New Antibiotics & New Insights into Old Antibiotics Louisiana Chapter of the American Academy of Pediatrics August 18, 2018 Baton Rouge, Louisiana John Bradley MD Rady Children s Hospital San Diego University of California, San Diego
Antibiotic Update: Disclosure Statement: John S. Bradley, MD Dr. Bradley has no personal financial relationship with any commercial interest that produces, markets, re-sells, or distributes antimicrobials. Dr. Bradley s employer, the University of California, has received research funds for clinical trials during the past 12 months for study of daptomycin, ceftolozane/tazobactam, tedizolid (Cubist/Merck), dalbavancin (Durata/Allergan), oritavancin, lefamulin (Melinta), colistin (NIH), piperacillin/tazobactam (CHOP) and ceftaroline (AstraZeneca, Pfizer, RCHSD Foundation) The Regents of the University of California hold consulting contracts with Cubist/Merck, AstraZeneca, Actavis/Allergan This presentation will include discussion of unapproved or off-label uses of pharmaceuticals.
Why Do We Need New Antibiotics? 1. Increasing antibiotic resistance! Skin, bone/joint: Staph aureus R: Clindamycin, methicillin Urinary tract: E. coli, Klebsiella R: Ampicillin, TMP/SMX, cefixime/cefotaxime Nosocomial infections: Pseudomonas, Acinetobacter, Stenotrophomonas R: Ceftaz, cefepime, meropenem, ciprofloxacin not so much of a need for new therapy of AOM or strep throat!
Why Do We Need New Antibiotics? 2. Oral therapy would be better than IV 3. Less frequent dosing Once daily would be nice Once weekly would even better for extended therapy 4. Less toxicity would be nice
Antibiotics for MRSA An 8 yo boy was playing baseball in empty field; later that evening noted to have a small area of erythema later over his elbow. No known trauma; unsure about bug bites. Small pustule formed over area with mild warmth and erythema. Seen by PMD in clinic with expression of pus with culture taken. Begun on Bactrim therapy and topical antibiotic ointment but with continued pain with increased swelling over the week
Antibiotics for MRSA Completed at least 8-9 days of therapy with Bactrim, but still developed new fever and significant drainage from area - at that point went to ED for further workup Admitted to our hospital for r/o septic elbow with soft tissue abscess/cellulitis Ortho consult for septic elbow; started on IV clindamycin (we have about 90% susceptibility for MSSA and MRSA locally); was drained in the OR; got better!!
Antibiotics for MRSA Report from Referring ER
Home Oral Therapy for MRSA Clindamycin? Intermediate (not fully susceptible) taking a chance as killing with clindamycin is concentration-dependent Erythromycin? Only bacteriostatic We don t usually use for invasive infection Tetracycline? Also bacteriostatic Intermediate, but he is over 7 yrs of age TMP-SMX? bactericidal, but He failed that already
Linezolid Antibiotics for MRSA Most microbiology labs include susceptibility to linezolid 98% of MRSA are susceptible Virtually 100% bioavailable 30 mg/kg/day divided tid FDA approved for children ~20 yrs ago Costly, even generic! Safe for short term (less than 2 weeks) of therapy, but long term associated with thrombocytopenia and neutropenia
Clindamycin vs. TMP-SMX for UNCOMPLICATED Skin Infections
Antibiotics for Uncomplicated MRSA Creech et al 2015 Patients were categorized as having Cellulitis (defined as inflammation of the skin and associated skin structures without signs of a drainable fluid collection) Abscess (defined as a circumscribed, drainable collection of pus), or Both (if lesions of both cellulitis and abscess were present) All abscesses were treated by means of incision and drainage
Clindamycin Susceptibility in MSSA and MRSA Across the USA
Clindamycin Susceptibility in MSSA and MRSA Across the USA Clindamycin % Susceptible Hospital MSSA MRSA Seattle Children s 82 74 Rady San Diego Children s 92 91 Primary Children s (Salt Lake City) 84 70 Texas Children s (Houston, TX) 80 81 Mercy KC Children s (Kansas City) 84 91 Cincinnati Children s 59 75 Sanford Children s (Sioux City, SD) 80 64 LeBonheur Children s (Memphis, TN) 80 79 Duke Children s (North Carolina) 79 72 Morgan Stanley Children's (NY- Presbyterian) 71 63
Clindamycin Susceptibility in MSSA and MRSA: Shreveport
Oral Antibiotics for MRSA Take home messages: 1. Many MRSA strains are not susceptible to clindamycin (up to 40% in some regions) Most resistance occurs in strains that are ALSO resistant to erythromycin (binding site on MRSA is altered for BOTH classes) 2. Sometimes you just need drainage! 3. Bactrim/Septra should work for uncomplicated, drained Staph skin infections
Finally! New FDA-approved Beta-lactam IV Therapy for MRSA in Children Ceftaroline (Teflaro ) FDA Package Label: For 2 months of age and older for: Skin Community pneumonia Neonatal studies completed and submitted to FDA
Finally! New FDA-approved Beta-lactam IV Therapy for MRSA in Children Ceftaroline (Teflaro ) [Similar to cefotaxime/ceftriaxone]
Finally! New FDA-approved Beta-lactam IV Therapy for MRSA in Children Ceftaroline (Teflaro )
Finally! New FDA-approved Beta-lactam IV Therapy for MRSA in Children Ceftaroline (Teflaro )
Finally! New FDA-approved Beta-lactam IV Therapy for MRSA in Children No unexpected treatment failures or adverse events (toxicity) reported since approval in children This takes us back to the cefazolin days (beta-lactam therapy) for Staph aureus less toxic than vancomycin, do not need to follow renal function or drug levels No head-to-head comparisons with clindamycin for deeper Staph infections
Finally! New FDA-approved Beta-lactam IV Therapy for MRSA in Children Ceftaroline might be preferred in children with more serious MRSA infections when you worry about pushing the dose of vancomycin (MIC > 2) to toxicity (possibly used in combination with gentamicin) Ceftaroline might be preferred in regions with relatively high clindamycin resistance for those who wish to avoid vancomycin use FDA-approved only for skin and pneumonia
Daptomycin IV Therapy Approved for MRSA Skin Infections in Children Daptomycin (Cubicin ) Cubist/Merck Pediatric data (took 15 years after adult approval) Multi-center, evaluator-blinded trial in children 1-17 yrs old with complicated skin/skin structure infection Randomized 2:1, intravenous daptomycin vs standardof-care (SOC) for 14 days; oral switch was permitted after 24 hours Daptomycin dose (population PK-derived) 12-17 yrs, 5 mg/kg; 7-11 yrs, 7 mg/kg; 2-6 yrs, 9 mg/kg; 12-23 mos, 10 mg/kg Bradley J, Glasser C, Patino H, Arnold SR, Arrieta A, Congeni B, Daum RS, Kojaoghlanian T, Yoon M, Anastasiou D, Wolf DJ, Bokesch P. Daptomycin for Complicated Skin Infections: A Randomized Trial. Pediatrics. 2017 Mar;139(3).
Daptomycin IV Therapy Approved for MRSA Skin Infections in Children Pediatric data The intent-to-treat population: 257 daptomycin and 132 SOC patients (primarily clindamycin or vancomycin) 35% had confirmed MRSA Clinical success rates 7-14 days after end-of-treatment) were similar for daptomycin (91%) and SOC (87%; 95% confidence interval for treatment difference: -3% to 11%) Treatment-related adverse events were similar between daptomycin (14%) and SOC (17%) Cautions for use in children less than one year!
New Antibiotics in Pediatric Clinical Trials for MRSA Approved for adults, under study in children: Dalbavancin (one IV dose equivalent to 10d vanc!)* Oritavancin (one IV dose equivalent to 10d vanc!) Telavancin (once daily) Tedizolid (once daily PO/IV safer than linezolid) Under study in adults and children: Lefamulin (protein synthesis inhibitor) *Gonzalez D, Bradley JS, Blumer J, Yogev R, Watt KM, James LP, Palazzi DL, Bhatt-Mehta V, Sullivan JE, Zhang L, Murphy J, Ussery XT, Puttagunta S, Dunne MW, Cohen-Wolkowiez M. Dalbavancin Pharmacokinetics and Safety in Children 3 Months to 11 Years of Age. Pediatr Infect Dis J. 2017 Jul;36(7):645-653.
Antibiotics for MDR E. coli UTI What is an ESBL-E. coli organism? Are they taking over? Extended Spectrum Beta Lactamase Just the usual E. coli, but now resistant. These resistance enzymes are only active against beta-lactam antibiotics (penicillins and some cephalosporins), but not aminoglycosides, TMP-SMX, FQ, tetracyclines
Antibiotics for MDR E. coli UTI Remember when all Haemophilus and all E. coli were susceptible to ampicillin? Then came beta-lactamases (TEM, SHV, etc) and we needed to use chloramphenicol and second/third generation cephalosporins like ceftriaxone/cefotaxime IV, and cefixime/cefdinir PO
Antibiotics for MDR E. coli UTI Remember when all Haemophilus and all E. coli were susceptible to ceftriaxone? Then came extended spectrum betalactamases in enteric bacilli There are now over 200 sequenced variations of TEM, SHV etc, that are active against 3 rd generation cephalosporins, some more active than others In Pediatrics, still only 5-10% prevalence
Antibiotics for MDR E. coli UTI For treatment of most ESBL E. coli: Carbapenems (meropenem) IV/IM Piperacillin/tazobactam IV Aminoglycosides (gent, tobra) IV/IM Fluoroquinolones (ciprofloxacin) IV/PO It is OK to use oral ciprofloxaxin for ESBL UTI! Jackson MA, Schutze GE; COMMITTEE ON INFECTIOUS DISEASES. The Use of Systemic and Topical Fluoroquinolones. Pediatrics. 2016 Nov;138(5).
ESBL s and Your Hospital s Antibiogram Cipro floxa cin 98
E. coli ESBL Susceptibility
Antibiotics for MDR E. coli UTI in Outpatient Children in the US Amoxicillin, Cephalexin, Cefixime TMP- SMX Fluoroquinolone (cipro) Meropenem, ertapenem Piptazo Gent, amikacin E. coli: ESBL-positive R 70% S 98% S 99% S 98% S 95% S Green = Oral Red = IV/IM Harris PN et al. β-lactam and β-lactamase inhibitor combinations in the treatment of extended-spectrum β-lactamase producing Enterobacteriaceae: time for a reappraisal in the era of few antibiotic options? Lancet Infect Dis. 2015 Apr;15(4):475-85.
Antibiotics for ESBL E. coli UTI For oral therapy of UTI: Check to see if TMP-SMX susceptible, then Check to see if ciprofloxacin susceptible, then You might need to go to IV/IM therapy For outpatients, once daily IM/IV therapy can be provided with ertapenem or amikacin as a last option
Antibiotic Selection for Increasingly Resistant Gm Neg Bacilli AAP Nelson s Antibiotic Therapy 2018
Antibiotics for MDR E. coli UTI New antibiotics approved for adults, under study in children (More are under study) Ceftazidime/avibactam Ceftolozane/tazobactam Meropenem/vaborbactam Plazomicin With stewardship, we all hope to decrease resistance! By federal law, every antibiotic approved for adults MUST also be studied in children (when they will be used in children): Pediatric Research Equity Act
Questions????
How We Select the Dose (Neonates) 0.125 0.25 % of simulated patients achieving %ft>mic target of 60% 0.5 1 2 4 8 16 32 % of patients achieving %ft>mic target 100 80 60 40 20 0 100 80 60 40 20 GA 28 weeks GA 30 weeks GA 32 weeks GA 34 weeks GA 36 weeks GA 38 weeks 0 4 mg/kg, 2 hr inf, q8h 6 mg/kg, 2 hr inf, q8h 8 mg/kg, 2 hr inf, q8h 10 mg/kg, 2 hr inf, q8h 12 mg/kg, 2 hr inf, q8h 4 mg/kg, 1.5 hr inf, q8h 6 mg/kg, 1.5 hr inf, q8h 8 mg/kg, 1.5 hr inf, q8h 10 mg/kg, 1.5 hr inf, q8h 4 mg/kg, 1 hr inf, q8h GA 40 weeks 0-1 month old GA 28 weeks GA 30 weeks GA 32 weeks GA 34 weeks GA 36 weeks GA 38 weeks 1-2 months old 6 mg/kg, 1 hr inf, q8h GA 40 weeks 0-1 month old GA 28 weeks GA 30 weeks GA 32 weeks GA 34 weeks GA 36 weeks GA 38 weeks 1-2 months old 8 mg/kg, 1 hr inf, q8h GA 40 weeks 0-1 month old GA 28 weeks GA 30 weeks GA 32 weeks GA 34 weeks GA 36 weeks GA 38 weeks 1-2 months old 10 mg/kg, 1 hr inf, q8h GA 40 weeks 0-1 month old GA 28 weeks GA 30 weeks GA 32 weeks GA 34 weeks GA 36 weeks GA 38 weeks 1-2 months old 12 mg/kg, 1.5 hr inf, q8h 12 mg/kg, 1 hr inf, q8h GA 40 weeks 0-1 month old 1-2 months old 100 80 60 40 20 0