Choosing the Best Antibiotic in Problem Outpatient Infectious Disease Cases Dr. Earl Rubin Associate Professor Department of Pediatrics Division of Infectious Diseases Montreal Children s Hospital
Disclosures Have served previously on Advisory Boards for Novartis, Roche, Pfizer but NONE in the past 5 years
Ouch, my ear isn t getting better! 3 year old male, previously healthy, except for an AOM 2 months previous to presentation. Presents on day 2 of left ear pain, and 1 day of fever Had a preceeding URI the week prior to the onset of the ear pain
No doubt about the diagnosis
AOM is a Symptomatic Disease Antecedent URTI in 93% Compared with a simple URTI children with AOM are somewhat or much more likely to have: Ear pain in a verbal child and/or Fever Nighttime restlessness Irritability Faden PIDJ 1998, Kontiokari PIDJ 1998
Mom has some requests This can be a stubborn child who often refuses to take his medication The preschool will not administer meds to him She requests a once a day medication if possible.
Once daily choices 14 drugs approved by the FDA for the use in AOM The following are given once daily: Cefixime (Suprax) Azithromycin (Zithromax) IV/IM Ceftriaxone Which do you prefer and why?
Time for patient education Convince the mother that amoxicillin is really the treatment of choice Studies have shown that bid dosing is sufficient to treat otitis media The issue is the dose Regular dose: 40-60 mg/kg/day High dose: 80-100 mg/kg/day
The child weighs 15 kg Regular dose: 40-60 mg/kg/day 600-900 mg/day 250 mg/5cc Therefore 6 to 9 cc twice daily High dose: 80-100 mg/kg/day 1200-1500 mg/day 12-15 cc twice daily Of interest, in the US, the amoxicillin also comes as 400 mg/5cc!
Compromise is reached Regular dose amoxicillin given twice daily The child returns after 36 hours with ongoing fever, and now both ears hurt
Etiology of AOM: Bacteria GAS 3% M. catarrhalis 14% No growth 25% H. influenzae 22% S. pneumoniae 36%
H. Influenzae ß lactamase production H.Influenzae (22%) ß + 34% ß - 66%
M.catarrhalis ß lactamase production M. catarrhalis (14%) ß + 85% ß - 15%
PENICILLIN RESISTANT PNEUMOCOCCUS GAS NO GROWTH PENICILLIN RESISTANT PNEUMOCOCCUS sensitive 80-95% resistant 5-20% H.FLU M.CAT PNEUMO
Overcome resistance with dose
WHAT ABOUT AOM DUE TO Pen NON Suscpetible PNEUMO? DEFINITION: MIC <0.06 : sensitive 0.1-1: intermediate >2: high level resistant Sensitivity is NOT all or none, as with betalactamase, but can be overcome with higher doses
SPONTANEOUS RESOLUTION PATHOGEN DEPENDENT % RESOLUTION STREPTOCOCCUS PNEUMONIAE 19% H. INFLUENZAE 48% M. CATARRHALIS 79% Reference: McCraken GH, PIDJ, 13 (11):1054
WHAT DID THE REGULAR DOSE AMOXICILLIN NOT ADEQUATELY COVER? ß lactamase producing organisms 34 % of H. influenzae 34% of 22% = 7.5% BUT 48% resolve spontaneously THEREFORE ACCOUNTS FOR 3.9% OF FAILURES 85% of M. catarrhalis 85% of 14% = 12% BUT 79% resolve spontaneously THEREFORE ACCOUNTS FOR 2.5% OF FAILURES
WHAT DID THE AMOXICILLIN NOT ADEQUATELY COVER? PENICILLIN RESISTANT PNEUMOCOCCUS ~ 10-15% of 36%= 3.6-5.4% BUT 21% resolve spontaneously THEREFORE ACCOUNTS FOR 2.8-4.3% OF FAILURES
Overall failure of Regular dose amoxicillin About 4% due to H. flu About 2.5% due to M. cat About 3.5% due to Pneumococcus Therefore a 10% clinical failure rate Of which 65% are due to Beta lactamase production
What should your 2 nd line therapy then be? Beta lactamase stable agent 2 nd or 3 rd generation cephalosporin Cefprozil Cefuroxime axetil Cefixime Non-Beta-lactam Azithromycin Clarithromycin Combination with Beta lactamase inhibitor Amoxicillin-Clavulanic acid (regular dose)
What should your 2 nd line therapy then be? Double dose amoxicillin Combination of both high dose amoxicillin with a Beta lactamase inhibitor
Amoxicillin-Clavulanate Suspension 4:1 ratio of amoxil to clavulanate 125 mg/5cc 250 mg/5cc 7:1 ratio 200 or 400 mg/5cc In USA: 14:1 ratio called Augmentin ES Can mimic this with combining regular dose amoxil at 40 mg/kg/day with 7:1 clavulin at 40 mg/kg/day
Amoxicillin-Clavulanate Tablets All the tablets have the same amount of Clavulanic acid, 125 mg as Potassium salt Therefore the ratio of amoxil to clav is very different depending on the tab prescribed 250 mg tabs have a ratio of 2:1 500 mg tabs have the ratio of 4:1 To get the 7:1 ratio, the tab is 875 mg, but is very large! Therefore 2 x 250 does NOT equal 500!
Practically speaking, what should you do? Greatest bang for your buck will be the combination of amoxil with the 7:1 Clavulin Be very specific and write out your logic in the prescription, so the pharmacist does not call you! Difficulties? 80 mg/kg of the 7:1 Clavulin, warn about the price and increased diarrhea Try any other second line agent, and if this fails, the 3 rd line would be double dose amoxicillin
Should we have started with High dose amoxicillin? CDC now recommends this Higher rates of Penicillin non susceptible Pneumococci Use high dose if risk factors for PRP Previous antibiotic use in the last 1-3 months Attendance at an out of home daycare If you start with HD amoxicillin Second line agent could be almost anything Resistance would be beta lactamase induced
Quiz: What would your second line therapy be, should the following fail? Regular dose amoxicillin? Double dose amoxicillin? 2 nd or 3 rd generation cephalosporin? Macrolide?
Any questions?
My throat really hurts! Previously well 5 year old female, at 3 pm complains of a sore throat and fever to 40 At 6 pm, she has a normal exam except for a red throat with pus, petechiae on the palate, and tender tonsillar nodes Rapid strep test is negative What do you do now?
Pharyngitis Formal throat culture is taken What do you want to do now? Start Penicillin Wait on the culture results By the way, he is Penicillin allergic
False negative rapid strep Next day the preliminary culture comes back positive for beta hemolytic group A strep Your choice of antibiotic? Azithromycin 10 mg/kg on day 1, then 5 mg/kg on days 2-5 Clarithromycin 15 mg/kg/day bid, for 10 days Erythromycin or other choice? Proper dose of Azithromycin is 12 mg/kg/day for 5 days!
Next day she is no better! Generally speaking after 24 hours of treatment, you should almost be perfect! Potentially reason for slow response? Has a viral illness, and is a strep carrier Resistant to treatment choice Has a suppurative complication, retropharyngeal cellulitis/abscess Has EBV
Lab calls The Group A streptococcus is penicillin sensitive, but resistant to erythromycin and clindamycin (inducible resistance) You ask about Azithro/Clarithro About 5-10% are macrolide resistant, 0% are penicillin resistant
You call the patient back Throat looks terrible (but no shift of the uvula) and big cervical nodes This penicillin allergy was to cloxacillin, it was a pinpoint rash that lasted 2 days. The child received pondocillin afterwards for an otitis media without problems What do you want to do? Give the child amoxicillin Give the child penicillin Stop all therapy because it is viral
Not again! Mom calls you the next day because the child has a red rash all over!
What do you think is going on? Penicillin allergy? Viral exanthem Amoxicillin associated rash of EBV Happens in 85-95% of cases of amoxil in the face of EBV Hypersensitivity reaction Reported with many antibiotics but lower frequency
Monospot is positive Do you want to discontinue all antibiotics? Rate of GAS in mononucleosis ranges from 3-33% Older literature suggest to treat the GAS Some newer studies say that it may not be necessary Controversial
Any questions?
My baby s urine smells disgusting! 18 month old, with known grade III VUR, is on Septra prophylaxis Presents with a 3 day history of fever, and some loose stool Urine dipstick is positive for leukocytes 3+, and RBCs 2+, and nitrite positive You send her to the ER for a catheterized urine culture, and you start her on?
Common Antibiotic choices for UTIs in children Amoxicillin Septra/Bactrim Cephalexin Amoxicillin/clavulanic acid Cefixime (Suprax)
Next day, the lab calls Greater than 10 8 of E. coli You call the patient, and still has fever after 2 doses What do you do? Next day, the lab calls and tells you that the preliminary sensitivities: Resistant to ampicillin, cephalothin, septra, clavulin, cefixime Sensitive to gentamicin, tobramycin, amikacin They tell you that tomorrow some other sensitivities. What kind of E. coli do you think this is?
What the heck is an ESBL/KPC/CRE? Extended Spectrum Beta Lactamase Seen with E. coli and Klebsiella Resistant to all Beta Lactams Combination drugs with beta lactamase inhibitors are also ineffective Klebsiella Producing Carbapenemases/Carbapenemas resisitant enterobacteracieae Resisant to carbapenems as well as multiple others
What choice do I have? Once daily aminoglycoside (IV) Need to arrange home care Quinolones, ie. Cipro Not approved for the use in Pediatrics Many ESBL/KPCs are also resistant Carbepenems Ertapenem is once daily if >12 years, otherwise it is bid
What do I do as far as prophylaxis after this UTI? Go back to Septra Go to Nitrofurantoin Go to quinolone Go to amoxicillin Since this E. coli was resistant, there is no prophylaxis to choose from
Any questions?