, which is the result of infection related to a clinical signs of infection, are associated with clinical distant site. In the hospital setting, wound infection and significance, i.e. infection rather than contamination; and vascular line- or catheter-related infection (central > 5 Previous colonisation with staphylococci or recent peripheral > urinary catheters) are the most common (within three months) isolation of staphylococci in sources of bacteraemia (35%). Other sources include blood cultures. cellulitis or other skin and soft-tissue infection (17%), endocarditis (13%), bone infections (osteomyelitis), septic Your patient exhibited no obvious sign of local infection arthritis or prosthetic joint infections, and pneumonia. but had sepsis, as he exhibited symptoms of infection (fever, rigors) and a systemic inflammatory response to Your patient had no evidence of obvious wound or the infection (i.e. two out of four of temperature <36 or ‘venflon’ site infection but you notice that the >38°C, tachycardia >90/min, tachypnoea >20/min, or emergency central line had been in situ for 12 days WCC <4,000 or >12,000/mm3). The staphylococci were before removal. It had been removed because of ‘entry isolated in both bottles within 24 hours of being taken by site infection’; treated with line removal and five days of the resident. You note previous laboratory results of oral flucloxacillin. He also has a right hip prosthesis isolation of MRSA in a foot ulcer (right toe) during his inserted five years previously and a sternotomy scar previous admission three months ago as well as a positive from CABG three years ago. The hip was fine, with no MRSA screen on that occasion. pain or immobility,and the midline sternotomy scar was normal, although minimal tenderness was elicited on WHAT IS THE LIKELIHOOD THAT THIS deep palpation. Auscultation of the heart revealed no STAPHYLOCOCCAL BACTERAEMIA IS MRSA? definite abnormality but possibly a soft systolic murmur in the left sternal edge. Chest examination was normal. The rate of nasal carriage of S. aureus varies from 10–40% in both community and hospital populations. There are WHAT IS YOUR WORKING DIAGNOSIS? many risk factors that promote colonisation with MRSA. These are outlined in Table 1. Most patients presenting to On the basis of the above findings, the patient most likely

has an SAB secondary to a central-line infection. You are TABLE 3 Reduced prognostic model of complicated concerned that infection from the line has metastasised Staphyloccocus aureus bacteraemia.4 to another site causing a ‘complicated bacteraemia’. Variable Odds ratio P value Possible complications in this patient are endocarditis, (95% CI) although there are no clear stigmata of endocarditis, or a sub-acute right prosthetic hip infection, or sternal Community acquired 3·10 <0·001 (1·96–4·87) osteomyelitis. Fowler et al.4 recently developed a prognostic model to aid estimation of the likelihood of Skin examination findings 20·04 0·002 complicated bacteraemia (see Table 3) to identify cases suggesting the presence of (1·30–3·18) warranting aggressive investigation. The four identified acute systemic infection risk factors (community acquisition, skin findings Positive follow-up blood 5·58 <0·001 suggestive of acute infection, positive follow-up blood culture result (3·93–7·95) culture, and persistent fever) can be used to calculate the Persistent fever at 72 h 2·23 <0·001 probability of complication, with positive follow-up (1·55–3·12) culture being the most heavily weighted risk factor. fluid obtained by blind or CT-guided needle aspiration,or WHAT FURTHER INVESTIGATIONS WOULD surgical washout demonstrating pus cells, with or without YOU CONSIDER? organisms, on microscopy or culture.

You should repeat the blood cultures from a peripheral SHOULD YOU START EMPIRIC TREATMENT site. In S. aureus endocarditis the first two blood cultures AND WHY? are positive in 90% of cases. If there is a central line, in situ simultaneous blood cultures should be taken from this. As the patient has features of sepsis you consider this is This is helpful in diagnosing central-line infection,indicated significant bacteraemia rather than a contaminant. You by negative peripheral cultures with positive line cultures. should therefore start anti-staphylococcal therapy The volume of blood sampled is crucial in detecting the immediately. There is some evidence that in an unwell low levels of bacteraemia found in partially treated or patient or in a patient in the critical care, setting early relapsing infection. Simultaneous cultures, particularly, aid appropriate therapy has a better clinical outcome decision making if there is a clinical indication to retain the compared with patients who receive inappropriate central venous access. The line should ideally be removed treatment at the onset. at the earliest opportunity. CME The rationale behind the antibiotic choice here will be You should then organise an echocardiogram as hospital- dependent on the likelihood of the organism being MRSA, acquired S. aureus infections lead to endocarditis in 13% of the severity of the infection (i.e. the likely consequences if cases. In some centres all patients with SAB undergo not optimally treated), the patient co-morbidity, and age. TOE, but others recommend that a normal TTE in a A risk assessment must be made, balancing the benefits patient with low pre-test probability is sufficient. In one against the risk that using a broader spectrum agent may study, 31·7% of TOE examinations in patients with SAB foster future resistance. had confirmed endocarditis but this group was highly selected by physician referral. The same study found that The choice in this patient, on balance, is vancomycin, MRSA was less likely to be associated with endocarditis although some argue that high-dose flucloxacillin for 24 than sensitive strains. hours, before identification of the species and antimicrobial susceptibility, may also be a reasonable If the echocardiogram is negative, other potential sources strategy. Antibiotic choice should ideally be in discussion of ongoing bacteraemia must be considered. In this with microbiology or infectious diseases and based on patient, sternal osteomyelitis may be suggested by the local policy or guidelines. tenderness on deep palpation. Staphylococcus aureus is the causative organism in 50–70% of osteomyelitis. His SHOULD I CONSIDER ADDING ANOTHER previous sternotomy and the presence of surgical wires ANTIBIOTIC? increase his risk of osteomyelitis. Plain X-ray changes can The rationale for combining either rifampicin or take several weeks to develop and more sensitive imaging, gentamicin with either flucloxacillin or vancomycin is i.e. bone scan, CT, or MRI, should be carried out at this based around bacterial synergy, excellent tissue and stage. Another potential site of infection in this patient is biofilm penetration in the case for rifampicin, and the his prosthetic hip joint, i.e. septic arthritis, either as the potential for more rapid clearance of bacteraemia. source of bacteraemia or as a result of haematogenous Despite this, addition of either drug has never been spread from another site. This is not likely as the patient shown to improve outcomes in MSSA or MRSA has no localising signs. The diagnosis of septic arthritis is bacteraemia. However, they are often used or confirmed by MRI scanning or examination of synovial

TABLE 4 Summary of treatment recommendations for examination should be undertaken at least daily. staphylococcal endocarditis.3 Laboratory markers of inflammation, i.e. white cell count Methicillin Flucloxacillin (2 g, 4–6 hourly IV) and CRP, are particularly useful in monitoring longer sensitive term response to treatment. Methicillin Vancomycin (1 g, 12 hourly IV)* HOW SHALL I PROGRESS? resistant plus Rifampicin (300–600 mg, 12 hourly by mouth)† The TTE is negative but the TOE confirms tricuspid or endocarditis. Gentamicin (1 mg/kg body weight, 8 hourly)*† or Sodium fusidate (500 mg, 8 hourly by mouth)† Staphylococcus aureus endocarditis Infective endocarditis was an invariably fatal infection Endocarditis Flucloxacillin (2 g, 4–6 hourly IV) before the availability of antimicrobials. Even after the in presence of or intracardiac vancomycin (1 g, 12 hourly IV)* introduction of antibiotic therapy and valve replacement, prosthesis plus the reported early mortality rate of IE remains high Rifampicin (300–600 mg, 12 hrly by mouth) † (16–31%), and the mortality rate after five to ten years’ and/or follow-up ranges from 25–50%. Among cases of IE caused Gentamicin (1 mg/kg body weight, 8 hourly)*† by the most frequent micro-organisms, IE caused by S. and/or aureus carries the worst prognosis and has a high Sodium fusidate (500 mg, 8 hourly by mouth)† prevalence of embolic episodes and neurological involvement. Infection caused by MRSA is increasing. * Dose modified according to renal function. MRSA acts as a significant cause of IE internationally, † According to sensitivity. accounting for almost 40% of the IE caused by S. aureus in recommended by infection specialists (see BSAC certain regions. Endocarditis was associated with guidelines). rheumatic heart disease but is now more commonly associated with IV drug use and vascular catheters. SHOULD I CONSIDER LINEZOLID HERE? However, it is important to note that approximately 20% of patients with MRSA IE developed their infection in the Linezolid is a novel synthetic antibiotic. It is the first absence of identifiable healthcare contact. It should be in CME oxazolidinone and has good oral bioavailability and activity the differential diagnosis of any hospital-acquired pyrexia against methicillin- and glycopeptide-resistant strains of S. and must be looked for in all cases of SAB. aureus. It is currently only indicated for severe pneumonia and complicated skin and soft tissue infections under The S. aureus organism carries particular adhesin expert supervision. There has not been enough clinical molecules that attach to inflamed endothelial cells, experience to recommend linezolid as first-line therapy in which accounts for the development of vegetations on the context of bacteraemia. Indications for considering structurally normal heart valves. The bacteria can linezolid include intolerance or allergy to glycopeptides, either internalise and persist locally, protected from lack of IV access, renal impairment, and lack of response antibiotic therapy and host defences, or lyse the on first-line therapy or specific resistance patterns. endothelial cells, causing local tissue destruction and distant emboli. This helps explain the potential for S. HOW LONG SHOULD I CONTINUE AND HOW aureus endocarditis to present either acutely or with a SHOULD I MONITOR RESPONSE TO more indolent presentation. TREATMENT? Antimicrobial sensitivity of the organism is often only The blood culture the following day is confirmed as available 24 hours after the first positive culture. New MRSA,susceptible to vancomycin,rifampicin and linezolid. techniques to detect bacteria, including the specific strain, using PCR are being developed. The proposed method In uncomplicated MRSA bacteraemia, i.e. with no focus of would allow identification and typing of S. aureus from deep-seated infection, IV vancomycin for a minimum of blood within 1·5 hours allowing more rapid initiation of ten days is recommended. In your patient you suspect appropriate therapy. endocarditis so should augment the vancomycin therapy, as outlined below, while awaiting confirmatory imaging. Patient assessment The patient should be assessed for complications of To monitor the response to treatment, the patient endocarditis, particularly septic emboli and cardiac failure. should be assessed frequently for clinical signs of sepsis In your patient, with tricuspid endocarditis, the with regular heart rate, respiratory rate, temperature, development of cavitating pulmonary infection is the and blood pressure recordings. Clinical systems primary concern, and chest X-ray examination is

mandatory. Fulminant cardiac failure (less likely in right- Eradication is not guaranteed and repeat swabs are sided endocarditis) is an indication for early operative indicated. Advice can be obtained from your hospital intervention despite the associated high mortality rate. infection control team. All cases should be discussed with a cardiothoracic surgeon. Ongoing pyrexia, other signs of sepsis, and WHAT IS THE EPIDEMIOLOGY OF HOSPITAL- persistently raised inflammatory markers are indicative of ACQUIRED (NOSOCOMIAL) STAPHYLOCOCCUS treatment failure. AUREUS BACTERAEMIA?

Antibiotic therapy Staphylococcus aureus is a leading cause of community- and Traditionally, gentamicin is recommended in addition to healthcare-associated infection. Infection is considered to flucloxacillin in MSSA endocarditis for the first 3–5 days. be community-acquired if it occurs within 48 hours of This is due to demonstrated synergistic effects in admission, and hospital-acquired from 48 hours post- laboratory testing and some clinical evidence that it admission. Rates of invasive infection, i.e. bacteraemia, reduces the burden of vegetations when used early. have increased markedly in the last 20 years and, despite However, the BSAC published guidelines for the recent advances in antibiotic therapy, the mortality management of endocarditis in 2004 that recommended associated with bacteraemia remains high at 19–34%. against the use of gentamicin (see Table 4). Around 30% of healthy adults carry S. aureus in the anterior nares and they are three times more likely to In your patient with MRSA endocarditis of a native valve, have a nosocomial bacteraemia than non-carriers. the recommended therapy is vancomycin (1 g IV every 12 However, the mortality of S. aureus infection is less in hours) plus rifampicin (300–600 mg by mouth every 12 carriers. Risk factors for invasive infection include the hours) or gentamicin (1 mg/kg every eight hours) or presence of vascular or urinary catheters. There is a sodium fusidate (500 mg by mouth every eight hours). considerable burden on healthcare resources associated Exact choice of regime will depend on the sensitivity of with S. aureus infection, with affected patients having a the particular strain of MRSA so will be guided by three times longer length of inpatient stay, a three times microbiological and/or infectious diseases advice. increase in cost of stay, and five times the mortality on Rifampicin is particularly useful in prosthetic valve average compared with other patients. infections due to its property of increased activity against bacteria attached to foreign material and against Infection with MRSA is associated with an attributable intracellular bacteria. It is therefore often recommended excess mortality compared with sensitive strains and is as an adjunct in S. aureus bone and joint infection, now responsible for approximately 40% of S. aureus CME particularly involving a prosthesis. bacteraemias. The rate of MRSA infection in hospitals has increased from 2·1% in 1975 to 35% (and up to 70% in Treatment is IV for an absolute minimum of four weeks some centres) by 1991. Although MRSA infection was for native valve endocarditis and six weeks for prosthetic considered to be exclusively hospital-acquired, increasing valves. A shorter duration of therapy has been successful rates of community-acquired infections are being in several trials in right-sided endocarditis in IV drug detected and studied to determine their true origin users. Intravenous access is a problem in these patients (hospital or community). A recent cohort study in but early switch to oral can only be advocated in the Oxford found that 91% of admissions with MRSA absence of complications. There is increasing availability bacteraemia and 77% of those with MSSA bacteraemia of outpatient IV antibiotic services in the UK which allows had previous recorded hospital contact.8 There are, flexibility of care once the patient is over the most acute however, increasing isolates of community-acquired phase of the illness. Attempts to shorten the duration of MRSA, particularly in the US, with different resistance treatment often results in a relapse of infection and a patterns to hospital strains, that are predicted to increase poorer outcome, except in the specific case of right-sided in prevalence. Although community-acquired MRSA endocarditis in IV drug users. infections have emerged as a significant public health problem, it is difficult to determine what effect these What infection control issues should I consider? infections will have on the incidence of MRSA infections Your patient has previously had a positive screen for among hospitalised patients. MRSA and now has invasive infection. A repeat set of screening swabs should be taken involving the nose, KEYPOINTS throat, perineum, and any wound, e.g. central-line site, in this patient. Universal Infection Control precaution • Staphylococcus aureus bacteraemia is associated with should apply and eradication of colonisation should be significant mortality and economic healthcare burden. attempted. This will not usually be achieved by systemic • Underlying patient factors are important in antibiotic therapy. A suitable eradication regime is topical determining the likelihood of complicated infection nasal mupirocin three times daily for five days, and and/or infection with MRSA. chlorhexidine or triclosan body wash for two weeks. • Endocarditis is the most common and important

complication of SAB. • Antibiotic therapy is guided by culture results, national • Appropriate antibiotic choice and duration of guidelines, local policy, and specialist advice. treatment improves outcomes.

REFERENCES 54(6):971–81. 4 Fowler VG Jr, Olsen MK, Corey GR et al. Clinical identifiers of 1 Gemmell CG, Edwards DI, Fraise AP, Gould FK, Ridgway GL, complicated Staphylococcus aureus bacteremia. Arch Intern Med Warren RE, for the BSAC/HIS/ICNA MRSA Working Party. 2003; 163(17):2066–72. Guidelines for the prophylaxis and treatment of meticillin (methicillin)- 5 Jensen AG, Wachmann CH, Poulsen KB et al. Risk factors for resistant Staphylococcus aureus (MRSA) infections in the United hospital-acquired Staphylococcus aureus bacteremia. Arch Intern Kingdom: draft for consultation. BSAC 2005. Med 1999; 159(13):1437–44. 2 Coia JE, Duckworth G, Edwards DI et al., for the Joint Working 6 Khatib R, Riederer K, Saeed S et al. Time to positivity in Party of the British Society of Antimicrobial Chemotherapy, the Staphylococcus aureus bacteremia: possible correlation with the Hospital Infection Society, and the Infection Control Nurses. source and outcome of infection. Clin Infect Dis 2005; Association Guidelines for the control and prevention of meticillin- 41(5):594–8. resistant Staphylococcus aureus (MRSA) in hospitals: draft for 7 Lodise TP Jr, McKinnon PS, Rybak M. Prediction model to identify consultation. BSAC 2005. patients with Staphylococcus aureus bacteremia at risk for 3 Elliott TS, Foweraker J, Gould FK, Perry JD, Sandoe JA; Working methicillin resistance. Infect Control Hosp Epidemiol 2003; Party of the British Society for Antimicrobial Chemotherapy. 24(9):655–61. Guidelines for the antibiotic treatment of endocarditis in adults: 8 Wyllie DH, Peto TEA,Crook D. MRSA bacteraemia in patients on report of the Working Party of the British Society for arrival in hospital: a cohort study in Oxfordshire 1997–2003. BMJ Antimicrobial Chemotherapy. J Antimicrob Chemother 2004; 2005; 331:992–5.

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