Management of the Febrile Infant Risk Minimizers vs. Test Minimizers Steven E. Krug, M.D. SAEM Annual Meeting St. Louis, MO -- May, 2002.

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Management of the Febrile Infant Risk Minimizers vs. Test Minimizers Steven E. Krug, M.D. SAEM Annual Meeting St. Louis, MO -- May, 2002

Fever, What’s The Big Deal ? l 65% of children 0-2 years visit a physician for a febrile illness F 10 to 20% of all pediatric visits to EDs F 20 to 30% of pediatric office visits l Fever without a source accounts for as many as 50% of these visits l A self limited illness in the vast majority l A small percentage will have a SBI

Occult Bacteremia in Febrile Children How It All Began McGowan JE, et al: NEJM 1973; 288:1309 l Febrile children at Boston City Hospital F “24 hour pediatric walk-in clinic” l Temp > C -- all ages - 3 month study l Results: F 10,535 visits   2165 children with fever F 708 blood cultures  31 (4.4%) true positives Note: 43 cultures (6.1%) produced false positives

So, Are You a Risk-Minimizer ? Green SM, Rothrock SG: Ann Emerg Med 1999; 33:211 l Desire to lower the risk of adverse sequelae from occult infections - “ROWS” l Do not believe that clinical evaluation is sufficient to reliably identify ill children l Use risk stratification to target higher risk patient groups for intervention l Believe that the potential benefit of reducing adverse sequelae justifies empiric diagnostic testing and treatment

If Not, Perhaps a Test-Minimizer ? Green SM, Rothrock SG: Ann Emerg Med 1999; 33:211 l Believe the occurrence of adverse outcomes is so low as to not justify time, expense and invasiveness of risk stratification l Believe that clinical evaluation and follow up will serve to identify nearly all ill children l Believe that parents prefer less testing and treatment l Are willing to accept a greater chance of being wrong

Well Intentioned Risk Minimizers at Work Can We Identify High Risk Children ? l Demographic and clinical parameters F age, temperature, petechiae l Lab screening profiles F CBC, ESR, CRP, UA, etc. F OB/SBI risk appears to correlate with some F sensitivity, specificity and positive predictive value for OB and SBI were less than ideal l Clinical scoring systems (McCarthy, et al.) F initially very promising, ultimately disappointing

Identification of High Risk Patients Sensitivity of the Physical Exam l McCarthy, et al. Pediatrics 1982; 70:802 F Yale Observation Score (AIOS) F incidence of SBI related to score v 10 = 40.2%, > 16 = 92.3% F sensitivity 88%, specificity 77%, low PPV F negative predictive value of normal Hx & PE findings plus low AIOS was 96% AIOS was fairly good in its ability to identify the sick, but perhaps even better in identifying the well ?

Failure of Clinical Assessment Teach SJ, Fleisher GR: J Pediatr 1995; 126:877 l Prospective application of the Yale Obs. Scale F children months with T > C F 611 children in study, 192 with bacteremia F median YOS (6) was the same for both groups F YOS > 10: v sensitivity 5.2%; specificity 96.7%, v positive predictive value 4.5%, v negative predictive value 97.1% The YOS has performed similarly in other recent studies

Social Smile & SBI  Bass JW, et al: Pediatr Infect Dis J 1996; 15:541 l Do smiling febrile children have bacteremia? F 512 children aged 3 to 36 months of age F T > C and WBC > 15,000 F social smile associated with shorter fever duration F smile present in 45% of bacteremic children F smile present in 49% of non-bacteremic pts. F no demographic or laboratory differences found between the groups Yikes !! - So, is that a smile, or is it a grimace ?

Lessons Learned From the Search for OB/SBI Risk Factors for OB/SBI l Age: neonates, days, 3-36 months l Fever: OB risk increases with temperature F hyperpyrexia (T > C) - 8 to 25% OB l Petechiae - 15 to 20% occurrence of SBI l Immunodeficiency - e.g. HIV, SCD l WBC > 15,000; Bands > 1000 F 5 fold increased risk for occult bacteremia l Ill patient or toxic appearence The big question -- Are all of these still true ??

Identification of Low Risk Patients Physical & Laboratory Screening Profiles l Rochester Criteria Dagan et al: J Pediatr 1985; 107:855 F T > 38 0 C, term, well appearing, secure follow-up F peripheral WBC between 5-15,000/mm 3 F band count < 1500 /mm 3 F urinalysis with < 10 WBC/hpf F no evidence of ear, soft tissue or bone infection l Performance: 233 infants 0-2 months of age F 1 of 144 (0.7%) low risk infants had SBI F 22 of 89 (25%) high risk infants had SBI

Identification of Low Risk Patients Dagan R, et al: J Pediatr 1988; 112:355 l Modified Rochester Criteria F added diarrhea to criteria: v if present < 25 WBC/hpf on stool smear l Performance F 237 infants 0-2 months of age F 0 of 148 low risk infants had SBI F 21 of 88 (24%) high risk infants had SBI So, perhaps we can identify the low risk children !

Identification of Low Risk Patients Baker MD, et al: NEJM 1993; 329:1437 l CHOP Low Risk Criteria F T > C, well appearing, low IOS F WBC < 15,000 /mm 3 ; BNR < 0.2 F urinalysis with < 10 WBC/hpf F CSF with < 8 WBC/mm 3 & (-) gram stain F negative chest x-ray l Performance: 747 patients aged days F 64/65 patients with SBI noted as high risk F 1/287 assigned to low risk had SBI F OPD assignment saved $ 3,100/patient

CHOP Low Risk Protocol: More Data Baker MD, et al: Pediatrics 1999; 103:627 l Three year study ( ) at CHOP l Infants 29 to 60 days of age with T > C F 422 infants F 43 (10%) with SBI v UTI (4%); OB (2.1%); BM (1.2%); BGE (1.2%); cellulitis (1.2%) F 101 (24%) identified as low risk v no SBI in the low risk infants Note: Over 8 years this protocol has shown a nearly perfect 100% negative predictive value for >1200 infants

Are Febrile Neonates Different Baker M, Bell L: Arch Pediatr Adol Med 1999; 153:508 l Can laboratory screening profiles reliably identify febrile neonates with low risk for SBI ? F applied CHOP protocol to 254 infants ( days) F 43% of infants qualified for OPD management F 32 infants (12.6%) with SBI v 17 UTI (6.7%); 8 OB (3.1%); 4 BM (1.6%), BGE (.8%) F 5 “low risk” infants had serious infections v would miss 20 infants with SBI per 1,000 Yes, febrile neonates are indeed different

Identification of Low Risk Patients Baskin M, et al: J Pediatrics 1992; 120:22 l The BCH Low Risk Criteria F T > 38 0 C, low IOS, presence of secure follow-up F peripheral WBC < 20,000/mm 3 F CSF WBC < 10/mm 3 F urinalysis dip with (-) leukocyte esterase F all patients treated with ceftriaxone l Performance: 503 patients aged days F 27 of 503 (5.4%) who met the criteria had SBI v 9 OB (1.8%), 8 UTI (1.6%), 10 BGE (2.0%) F all were treated and were well at follow-up

Components of Fever Protocols Avner J, Baker MD: EMCNA 2002; 20:49

Empiric Antibiotic Therapy Does it Work? Carroll WD, et al: Pediatrics 1983; 72:608 l Small study (10 patients) - PCN vs. placebo l Difference between groups was not great Jaffe DM, et al: NEJM 1987; 317:1175 l Large multi-center study - amoxicillin vs. placebo l Enrolled 955 children 3-36 months with T > C l 27 (2.8%) with bacteremia -- small number of cases l Outcome differences between groups were not great

Empiric Antibiotic Therapy Does it Work? Bass JW, et al: Pediatr Infect Dis J 1993; 12:466 l Prospective study - augmentin vs. ceftriaxone F 519 children aged 3-36 months (11.6%) with OB F T > C - or - T > C and WBC > 15 K l Both Rx regimens appeared to be adequate Fleisher GR, et al: J Pediatr 1994; 124:504 l Multi-center study - ceftriaxone vs. amoxicillin F 6733 patients (2.9 %) with bacteremia l “...ceftriaxone eradicated bacteremia, had fewer focal complications, and less persistent fever…”

Is There a Cost Effective Strategy? Lieu TA, et al: Pediatrics 1992; 89:1135 l Decision analysis, cost-effectiveness model F 6 strategies for management of febrile infants F 28 to 90 days with Temp > C F used data from literature (e.g. Baskin, Baker) l Clinical judgment alone appeared to be the least effective clinical model and the 2nd least cost effective strategy l Full sepsis W/U and outpatient IM ceftriaxone was judged to be the most effective strategy

Practice Guidelines Baraff L, et al*: Ann Emerg Med 1993 & Pediatrics 1993 l Expert consensus panel recommendations l Based on meta-analysis of the literature l Fever is defined as > C for 0-3 months and > C for 3-36 months l Infants at greatest risk during 0-3 months l Rochester criteria selected as screening criteria for high vs. low risk * Note: Panel members confessed risk-minimizers

Consensus Panel Guidelines l Toxic-Appearing Infants and Children F Hospitalize, evaluate and treat for presumed sepsis, meningitis, or SBI F This holds for all age groups F THIS SHOULD BE A NO BRAINER

Consensus Panel Guidelines l Febrile (low risk) Infants < 28 days of age F Despite low probability of sepsis and studies showing favorable outcome for outpatient observation, the panel recommends SBI evaluation and hospital admission for all infants with either parenteral therapy or close observation

Consensus Panel Guidelines l Low-Risk Infants Days of Age F Obtain urine culture and provide close follow-up - OR - F Full sepsis evaluation (blood, urine, CSF) and treat with IM ceftriaxone F All children who receive presumptive therapy should have an LP

Consensus Panel Guidelines l Low-Risk Infants 3-36 Months of Age F Urine culture for males < 6 mo & females < 2 yrs F Stool culture if blood or mucus or > 5 WBC/hpf F Chest x-ray if decreased breath sounds or SOB F Blood culture if T > C and WBC > 15,000 F Empiric therapy if T > C and WBC > 15,000 F No diagnostic tests or antibiotics if T < C

The Febrile Infant Variability in Management Approaches Ros SP, et al. Pediatr Emerg Care 1994; 10:264 l Surveyed members of AAP Section on EM l Numerous fever and age group definitions l 74% routinely screen with a CBC l 45% routinely draw blood cultures F 36% use clinical appearance as basis for culturing l 53% routinely administer antibiotics F 44% use lab criteria as basis for antibiotic Rx Despite published guidelines, no clear standard of care!

What Do Parents Prefer Oppenheim PI, et al: Ann Emerg Med 1994; 24:836 l Interviewed parents regarding management options for febrile infant/child scenarios l Parents successfully identified the strategies associated with a higher probability for an adverse outcome l 71% chose options with less testing and treatment (and greater risk!) So, perhaps parents are test minimizers??

What do Parents Prefer Bennett JE, et al: Arch Pediatr Adol Med 2000; 154:43 l Survey of parent utilities for outcomes of OB F convenience sample, single urban PED F 94 subjects interviewed F provided with 8 possible outcomes F blood drawing viewed to be of minimal risk and concern l Parents were intolerant of adverse outcomes Okay, so maybe parents are risk-minimizers

Parents, Physicians & Antibiotics Bauchner H, et al: Pediatrics 1999; 103:395 l Survey of AAP general pediatricians F 610 responses (67%) F 40% indicated that parents frequently ask for antibiotic when the MD feels it is not needed v 48% stated parents often pressure them to prescribe antibiotic therapy F nearly 1/3 stated they occasionally or frequently comply with that pressure F parental pressure viewed as #1cause of the unnecessary use of antibiotics

Risk Minimizers vs. Test Minimizers - Published guidelines - “ROWS” - Risk of OB sequelae - Parental preferences - Cost of care - Changing Hx of OB/SBI - Risk of testing - Risk of Rx - Parental preferences Attorneys, Payors, and Other Predators “To Test/Treat - or - Not To Test/Treat”

Management of the Febrile Infant What’s Controversial, What’s Changed? l Eradication of Hemophilus influenzae F what is the current risk of OB and SBI F what is the natural history of pneumococcal OB F do the 1993 consensus guidelines make sense l Continuous blood culture monitoring systems l True efficacy of empiric antimicrobial therapy l The febrile infant with a viral infection l OB/SBI risk with hyperpyrexia; petechiae

Disappearance of H. influenzae l Prior to introduction of Hib vaccine (1987) F 10-15% of OB and majority of OB related SBI F 12,000 cases/yr invasive H. flu in children < 5 yrs. v 33-60% develop focal infection, 15-25% develop BM v 12 times more likely than pneumococcus l Currently about 300 cases per year (94/95) F no longer a leading cause of sepsis/meningitis F incidence now greatest in children < 5 months Median age for BM: 1986 = 15 mo.  1995 = 25 yrs.

Risk of Bacteremia in the Post-Hib Era Lee GM: Arch Pediatr Adol Med 1998; 152:624 l Three year study ( ) at BCH* l Children aged months with T > C F 11,911 patients F 75% received CBC, 74% had blood cultures F 149 positive blood cultures (1.6%) v 92% pneumococcal v no H. influenzae isolates!! *Is BCH the center of the risk-minimizer universe ?

Bacteremia in Boston Lee GM: Arch Pediatr Adol Med 1998; 152:624 l Prevalence greatest in month age group l WBC and absolute neutrophil counts were the most accurate predictors for bacteremia F WBC > 15 x {Sens. = 86%, Spec. = 77%} F attributed to higher WBC with pneumococcal OB l OB risk associated with temperature F OR: > 40.0 =1.9; > 40.5 = 2.6; > 41.0 = 3.7 l Lower OB rate not explained by Hib vaccine

Outcome of Pneumococcal Bacteremia Bachur R, Harper MB: Pediatrics 2000; 105:502 l Re-evaluation of children in ED with OPB l Nine year study at BCH ( ) l 548 episodes of OPB F 40 (7%) with PB or new focal infection F 14 PB(2.5%); 8P(1.5%); 8M**(1.5%); 6C(1.0%); 4 PC(0.7%) F patients not initially Rx, and those treated who remained febrile were are greatest risk for PB F majority with OPB can be managed as outpatients ** Three diagnoses/cases of BM were controversial

Persistent Bacteremia/Meningitis in OPB Bachur R, Harper MB: Pediatrics 2000; 105:502

Prevalence/Outcome of Occult Bacteremia Alpern ER, et al: Pediatrics 2000; 106:505 l Three year retrospective study ( ) F 5900 children aged 2-24 months, T > 39.0 l Prevalence of OB = 1.9% F 83% pneumococcal; H. influenzae not isolated l Focal bacterial infections in 17 (0.3%) F pneumonia (8), cellulitis (4), osteo (2), others (3) l Serious adverse outcome in 2 (0.03%) F meningitis (1), sepsis/death (1) Note: 96% OB with spontaneous resolution without Rx

Occult Bacteremia in Philadelphia Alpern ER, et al: Pediatrics 2000; 106:505 l Mean time to culture shorter for true positives F mean times: true (+) = 14.9 hrs; false (+) = 31.1 F < 18 hours 13x more likely to be true pathogen l Nearly all true positives re-evaluated in ED F average time from notification 10.6 (+ 9.7) hrs F 33% were still febrile F 53% admitted to the hospital F 4.8% found to have persistent bacteremia v oral antibiotics Rx at 1st visit did not affect rate of PB Perhaps blood cultures can be an effective screen?

Prevalence/Outcome of False (+) Blood Cultures Alpern ER, et al: Pediatrics 2000; 106:505 l Overall contamination rate was 2.1% l 85% were re-evaluated in ED l 35% were still febrile and were admitted l 1.9% of repeat cultures also contaminated! At least in Philadelphia, the risk of a contaminated blood culture equals or exceeds that of a true positive ! Remember the data from McGowan, 1973?

Prevalence of False (+) Blood Cultures Alpern ER, et al: Pediatrics 2000; 106:505

Use of Antibiotics to Prevent SBI Bulloch B, et al: Acad Emerg Med 1997; 4:679 l Meta-analysis of published RCCT’s F 4 studies: Carroll, Jaffe, Fleisher, Bass l Antibiotic use trended to  risk for SBI F odds ratio = 0.60 (P.O.) & 0.38 (I.M.) F need to treat 414 kids to prevent 1 SBI case F no significant effect of antibiotic therapy l Concluded that widespread antibiotic use should not replace clinical judgement

Outcomes in Occult Bacteremia Bulloch B, et al: Acad Emerg Med 1997; 4:679 Does empiric therapy truly reduce the risk for SBI?

Predictors of Pneumococcal Bacteremia Kuppermann N, et al: Ann Emerg Med 1998; 31:679 l With invasive H. influenzae infections out of the picture, are there unique predictors for OPB l Multivariate analysis - 6,500 children 3-36 months F 164 children (2.5%) with OPB l Three variables retained association with OPB F ANC: OR of 1.15 for each 1,000 cells/mm 3  v if ANC > 10, OPB rate 8.2% F temp: OR of 1.77 for each 1 0 C  F age < 2 years: OR of 2.43 vs. 2-3 years of age

Band Counts in Young Febrile Children Kuppermann N, et al: Arch Pediatr Adol Med 1999; 153:261 l Compared CBC findings in febrile children with a documented SBI (bacteremia or UTI) versus a proven respiratory viral infection l Children with SBI had a greater mean ANC F 11.3 x 10 9 vs 5.9 x 10 9 l No differences in percentage band count or absolute band count between the groups

Identification of Children with UMD Kuppermann N, et al: Pediatrics 1999; 103:e20 l Clinical/hematologic features of children with unsuspected meningococcal disease (UMD) F retrospective, four center study, F 381 children with meningococcal disease F 45 (12%) with UMD [discharged home !!] F compared to 6400 culture negative children v no difference in Temp, WBC, ANC v significantly higher band counts in UMD v predictive value of band count was low (PPV 0.06%) Bad news… There is still no crystal ball for UMD

Febrile Children with Bronchiolitis Kuppermann N: Arch Ped Adoles Med 1997; 151:1207 l Evaluated risks of bacteremia and UTI in febrile children with/without bronchiolitis F 432 children aged 0-24 months l Children with bronchiolitis had significantly fewer positive cultures F blood 0% vs. 2.7%; urine 1.9% vs. 13.6% F none of the children < 2 months of age with bronchiolitis (36) had bacteremia or UTI

SBI Risk in Children With Recognizable Viral Syndromes Greene DS, Harper MB: Pediatr Infect Dis J 1999;18:258 l Five year retrospective study ( ) l Children aged 3-36 months with T > 39 0 C F 1347 children diagnosed with a “RVS” v croup, varicella, bronchiolitis, stomatitis F blood cultures obtained in 65% F 2 of 876 (0.2%) blood cultures were positive Office-based physicians have known this for a very long time.

Bacteremia in Fever & Petechiae Mandl KD, et al: J Pediatr 1997; 131:398 l Prior studies suggest a high risk for bacteremia F 7 to 11% incidence of meningococcemia l Enrolled 411 children -- (58% 3-36 mo.) F 8 (1.9%) with bacteremia or clinical sepsis v six with serious invasive bacteremia F none of 357 well-appearing children had OB F toxic appearance had sensitivity of 100% F WBC > 15 K or < 5K had sensitivity of 100% F all children with meningococcemia had purpura

Occult Pneumonia in Febrile Children Bachur R, et al: Ann Emerg Med 1999; 33:166 l What is the incidence of occult pneumonia in febrile children with high WBC ? l Prospective cohort ED study F age 39 0 C, WBC > 20,000 F radiographs obtained in 225 of 278 patients F positive radiographic findings in v 40% of those with a suggestive clinical exam v 26% of those without clinical evidence for pneumonia F recommends empiric chest radiography

UTI’s in Febrile Infants Shaw KN, et al: Pediatrics 1998; 102:e16. l UTI is by far the most frequent SBI F fever may be only presenting sign of UTI l What is the prevalence of UTI in febrile infants F 2400 febrile infants -- overall 3.3% v gender -- male: 1.8%; female: 4.3% v race -- white: 10.7%; AA: 2.1%; others: 5.7% v other source -- yes: 2.7%; no: 5.9% v temperature : 3.9% Should we screen all febrile children for UTI ?

UTI’s in Febrile Children Gorelick, Shaw: Arch Ped Adol Med 2000;154:386. l Developed clinical decision rule [  ] F T > C  fever > 2 days F white race  age < 1 year F absence of another potential source l All with UTI had at least one risk factor l Presence of any two factors F sensitivity 95%, specificity 31% l Rule eliminated 30% of unneeded cultures

Risk of SBI in Febrile Seizures Trainor J, et al: Clin Pediatr Emerg Med 1999; 1:13 l Multi-center study of ED management of simple febrile seizures (Chicago, 1998) l 455 children with febrile seizure F 1.3% with bacteremia F 5.9% UTI F 12.5% with abnormal chest x-ray F normal CSF in all who had an LP (135)

Meningitis Risk in Simple Febrile Seizures: What’s Been Reported ? l Literature review of reported cases of febrile seizures and meningitis F 2,870 cases of febrile seizures with LP’s F 1.7% with bacterial meningitis F 17% of those with meningitis described as clinically inapparent l Is occult bacterial meningitis a significant clinical entity ?

Meningitis Risk in Febrile Seizures Green SM, et al: Pediatrics 1993; 92:527 l Studied children with meningitis -- how many presented solely with seizures? F 486 children with bacterial meningitis F complex seizures present in 79% F 93% of those with seizures were obtunded F of the few with “normal” LOC, 78% had nuchal rigidity v the two patients without meningismus had other straightforward indications for LP l Occult meningitis is more myth than fact

What is the Cost Effective Strategy? Yamamoto LG, et al: Am J Emerg Med 1998; 16:193 l Updated decision analysis which considered: F low incidence of H. influenzae infections F emergence of resistant S. pneumoniae F negative consequences of unnecessary Rx l Assuming zero or low Rx consequences -- empiric therapy associated with best outcomes l Assuming realistic Rx consequences - no testing and no treatment option may be best

Cost Effectiveness Post-Vaccine? Lee GM, et al: Pediatrics 2001; 108:835 l Updated prior decision analysis, considering: F Elimination of H. influenzae F Lower rate of occult bacteremia (1.5%) F Published efficacy of empiric Rx F Negative consequences of unnecessary Rx l At current rate of OB, CBC plus selective blood culture and treatment is still best l If OB rate < 0.5%, strategies employing empiric testing & treatment should be eliminated

Serotyping of Pneumococcal OB Alperin ER, et al: Pediatrics 2001; 108:e23 l What is potential efficacy of pneumococcal vaccine in the prevention of OB l S pneumoniae accounts for the vast majority (83%) of pathogens in children with OB l Eight serotypes isolated: F 6A, 9V, 19F, 18C, 4, 6B, 23F, 14 l 98% of serotypes would be covered by the currently licensed vaccine -- all except 6A Good news…We may soon erradicate OPB

Food For Thought And A Little Math l Current risk of OB: 1.5 to 1.9% F 92% pneumococcal l Risk of meningitis in OPB: 1 to 2% l Risk of adverse sequelae in BM: % l Need to treat 2500 febrile kids to prevent one case of BM; per adverse sequelae F remember that antibiotics may not prevent BM! F incidence of ADR’s: (?)/ case of BM F alarming growth rate of antibiotic resistance

Evolving Pneumococcal Resistance Kaplan, et al: Pediatrics 1998; 102:538. l Prospective surveillance study of invasive pneumococcal infections F three year ( ), eight center study F 1291 systemic pneumococcal infections l Proportion of non-susceptible isolates (PCN, ceftriaxone) increased annually F nearly doubled over the three year period v penicillin resistance 21% v ceftriaxone resistance 9.3%

So, What Do We Actually Know l Extremely common presenting complaint l Much concern (phobia?) regarding fever l Fairly effective strategies to identify low risk infants - these do not apply to neonates l #1 bad actor (H. flu) effectively erradicated l UMD - “pediatrician’s nightmare” - still out there l Risk of OB, now under 2%, primarily OPB l Can apply risk stratification to OPB l 93-96% spontaneous resolution of OPB

So, What Do We Actually Know l No consensus regarding optimal approach to the febrile infant l Not entirely clear what parents want l Empiric Rx does not prevent sequelae l Rising rates of antimicrobial resistance l UTI remains the most common occult “SBI” l RVS are a reasonable explanation for fever l Pneumovax may make this all a moot point

Some Friendly Advice l Keep abreast of the literature l Discuss this with colleagues & mentors F local practice variations F institutional practice guidelines F antimicrobial resistance rates l Both approaches (RM & TM) are defensible l Choose the best strategy for you l Be consistent l Always treat the ill appearing child with fever

Notable Quotes l “Unfortunately, many practitioners have become reluctant to rely on clinical judgement, preferring diagnostic tests and frequent use of antibiotics.”……. “We should resist the urge to use antibiotics empiricially, especially in a patient who looks well, for whom antibiotics have not been shown clearly to be beneficial” -- JK Stamos, ST Shulman: Lancet 1997 l “Antibiotics are not antipyretics” -- SE Krug: Overheard many evenings in CMH ED