Antibiotics:Novel and Rediscovered

Stephen Swanson, MD, DTM&HPediatric 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-resistantS. aureus (MRSA)

S. aureus

Penicillin

[1950s]

Penicillin-resistant

CA-MRSA amongIV 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

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/SMX 100 %

Gentamicin 100 %

Vancomycin 100 %

Linezolid 100 %

Rifampin 99 %

Mupirocin 97 %

Antibiotic % Susceptible

Source: MDH

CA-MRSA Antibiotic Susceptibilities in MN, 2006 (N=492)

CA-MRSA Antibiotic Susceptibilities in MN, 2006 (N=492)

Erythromycin 17 %

Clindamycin 95 %

Ciprofloxacin 72 %

Tetracycline 96 %

TMP/SMX 100 %

Gentamicin 100 %

Vancomycin 100 %

Linezolid 100 %

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/SMX 100 %

Gentamicin 100 %

Vancomycin 100 %

Linezolid 100 %

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/SMX 100 %

Gentamicin 100 %

Vancomycin 100 %

Linezolid 100 %

Rifampin 99 %

Mupirocin 97 %

Antibiotic % Susceptible

Source: MDH

What about rifampin and gentamicin?

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

BACTRIM:

Why Bactrim Might Fail with ca-MRSA infections…

Why Bactrim Might Fail with 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)

• 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)

Ceftobiprole - another 5th 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 2004Hancock, 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 2004Hancock, RE Lancet 2005N Engl J Med 2006; 355:653-665Adura M, et. al. “Daptomycin therapy for invasive Gram-positive bacterial infections in children.” PIDJ 2007: 1128-1132

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.