Appropriate

Antimicrobial Therapy

for Treatment of Staphylococcus aureus

infections

( MRSA )

By : A. Bojdi MD Assistant Professor

Inf. Dis. Dep.

Imam Reza Hosp.

MUMS

Antibiotics Still Miracle Drugs

Paul Ehrlich’s Magic Bullets

Salvarsan No. 606

Fleming and Penicillin

Anti-Staphylococcal Penicillins

► Methicillin, nafcillin, oxacillin, cloxacillin and dicloxacillin.

► Resist degradation by penicillinase.

► Useful for treating S. aureus. No added benefit in treating Strep. species.

► Methicillin is rarely used due to toxicity.

► Dicloxacillin - highest serum levels orally.

►Nafcillin - preferred parenteral drug.

First Generation

►Cefazolin (Ancef; IV.IM; $9.60/day), Cephalexin (Keflex;

Oral; $0.78/day)

► Spectrum: Most gram positive cocci (Strep, S. aureus), E. coli, Proteus, Klebsiella.

► Use: S. aureus infection, surgical prophylaxis.

A first-generation cephalosporin such

as cefazolin (2 g IV every eight hours)

is an acceptable alternative in patients with

hypersensitivity to the preceding agents.

In some cases, cefazolin may be more

practical and better tolerated for

continuation of intravenous therapy in

outpatient settings.

In an observational study of 505 patients with S. aureus bacteremia, nafcillin was superior to vancomycin for preventing relapse or persistent MSSA bacteremia;

the failure rate was 4 versus 20 percent.

In another study of 294 patients with S. aureus bacteremia, vancomycin therapy was associated with a higher risk of relapse.

Methicillin resistance in Staphylococcus

aureus is defined as an oxacillin minimum

inhibitory concentration (MIC) ≥4 mcg/mL.

Isolates resistant to oxacillin or methicillin

are also resistant to other beta-lactam

agents,including dicloxacillin and cefazolin.

Vancomycin

► Tricyclic glucopeptide - Streptomyces orientalis.

► Inhibits synthesis of cell wall phospholipids and prevents cross-linking of peptidoglycans at an earlier step than B-lactams.

► Active against gram positive bacteria, highly resistant Strep. pneumo, Clostridia, Enterococcus, Staph. epi and MRSA.

— Vancomycin

is a glycopeptide that inhibits cell wall synthesis.

It remains an important antibiotic for the treatment of invasive methicillin-resistant S. aureus (MRSA) infections,

despite increasing concern about "minimum inhibitory concentration (MIC) creep"

(ie, a reported overall decrease in susceptibility of S.

aureus isolates to vancomycin in different geographic regions).

— Vancomycin

Vancomycin has a relatively good safety profile and favorable pharmacokinetics that facilitate convenient administration.

In addition, vancomycin is the agent for which there is the greatest cumulative clinical experience for the treatment of a variety of invasive clinical syndromes, including bacteremia, endocarditis, pneumonia, and osteomyelitis.

— Vancomycin : MIC breakpoints for S.

aureus are defined as follows:

●Susceptible: MIC ≤2 mcg/mL

●Intermediate: MIC 4 to 8 mcg/mL. VISA

●Resistant: MIC ≥16 mcg/mL . VRSA

— Alternatives to vancomycin should be

considered in the setting of :

adverse effects due to vancomycin or

infection with a pathogen with inadequate

susceptibility to vancomycin coupled with a

poor clinical response.

— Usual dosage range : Initial intravenous dosing should be based on actual body weight; subsequent dosing adjusted based on serum trough vancomycin concentrations.

IV : Manufacturer’s labeling: Usual dose: 500 mg every 6 hours or 1,000 mg every 12 hours

Alternate recommendations: 15 to 20 mg/kg/dose every 8 to 12 hours. (ASHP/IDSA/SIDP [Rybak, 2009]); Note: Dose requires adjustment in renal impairment.

— Vancomycin dosing is based on actual body weight (even in the setting of obesity), and doses are rounded to the nearest 250 mg.

In general, the drug should be infused over 0.5 hours for each 500 mg increment (example, 500 mg over 0.5 hours, 1000 mg over 1 hour, etc).

In the setting of red man syndrome, the rate of infusion may be reduced to 500 mg over 1 hour.

Many institutions specify maximum limits of doses not to exceed 2 or 3 g.

—Obesity —To avoid individual doses greater than 2 g, the total daily dose (approximately 30 mg/kg/day) can be divided into three administrations (eg, every eight hours). The rate of infusion can also be adjusted as outlined above.

Impaired renal function — In patients with renal insufficiency, doses in the range of 15 to 20 mg/kg (based on target trough concentration) rounded to the nearest 250 mg should be administered at frequencies based on estimations of creatinine clearance.

— Vancomycin dosing :

Complicated infections in seriously ill patients:

A loading dose of 25 to 30 mg/kg (based on

actual body weight) may be used to rapidly

achieve target concentrations.

Vancomycin

►Adverse effects.

Fever, chills, phlebitis and red man syndrome. ►Slow injection and prophylactic antihistamines.

Ototoxic – may potentiate known ototoxic agents.

►Renal excretion (90-100% glomerular filtration).

Normal half-life 6-10 hours.

Half life is over 200 hours in pts with ESRD.

Teicoplanin — Teicoplanin is a glycopeptide; it has the same spectrum of activity and similar efficacy as vancomycin.

However, teicoplanin has a longer half-life than vancomycin and can be administered once daily with more rapid infusion rates than vancomycin.

It can also be given intramuscularly, facilitating outpatient management.

Teicoplanin

Teicoplanin tends to be better tolerated than vancomycin. This was illustrated in a meta-analysis of 11 clinical trials including 1276 patients.

Efficacy was similar in the two groups, but there were significantly fewer episodes of red man syndrome and other adverse events in patients treated with teicoplanin (13.9 versus 21.0 percent with vancomycin).

A meta-analysis noted a lower risk of nephrotoxicity with teicoplanin than with vancomycin.

Teicoplanin

Teicoplanin is not available in the United States.

In areas where it is available, some favor its use for patients with intolerance to vancomycin, while

others use it as the drug of choice for initial therapy of gram-positive pathogens.

Teicoplanin

Teicoplanin

Teicoplanin

Teicoplanin

Teicoplanin

Teicoplanin

Linezolid Linezolid is a bacteriostatic, synthetic

oxazolidinone antibiotic that inhibits initiation of protein synthesis at the 50S ribosome. It does not exhibit cross-resistance with other protein synthesis inhibitors.

Its mechanism of action as a protein synthesis inhibitor may lead to enhanced efficacy against strains producing toxins such as Panton-Valentine leukocidin, alpha-hemolysin, and toxic shock syndrome toxin-1.

Linezolid has excellent tissue distribution and may be administered parenterally or orally due to its high bioavailability.

Linezolid

Linezolid has received US Food and Drug

Administration (FDA) approval for

treatment of nosocomial pneumonia and

complicated skin and skin structure

infections due to susceptible pathogens

including MRSA.

Linezolid

Safety concerns limit the extended use

of linezolid.

Adverse effects include thrombocytopenia,

anemia, lactic acidosis, peripheral

neuropathy, serotonin toxicity, and ocular

toxicity.

Linezolid Linezolid can reversibly inhibit monoamine

oxidase; when administered with serotonergic agents (particularly selective serotonin reuptake inhibitors), it can induce the serotonin syndrome.

Appropriate linezolid dosing is 600 mg every 12 hours intravenously or orally.

Based upon the above toxicities, monitoring of blood counts and serum chemistries should be performed at least weekly during linezolid therapy.

Daptomycin is a cyclic lipopeptide bactericidal antibiotic that causes depolarization of the bacterial cell membrane.

The strongest data for use of daptomycin are in the setting of complicated skin and skin structure infections (cSSSI) and bacteremia with or without endocarditis due to MRSA and other selected gram-positive pathogens.

Daptomycin should not be used for treatment of MRSA pneumonia since its activity is inhibited by pulmonary surfactant.

Daptomycin

Ceftaroline — The active metabolite of ceftaroline, a fifth-generation cephalosporin, exhibits bactericidal activity against gram-positive organisms including

MRSA,

vancomycin-intermediate S. aureus [VISA], and

macrolide-resistant S. pyogenes as well as

gram-negative pathogens (including Enterobacteriaceae but

not Pseudomonas species or extended-spectrum beta-lactamase producers) .

Ceftaroline

Telavancin

Dalbavancin

Oritavancin

Tedizolid

Tigecycline

Quinupristin-dalfopristin

Clindamycin

Trimethoprim-sulfamethoxazole

Tetracyclines

Treatment of skin and soft tissue infections

due to MRSA

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