Staphylococcus aureus bacteremia Sumathi Nambiar MD MPH Medical Team Leader Division of Anti-Infective Drug Products US Food and Drug Administration

2 “Micrococcus, which when limited in its extent and activity, causes acute suppurative inflammation, produces, when more extensive and intense in its action on the human system, the most virulent forms of septicaemia and pyaemia” Ogston A. Micrococcus poisoning. J Anat 1882;17:24-58.

3 Epidemiology S.aureus is an important cause of bacteremia in both US and non-US hospitals. SCOPE project: : Second most common bloodstream isolate; 16% of hospital-acquired (HA) bacteremias. * : 9% of HA bacteremias in pediatric patients. ¶ 7-year study from a single institution in Switzerland; 14% of all bacteremias. § Incidence of S.aureus community-acquired (CA) bacteremia in Connecticut was 17/100, 000 persons. † * Edmond MB et al. CID 1999;29: ¶ Wisplinghoff H et al. PIDJ 2003;22: § Lautenschlager S et al. CID 1993;16: † Morin CA et al. JID 2001;184:

4 Epidemiology Increasing incidence of S.aureus bacteremia (SAB) paralleled by increase in incidence of S.aureus infective endocarditis (IE) % of native valve endocarditis caused by S.aureus. 329 patients with IE at a tertiary care facility from : 132/329 (40%) due to S.aureus. Frequency of S.aureus IE increased from 3/30 (10%) in 1993 to 26/38 (68%) in Cabell CH et al. Arch Intern Med 2002;162:90-94

5 What makes SAB different Wide spectrum of clinical manifestations. Complications are common and often difficult to identify or predict. Difficult to standardize extent of diagnostic procedures. Overlap with infective endocarditis; often difficult to differentiate clinically. Mortality remains high. Treatment issues Resistance Optimum length of therapy

6 Risk factors for SAB Intravascular catheters Hemodialysis Intravenous drug use Underlying illnesses Diabetes mellitus Immunosuppression

7 Classification of SAB Community vs. Hospital acquired Primary vs. Secondary Complicated vs. Uncomplicated

8 Source of SAB Frequency of identification of a primary focus for SAB varies among studies. depends upon type of investigations done presence or absence of an intravascular catheter population of IVDU versus non-IVDU. Community vs. hospital acquired On an average no focus is identified in about 20% of cases.

9 Jensen AG. Journal Hospital Infection 2002;52:29-36

10 Community vs. Hospital acquired Retrospective study of 105 cases with SAB; two distinct populations described: Group 1 (n=63)Group 2 (n=42) Apparent primary focusNo apparent primary focus Hospital-acquired diseaseCommunity-acquired disease OlderYounger Significant underlying illnesses IVDU Secondary foci less likely 2 had IE Secondary foci more likely 24 had IE Nolan CM, Beaty HN. Am J Med 1976; 60:

11 Community-acquired SAB Patients with CA-SAB are more likely to have Unknown portal of entry Metastatic disease Poorer prognosis Frequency of CA-SAB differs between studies. Positive culture within 48 hours; some have used hours. 48h cut off: 131/278 (47%) CA-SAB. † Prior contact with healthcare system. 120/192 (62%) patients with CA-SAB had prior healthcare contact. ¶ †Jensen AG et al. Arch Intern Med 2002;162:25-32 ¶ Morin CA et al. JID 2001;184:

12 Complicated vs. Uncomplicated SAB Definitions of complicated SAB: Focus of infection not identified/non-removable. Metastasis, deep-seated infections or complications. Attributable mortality, infection extension or metastasis, embolic stroke, or recurrent S.aureus infection ‡ : Risk factors for complicated SAB: Positive blood culture at hours Community acquisition Skin findings suggesting acute systemic infection Persistent fever at 72 hours ‡ Fowler et al. Arch Intern Med 2003;163:

13 SAB and Catheters Hospital and CA-SAB increasingly associated with intravascular catheters. Catheter usually considered the focus: No evidence of alternate source and Evidence of inflammation/infection at the catheter insertion site or Catheter tip culture positive for S.aureus In the absence of catheter microbiologic criteria, often a diagnosis of exclusion.

14 SAB and Catheters SAB from and compared ‡ : : 25% of HA-SAB were intravascular device-related. No documented catheter-related CA-SAB : 56% of HA-SAB and 22% of CA-SAB associated with intravascular devices :Intravenous catheter was focus in 363/724 (50%) patients with SAB ¶. ‡ Steinberg et al. CID1996;23:255-9 ¶Fowler et al. Arch Intern Med 2003;163:

15 SAB and Infective Endocarditis Incidence of IE in SAB patients varies from 6-64%; depends on population and extent of evaluation. Predicted by clinical characteristics: Community-acquired disease Absence of a primary focus of infection Evidence of metastatic disease IE can occur in patients with HA-SAB, presence of primary focus, and in non IVDU. Of 59 patients with S.aureus IE, 46% had HA-SAB. † 76 non-IVDU SAB patients : 59 had portal of entry, 13/59 (22%) had IE. ¶ † Fowler et al. CID 1999;28: ¶ Miriamanoff et al. Arch Intern Med 1982;142:

16 SAB and Infective Endocarditis IE is often missed based on clinical findings only. A 10-year study from Denmark found that IE was missed clinically in over half of the 152 pathologically confirmed IE due to S.aureus. ‡ Among 103 patients with SAB, 26 had IE ¶ : Clinical evidence was seen in only 7 patients; five had peripheral emboli and two had new murmurs. TEE identified vegetations in 22 patients, abscess in 2, perforation and new regurgitation in one each. ‡Røder et al. Arch Intern Med 1999;159: ¶Fowler et al. JACC 1997;30:1072-8

17 Risk factors for S.aureus IE Native valve disease Rheumatic heart disease Structural abnormalities such as mitral valve prolapse, bicuspid aortic valve Degenerative disease such as aortic valve sclerosis Congenital heart disease Prosthetic valve Intravenous drug use History of prior IE Community acquisition

18 Metastatic Disease Frequency of metastatic complications varies. Retrospective study of 281 patients with SAB † : 27% developed metastasis. Joints (36%), kidneys (29%), CNS (28%), skin (16%), and intervertebral disc (15%). 50% had more than one metastatic site. 4-year prospective study of 68 patients with SAB ¶ : 53% had metastatic foci. Comprehensive diagnostic monitoring including x- ray, echocardiography, bone/leukocyte scintigraphy. † Lautenschlager S et al. CID 1993;16: ¶ Ringberg H et al. Infection 2000;28:132-6

19 Metastatic Disease: Risk factors Community-acquired bacteremia Primary SAB Underlying cardiac valvular disease Presence of prosthetic devices Persistent bacteremia Of 104 patients with SAB, metastasis developed in 59% with positive blood culture > 24 hours after starting effective therapy versus 17% in those without sustained bacteremia. Lesens O et al. J Infect 2004;48:245-52

20 Metastatic Disease Time to development of metastases: 207 patients with left-sided IE † : Rate of embolic events decreased from 13/1000 patient days during the 1st week of therapy to less than 1.2/ 1000 patient days after completion of the second week of therapy. 39 patients with SAB ¶ : 9 developed metastatic complications; 8 after the first week of positive blood culture. †Steckelberg JM et al. Annals of Intern Med 1991;114: ¶ Libman H et al. Arch Intern Med 1984;144: 541-5

21 Length of therapy Depends on extent of disease and host risk factors. Complicated infections such as IE, deep tissue abscesses often need 4-6 weeks of therapy. Appropriate length of therapy for patients with uncomplicated disease still unclear. Some propose 14 days of therapy. Others propose longer duration based on higher complication rates seen with shorter therapy.

22 Outcomes Acute systemic complications: ARDS, DIC, and septic shock usually occur within 48 hours. Mortality 1930’s – 40’s: 71% - 82% 1980’s ’s: 16% - 34% Risk factors: Severity of illness at onset of SAB, unknown source, older age, non-eradicable foci. Recurrence develops in 12-15% Persistent bacteremia Retained intravascular device Non- eradicable foci

23 Challenges with SAB Clinical characteristics Community-acquired vs. hospital acquired Presence or absence of an apparent primary focus Overlap with IE Need for echocardiographic evaluation Metastatic disease Extent of diagnostic procedures, lack of drug effect Role of intravascular catheters Diagnosis of exclusion or laboratory criteria Treatment Need to initiate empiric therapy Choice of initial therapy Short versus long course therapy