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

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

Truth in Advertising

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

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

Minnesota Population Distribution and Sentinel Hospital Laboratories

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

USA300 MRSA (predominant lineage) is more susceptible to clindamycin

Erythromycin 17 % Clindamycin 95 % Ciprofloxacin 72 % Tetracycline 96 % TMP/SMX100 % Gentamicin100 % Vancomycin100 % Linezolid100 % Rifampin 99 % Mupirocin 97 % Antibiotic % Susceptible Source: MDH CA-MRSA Antibiotic Susceptibilities in MN, 2006 (N=492)

Erythromycin 17 % Clindamycin 95 % Ciprofloxacin 72 % Tetracycline 96 % TMP/SMX100 % Gentamicin100 % Vancomycin100 % Linezolid100 % Rifampin 99 % Mupirocin 97 % Antibiotic % Susceptible Source: MDH

Epidemiologic Trends of MRSA: USA300 and USA100 USA300 strain 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

CA-MRSA Antibiotic Susceptibilities in MN, 2006 (N=492) Erythromycin 17 % Clindamycin 95 % Ciprofloxacin 72 % Tetracycline 96 % TMP/SMX100 % Gentamicin100 % Vancomycin100 % Linezolid100 % Rifampin 99 % Mupirocin 97 % Antibiotic % Susceptible Source: MDH

CA-MRSA Antibiotic Susceptibilities in MN, 2006 (N=492) Erythromycin 17 % Clindamycin 95 % Ciprofloxacin 72 % Tetracycline 96 % TMP/SMX100 % Gentamicin100 % Vancomycin100 % Linezolid100 % Rifampin 99 % Mupirocin 97 % Antibiotic % Susceptible Source: MDH What about rifampin and gentamicin?

Clinical Practice Guidelines by IDSA for MRSA 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

BACTRIM:

Why Bactrim Might Fail with ca-MRSA infections…

Why Bactrim Might Fail with MRSA infections…

Take-home: Avoid TMP-SMX monotherapy if significant amount of tissue damage/necrosis

MRSA necrotizing pneumonia following influenza

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

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

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

Ceftaroline fosamil (Teflaro) 5 th 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)

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

The newer antibiotics… never to be approved for children?

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

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

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: Adura M, et. al. “Daptomycin therapy for invasive Gram-positive bacterial infections in children.” PIDJ 2007:

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)

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)

Thank you.