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Antibiotics: Novel and Rediscovered

Antibiotics: Novel and Rediscovered. Stephen Swanson, MD, DTM&H Pediatric Infectious Diseases, Travel Medicine Department of Pediatrics Hennepin County Medical Center. β – lactams. Antibiotic Groups. PENICILLINS CEPHALOSPORINS Monobactams, Carbapenems Vancomycin (Glycopeptide)

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Antibiotics: Novel and Rediscovered

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  1. Antibiotics:Novel and Rediscovered Stephen Swanson, MD, DTM&HPediatric Infectious Diseases, Travel Medicine Department of Pediatrics Hennepin County Medical Center

  2. β – lactams Antibiotic Groups • PENICILLINS • CEPHALOSPORINS • Monobactams, Carbapenems • Vancomycin (Glycopeptide) • Linezolid (Oxazolidinone) • Aminoglycosides • Macrolides • Clindamycin • Tetracyclines • Sulfonamides plus trimethoprim • Rifamycins • Quinolones • Metronidazole

  3. Truth in Advertising

  4. Objectives • MRSA Epi Trends • Old Antibiotics used for Gram-positive Infections • Newer Antibiotics: on Horizon and Approved

  5. Penicillin Methicillin Penicillin-resistant Methicillin-resistant S. aureus (MRSA) S. aureus [1950s] [1960s] [ 1998 ] [ 1981 ] [ 1999 ] “Community Acquired MRSA in Children With No Identified Predisposing Risk” -JAMA CA-MRSA among 4 Pediatric Deaths in MN and ND - MMWR IV Drug Users) Evolution of Drug Resistance in S. aureus S. aureus

  6. . . . . . . . . . . . . . Minnesota Population Distribution and Sentinel Hospital Laboratories

  7. CA-MRSA in MN: a shift from USA400 to USA300 lineage

  8. CA-MRSA in MN: a shift from USA400 to USA300 lineage USA300 MRSA (predominant lineage) is more susceptible to clindamycin

  9. CA-MRSA Antibiotic Susceptibilities in MN, 2006 (N=492) Antibiotic % Susceptible Source: MDH

  10. CA-MRSA Antibiotic Susceptibilities in MN, 2006 (N=492) Antibiotic % Susceptible Source: MDH

  11. Epidemiologic Trends of MRSA:USA300 and USA100 • USA300strain more common among: • Patients < 20 years • ~92% susceptible to clindamycin • Wound/abscess • USA100 • Blood, lower respiratory tract • Elderly (age > 65) • 95% resistance to clindamycin Activity of Ceftaroline and Epidemiologic Trends of Staphlyococcus aureus collected from 43 Medical Center in the United States in 2009; Richter et al., Antimicrob Agents Chemother. 2011

  12. CA-MRSA Antibiotic Susceptibilities in MN, 2006 (N=492) Antibiotic % Susceptible Source: MDH

  13. CA-MRSA Antibiotic Susceptibilities in MN, 2006 (N=492) Antibiotic % Susceptible What about rifampin and gentamicin? Source: MDH

  14. Clinical Practice Guidelines by IDSA for MRSA - 2011 • Addition of gentamicin or rifampin for bacteremia or native valve infective endocarditis not recommended in adults (A-II, A-1 evidence) • Data in children insufficient to support routine use of combination therapy. • Osteomyelitis – maybe helpful • Pneumonia – not likely helpful • Eradication – never rifampin monotherapy

  15. BACTRIM:

  16. Why Bactrim Might Fail with ca-MRSA infections…

  17. Why Bactrim Might Fail with MRSA infections…

  18. Why Bactrim Might Fail with MRSA infections… Take-home: Avoid TMP-SMX monotherapy if significant amount of tissue damage/necrosis

  19. MRSA necrotizing pneumonia following influenza

  20. Vancomycin Limitations: Newer Gram-positive Antibiotics Needed • Burden of MRSA increasing • USA300 entering hospital system • Treatment failures and poor outcomes with Vancomycin • Variable dosing/levels • Limited penetration of bone, lung epithelial fluid, CSF • Slow killing time, especially higher inocula • MIC creep (> 2 μg/mL) requires higher dosing

  21. Linezolid • Oxazolidinone-class antibiotic • Inhibits protein synthesis • Excellent bioavailability • Excellent CSF penetration • Covers GAS, S. pneumoniae, MSSA/MRSA, enterococcus, Listeria, oral anaerobes • Uses: • Pneumonia • Complicated SSTI • Osteomyelitis • Meningitis* • Failures: endocarditis (static) • Major side effect: reversible myelosuppression • Follow weekly CBC if using > 2 weeks

  22. Minocycline – the forgotten child • Oral and IV • Can be used in MRSA SSTI • Data lacking for more invasive infections • Very active against MRSA and CONS embedded in biofilms on catheters Raad I., et al. Antimicrob. Agents Chemother, May 2007

  23. Ceftarolinefosamil (Teflaro) • 5th generation cephalosporin • Low propensity for inducing resistance • Excellent safety profile • Gram-positive bacteria (CONS, MRSA, VISA, VRSA, resistant pneumococcus, resp gram negs) • 4-fold greater activity against MRSA than Vanc • 16-fold greater activity against MSSA than Ceftr • Active against daptomycin- and linezolid-resistant staph • Avoid in ESBLs, Pseudomonas, Acinetobacter • FDA approved in 2010 for CAP and cSSTI (adults)

  24. Ceftobiprole - another 5th gen ceph • Active against MRSA • Approved in Canada • FDA approval pending further evaluation

  25. The newer antibiotics… never to be approved for children?

  26. Daptomycin • An old drug, that did not receive FDA approval until 2003 • Rapid killing of almost all clinically relevant gram-positive bacteria • Effective all stages of bacterial growth T. Greenhow, MD

  27. Daptomycin • Clinical trials in complicated SSTIs showed it was equivalent to nafcillin / vancomycin • Cure rate >96% • Currently indicated for complicated SSTIs (adult) • Drug was found to be less effective than ceftriaxone in treating community-acquired pneumonia • Binds to surfactant which reduces its activity in the alveolar spaces of the lung Carpenter, CF and HF Chambers CID 2004 Hancock, RE Lancet 2005

  28. Daptomycin • Approved for right-sided endocarditis, S. aureus bacteremia (6mg/kg) • Prolonged half-life (once daily dosing) • Monitor weekly CPK levels (dose-dependent, reversible) • Not FDA approved in 2 – 17 year olds, but literature increasingly supportive • Pregnancy B category Carpenter, CF and HF Chambers CID 2004 Hancock, RE Lancet 2005 N Engl J Med 2006; 355:653-665 Adura M, et. al. “Daptomycin therapy for invasive Gram-positive bacterial infections in children.” PIDJ 2007: 1128-1132

  29. Daptomycin Pediatric Dosing • Dosing under study. Recommended starting doses: • Complicated SSTI • 9 mg/k IV QD (ages 2-6) • 7 mg/kg IV QD (ages 7-11) • 5 mg/kg IV QD (ages 12-17) • Osteomyelitis, Septic Arthritis, Bacteremia • 6-10 mg/kg IV daily • Failures more likely in patients with prior vancomycin exposure or elevated vancomycin MICs (adult data)

  30. Final notes • Azithromycin resistance rates • >20% for S. pneumoniae • 5-10+% for GAS • Clindamycin • S. pneumoniae (~88% susceptible) • Group A streptococcus (~10% inducible resistance) • Group B streptococcus (~70% susceptible)

  31. Thank you.

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