New Antibiotics & New Insights into Old Antibiotics

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1 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

2 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.

3 Why Do We Need New Antibiotics? 1. Antibiotic resistance! Skin, bone/joint: Staph aureus R to 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!

4 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

5 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

6 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!!

7 Antibiotics for MRSA

8 Home Oral Therapy for MRSA Clindamycin? Intermediate (not fully susceptible) taking a chance as killing with clindamycin is concentration-dependent Erythromycin? Static We don t usually use for invasive infection Tetracycline? Static Intermediate (bacteriostatic agent), but he is over 7 years of age TMP-SMX? Cidal, but He failed that already

9 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!

10 Clindamycin vs. TMP-SMX for UNCOMPLICATED Skin Infections

11 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

12 Clindamycin Susceptibility in MSSA and MRSA Across the USA

13 Clindamycin Susceptibility in MSSA and MRSA Across the USA Clindamycin % Susceptible Hospital MSSA MRSA Seattle Children s Rady San Diego Children s Primary Children s (Salt Lake City) Texas Children s (Houston, TX) Mercy KC Children s (Kansas City) Cincinnati Children s Sanford Children s (Sioux City, SD) LeBonheur Children s (Memphis, TN) Duke Children s (North Carolina) Morgan Stanley Children's (NY- Presbyterian) 71 63

14 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!

15 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

16 Finally! New FDA-approved Beta-lactam IV Therapy for MRSA in Children Ceftaroline (Teflaro )

17 Finally! New FDA-approved Beta-lactam IV Therapy for MRSA in Children Ceftaroline (Teflaro )

18 Finally! New FDA-approved Beta-lactam IV Therapy for MRSA in Children Ceftaroline (Teflaro )

19 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

20 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 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 Only FDA-approved for skin and pneumonia

21 Daptomycin IV Therapy Approved for MRSA Skin Infections in Children Daptomycin (Cubicin ) Cubist/Merck Pediatric data 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) yrs, 5 mg/kg; 7-11 yrs, 7 mg/kg; 2-6 yrs, 9 mg/kg; mos, 10 mg/kg

22 Daptomycin IV Therapy Approved for MRSA Skin Infections in Children Pediatric datathe 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%)

23 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)

24 Antibiotics for MDR E. coli UTI What is an ESBL-E. coli organism? Are they taking over? Extended Spectrum Beta Lactamase. Is only active again beta-lactam antibiotics (penicillins and some cephalosporins), but not aminoglycosides, TMP-SMX, fluoroquinolones, tetracyclines

25 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 then second/third generation cephalosporins like ceftriaxone/cefotaxime IV, and cefixime/cefdinir PO

26 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 (most all mutations from the original TEM, SHV, etc) In Pediatrics, still only 5-10% prevalence

27 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

28 ESBL s and Your Hospital s Antibiogram Cipro floxa cin 98

29 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 Apr;15(4):

30 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

31 Antibiotic Selection for Increasingly Resistant Gm Neg Bacilli AAP Nelson s Antibiotic Therapy 2018

32 Antibiotics for MDR E. coli UTI New antibiotics approved for adults, under study in children: Ceftazidime/avibactam Ceftolozane/tazobactam Meropenem/vaborbactam Plazomicin By federal law, every antibiotic approved for adults MUST also be studied in children (when there is a chance of use in children) Pediatric Research Equity Act

33 Questions????