1. Occult Bacteremia in Infants Current controversies and future developments Denise Watt Dec. 6, 2001

2. Outline background and epidemiology management algorithms evidence for Abx –oral vs. parenteral antibiotic resistance pneumococcal conjugate vaccine

3. Case 10 month old girl, previously well URI symptoms x 10 days –drinking well, wetting diapers, no N/V/D 2hr hx fever, lethargy, irritability O/E: 180, 42, T39.2, 95% –looks unwell, moaning/crying, HEENT normal, clear BS, some indrawing, CVS normal, abd benign, no rash

4. Occult Bacteremia: definitions FWS: rectal temp  38  C, no focus, no obvious virus, ‘non-toxic’, no significant underlying illness/immunocompromise OB: FWS and +ve BC 10-20% PED visits for febrile illness 20% febrile children <3yr: no source

5. Epidemiology: pre-HIB prior to early 1990’s OB incidence 3-12% of FWS –60-85% S.pneumo –5-20% HIB 40% complication rate

6. Epidemiology: post-HIB incidence of OB (FWS, 3-36 mos, T  39°C) –1.6-2.8%, highest age 1-2 yr (Kupperman 1998, Lee 1998) –90-95% S.pneumo –96%  invasive HIB <5 yr (Alpern 2000) –5% non-typhoid Salmonella –others: Neisseria, GAS, GBS, Moraxella, E.coli, S. aureus

7. Implications of OB 10% SBI if untreated, 17% persistent bacteremia (Harper, Baraff) meningitis: 1% (Baraff), 2.7% (Rothrock) –7.7% mort, 25-30% neuro sequelae overall risk of meningitis in untreated FWS = 0.02-0.05% natural course of OPB? –96% resolve without Abx (Alpern 2000)

8. Occult Bacteremia: Subsequent development of focus Dashefsky, J Pediatr 1983., Shapiro, J Pediatr 1986., Woods, AJDC 1990., Baraff, Pediatr Infect Dis J 1992.

9. Local Microbiology S. pneumo bacteremia rates vary widely across Canada –related to rates of BC drawn –rate in Calgary unknown 30 OPB/yr, 10 SBI/yr, 4-5 meningitis/yr 20 cases invasive HIB/yr (most adults) 139 +BC last year age 1-15 (all comers) –27% contaminants

10. Predicting OB Hx and PE unreliable –may appear well –subjective vs. objective ‘toxicity’ –YOS >10: sensitivity 77%, specificity 88% –age –fever OPB rare if temp 40 –similar response to defervescence ± OB (Baker 1989, Bonadio 1993)

11. Predicting OB lab tests insensitive –U/A: most common occult bacterial infection (2% febrile <5yr) –WBC >15x10 9 : sens 67-80%, spec 69% –ANC best predictor (Kuppermann 1998) >10x10 9 : sens 76%, spec 78% –band count unhelpful –one poke most practical (CBC + hold BC)

12. Blood Cultures 12% +ves return for F/U before BC result, 50% called back (Joffe 1992) –time to +ve = 36hr, time to F/U = 43hr –most pathogens +ve < 18hr  F/U more important than BC 76% SBI or PB called back (Bachur 2000)  BC allow earlier F/U and Rx faster lab techniques coming?

13. Approach to FWS 3 yr treated differently <1980s, all pt <3mos admitted for septic W/U and empiric Abx low risk criteria developed to avoid hospital admission

14. Low-risk criteria Rochester criteria 1985 (<2 mos) –NPV 98.9%, PPV 12% Boston criteria 1992 (<3 mos) –NPV 95% Philadelphia criteria 1993 (1-2 mos) –NPV 99.7%, PPV 14%

15. Baraff “expert consensus” (Pediatrics 1993) –1-3 mos, ‘low risk’ option 1: septic W/U and Abx option 2: urine C&S and observe –3-36 mos, non-toxic: septic W/U if T>39.0 update (Annals Emerg Med 2000) –3-36 mos T  39.0: U/A; T  39.5: WBC  BC (send if >15) –if empiric Abx, do LP!

16. Bachur 2001 Recursive partitioning model –U/A first step –WBC 20 –T > 39.6 –age < 13d 82% sensitive admit 28% (vs. 53% with Rochester)

17. Cost-Effectiveness of FWS strategies 1990’s: BC and empiric Abx for all Lee (Pediatrics 2001) –FWS, age 3-36 mos, OPB (1.5%) –meningitis 1° outcome incl. health care and societal costs –CE: CBC + selective BC + Rx if WBC  15 –$30,800 / life-year saved –if rate OPB , less aggressive aproach

18. Why guidelines need re-evaluation controversy among ‘experts’ lower incidence of OB elimination of HIB cost and complications of tests and Rx pen-resistant S. pneumo not followed anyway (Finklestein 2000) vaccine…..

19. Antibiotics and FWS Only 2 prospective RCTs with placebo –both small, pre-HIB –Jaffe 1987: no change in SBI Abx  fever, improved appearance large, retrospective study (Harpur 1995) –more focal infection, admissions w/o Abx Abx and meningitis (meta-analysis Baraff) –no Abx 5.8%; oral or parenteral Abx 0.4%

20. Rothrock 1997: Meta-analysis not all RCTs, underpowered no significant  meningitis significant  SBI (OR 0.35 p=0.003) NNT to prevent 1 meningitis = 651 NNT to prevent 1 SBI = 2190 NNH with Abx for every meningitis prevented = 567  no prospective studies post-HIB

21. Oral vs. Parenteral Antibiotics Fleisher (1994) –no sign difference in focal infections –  persistent fever with Ctx –not blinded, not intention-to-treat, pre-HIB Rothrock (1997); meta-analysis –meningitis OR=0.67 (oral vs. parenteral) –SBI OR=1.48 closer F/U with parenteral

22. Risks of Empiric Antibiotics cost (tests, Rx, F/U, hospitalization) side effects discomfort of tests, treatment altered presentation (Rothrock 1992) development of resistant strains missed/partially Rx focal infections parental preference? –will accept small risk of SBI vs. discomfort of tests & Rx (Kramer, Oppenheim)

23. Penicillin-resistant Pneumococcus Castillo –San Diego 1991-8: 18% pen resistance –14% int. resistance 1991, 42% in 1998 –no difference in mortality –NS increased resistance with prior Abx use

24. Pen and Cephalosporin resistance Silverstein –11 year review: 8% resistance –no diff in outcome, LOS in pen-resistant –Ceftriaxone-resistant: more focal infection, more LPs, more febrile at F/U, more admitted (NS),  HR and temp at presentation

25. Antibiotic resistant Pneumococcus in Calgary 15% pen resistance <2% amoxicillin resistance 10% Cefuroxime resistance 3-4% Ceftriaxone resistance –need higher MIC for CNS  clinically, has not been an issue

26. Conjugate Pneumococcal Vaccine heptavalent, 4 doses: 2,4,6,12-15 mos FDA approval Feb 2000 (Prevnar) 3 RCTs of safety and immunogenicity –Rennels (1998) –Shinefield (1999) –Black (2000) efficacy 97%, intention-to-treat 94% including ALL S.pneumo serotypes: 89% similar SE as DPTP/HIB, none severe

27. Pneumococcal Vaccine significantly  OM Black: ongoing trial on herd immunity long-term efficacy? strain selection? Bottom line: will significantly decrease burden of S.pneumo disease likely lag time to change practices

28. Impact Of Prevnar in N. California ~33,000 with ≥1 dose Feb 2000-Mar 2001 Shinefield et al. 3rd Int’l PID Conference Monterey, 2001

29. Pneumococcal Vaccine: Cost Effectiveness Lieu (JAMA 2000) –cost < savings if each dose <$46 (US) –present: $56 (US) = $278,000/life-yr saved –>2x savings for society vs. health payer  $760 million/3.8M infants/yr in US most from parental work loss,  productivity Calgary: $110/dose ($84 at ACH) current immunization budget: $17M/yr cost of SP vaccine: $13M/yr

30. Occult Bacteremia: Summary age, temp, appearance important don’t forget U/A save labs for ‘unwell’ faster BC techniques in distant future F/U most important tool empiric Abx have very limited role no clear evidence favouring parenteral

31. Occult Bacteremia: Summary II antibiotic-resistance is rising; impact small in Calgary vaccine WILL change the face of FWS –‘It’s viral!’ until then, the controversy continues! –“Are you a risk-minimizer or test- minimizer?” (Green, Rothrock. Annals Emerg Med. 1999)

32. Case revisited WBC 14.9 –ANC 8.3 BC +ve S.pneumo in 24hr (pen I) R/A: looks well, T 38.5 Mgt?

33. Case cont. Ceftriaxone IV F/U ID clinic: –well-looking –Ctx IV x 3 days, then Amoxil x 7 days

34. QUESTIONS ?