Download Manda Hryn Pam Lyons Advance Infectious Disease Formulary

Manda Hryn
Pam Lyons
Advance Infectious Disease
Formulary Restriction Project
9/14/12
Class E Antibiotics
Methicillin-resistant Stapholococcus aureus (MRSA) and Vancomycin-resistant
Enterococcus are two strains of bacteria showing increasing prevalence in the hospital setting,
especially in complicated skin and skin structure infections (cSSSI).1,2 As the resistance of these
bacteria grow, it is becoming increasingly more difficult to treat patients with the limited number
of antibiotics available on the current hospital formulary. Based on increasing prevalence of
resistant bacteria, it is appropriate to add new antibiotics to the hospital formulary that will offer
additional treatment options for patients suffering from complicated skin and skin structure
infections caused by MRSA and VRE.
The first antibiotic that should be added to the formulary is daptomycin. Daptomycin is a
cyclic lipopeptide antibiotic that is active against many gram positive organisms with good
activity against MSSA, MRSA, and Streptococcus species. It has acceptable to good activity
against enterococcus species, including VRE. As the only drug in its class, daptomycin destroys
its target bacteria using 2 novel mechanisms. First, it rapidly depolarizes the bacterial cell
membrane, inhibiting DNA, RNA, and protein synthesis.3 Rapid depolarization of the cell
membrane also disrupts bacterial metabolic processes dependent on cellular membrane potential.
Second, daptomycin interferes with the synthesis of lipoteichoic acid, a major component in
bacterial cell walls.3 Both of these mechanisms of action do not require that daptomycin be
transported into the bacterial cell in order to be effective, avoiding resistance by efflux pumps in
the bacterial cell wall.3 Multiple mechanism of action gives daptomycin an advantage in avoiding
bacterial resistance; bacteria would need to undergo multiple genetic mutations in order for
resistance to occur.
Daptomycin is a necessary addition to the hospital formulary for several reasons. Based
on the antibiogram, none of the drugs on the current formulary have acceptable success rates in
treating E. faecium, which is the main enterococcus species responsible for VRE. Only 20% of
E. faecium isolates are susceptible to vancomycin, and only 32% of isolates are susceptible to
doxycycline. The hospital is in desperate need of antibiotics that are active against E.
faecium/VRE.
Daptomycin also has good activity against MRSA.4,5 Though the formulary currently
includes several antibiotics that show good activity against S. aureus (including MRSA), there
are additional reasons that daptomycin should be included as MRSA coverage. The antibiotics on
the formulary that currently show activity against S. aureus/MRSA are vancomycin (100%),
doxycycline (97%) and trimethoprim/sulfamethoxazole (92%), however these drugs may not
provide adequate options for specific patient populations presenting with MRSA infections. For
example, many patients have sulfa allergies that would exclude TMP/SMZ use. Additionally, IV
TMP/SMZ is currently on backorder, making obtaining adequate supply of drug for patients
unable to take oral medications difficult and uncertain. Doxycycline is not approved for use in
children under 8 years old or pregnant women (doxcycycline: pregnancy category D,
daptomycin: pregnancy category B), which could potentially limit this drug’s use.6 Vancomycin
is still a viable option for most patients, however it is appropriate to have an alternative option
for patients who are intolerant to this first-line therapy.
The second antibiotic that should be added to the formulary is linezolid. Linezolid is an
oxazolid antibiotic that offers good coverage for most gram (+) organisms including VRE.4 As
the only drug in its class, linezolid offers an novel mechanism of action. It selectively binds to
23S ribosomal RNA portion of the 50S subunit, prevents 50 and 70 S from coming together.7
Although there are other antibiotics that bind to the 50S subunit of bacterial ribosomes, linezolid
reduces the chance of cross resistance by binding to a different place on the 50S subunit.
As mentioned before when discussing daptomycin, the hospital’s current formulary
contains no good option for treating VRE. Linezolid would give physicians another viable option
for patients with infections caused by VRE. With only 30% of the drug eliminated renally,
linezolid also offers a pharmacokinetic profile that is suitable for patients with severe renal
deficiency and required no adjustment for severely reduced kidney function.7 Other than
vancomycin (which is ineffective in VRE) linezolid is the only antibiotic that is approved for use
in pediatrics with VRE infections.7 Finally, linezolid comes in both and IV and PO formulation,
making transition from inpatient to outpatient care much simpler. This would reduce the length
and cost of inpatient stay while allowing the patient to be on the same drug that was used to
successfully treat the patient’s infection while in the hospital.
Although daptomycin and linezolid should be added to the formulary, ceftaroline and
televancin should not be added. It was decided that ceftaroline was an unnecessary drug to add
because the formulary already contains several cephalosporins. Therefore, ceftaroline does not
add a new mechanism of action to the formulary. Although ceftaroline has an extended spectrum,
including gram negative organisms, there are other drugs on the formulary that cover these
organisms including the tetracyclines, the aminoglycosides and aztreonam. The Focus 1 and
Focus 2 trials found ceftaroline to be non-inferior to vancomycin for coverage of gram positive
organisms.8 However, ceftaroline is more expensive than vancomycin and because it is not
superior to vancomycin, vancomycin should be used to treat these patients.9, 10
Televancin is a new antibiotic in the same class as Vancomycin with the same
mechanism of action. More is know about Vancomycin dosing, administration, and monitoring.
Televancin is also more expensive than vancomycin.10 Because televancin offers little advantage
over vancomycin, it has been left off the formulary.
Because both daptomycin and linezolid are powerful antibiotics that offer novel
mechanisms of action that can treat multi-drug resistant organisms, they will be placed on the
restricted antibiotics list. According to the IDSA guidelines for Developing an Institutional
Program to Enhance Antimicrobial Stewardship, antimicrobial restriction is the most effective
way to control antibiotic use and prevent overuse of these medications and therefore reduce
emergence of resistant organisms.11 If a physician suspects that his patient has VRE or HAMRSA and would like to use daptomycin or linezoid, he will be able to prescribe the first dose of
these medications. The antimicrobial stewardship team will then be called in to determine if the
patient is in fact in need of these restricted medications. If the patient shows risk factors for VRE
or HA-MRSA or presents with special circumstances that preclude the use of more conventional
therapies, the ID pharmacist will approve the continuation of daptomycin or linezolid for the
empiric therapy. Risk factors for HA-MRSA include:12


Diagnosis of MRSA > 48 hours after hospital admission
Recent:
o
o
o
o
Hospitalization
Admission to a nursing home, skilled nursing facility, or hospice
Dialysis
Surgery
 History of permanent indwelling catheters or medical devices
Risk factors for VRE include:13


Previously treatment with vancomycin or other antibiotics for long periods of time.
Recent or current hospitalization, especially those including prolonged antibiotic
treatment
 Immunocompromised patients
 Recent surgery, especially abdominal or chest surgery.
 Prolonged use of indwelling urinary or central intravenous (IV) catheters.
If the daptomycin or linezolid is initially not approved but the patient’s condition
deteriorates despite other empiric therapy, initiation of daptomycin/linezolid therapy may be
considered at the discretion if the infectious disease team. Otherwise, the patient’s antibiotic
regimen should be re-evaluated once culture and susceptibility data is available.
Our formulary decision also takes into account potential new antibiotics in the pipeline.
One new drug, Kibdelomycin, is a type II topoisomerase inhibitor which shows strong activity
against many Gram positive bacteria including MRSA and E. faecalis. According to Merck,
Kibdelomycin is “"the first truly novel bacterial type II topoisomerase inhibitor with potent
antibacterial activity discovered from natural product sources in more than six decades.14"
While still in the initial stages of discovery, Kibdelomycin shows promise in in vitro studies as a
powerful new antibiotic against resistant strains of Gram positive bacteria as it shows no cross
resistance with gyrase inhibitors including novobiocin and coumermycin. The initial research
showing the mechanism of action, the structure, and the in vitro activity of Kibdelomycin was
published in August, 2011.14 Since this new drug has not yet reached clinical trials, it will not
directly affect our formulary decisions for class E. However, we expect that the emergence of
this new drug and other new antibiotics in the future will affect the antibiotics on our current
formulary and play a role in formulary decisions in the future.
References:
1. Rivera AM, Boucher HW. Current concepts in Antimicrobial therapy against select grampositive organisms: methicillin-resistant Staphylococcus aureus, penicillin-resistant
Pneumococci, and vancomycin-resistant Enterococci. Symposium on Antimicrobial Therapy.
2011 Dec 11.
2. Evans RP. The silent epidemic: CA-MRSA and HA-MRSA. American Academy of
Orthopaedcic Surgeons. http://www.aaos.org/news/aaosnow/may08/research1.asp (Accessed 17
Sept 2012)
3. Daptomycin package insert. Lexington, MA: Cubist Pharmaceuticals Incorporated; 2010 Nov.
4. Gilbert DN, Meollering RC, Eliopoulos GM, et al. The Sanford Guide to Antimicrobial
Therapy. 42nd ed. Sperryville: Antimicrobial Therapy Incorporated; 2012.
5. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidleines by the Infectious Deseases
Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in
adults and children. Clin Infect Dis. 2011; 52(3):e18-e55.
6. Product Information: Vibramycin(R), doxycycline oral capsules, syrup, suspension. Pfizer
Laboratories, New York, NY, 2001.
7. Product Information: ZYVOX(R) IV injection, oral tablets, oral suspension, linezolid IV
injection, oral tablets, oral suspension. Pharmacia and Upjohn Company, New York, NY, 2008.
8. File TM Jr, Low DE, Eckburg PB, et al: Integrated analysis of FOCUS 1 and FOCUS 2:
randomized, doubled-blinded, multicenter phase 3 trials of the efficacy and safety of ceftaroline
fosamil versus ceftriaxone in patients with community-acquired pneumonia. Clin Infect Dis
2010; 51(12):1395-1405.
9. Beckwith C. New drug bulletin: ceftaroline fosamil (Teflaro - Forest Pharmaceuticals).
University of Utah Hospitals and Clinics. January 14, 2011.
http://healthcare.utah.edu/pharmacy/bulletins/NDB_219.pdf (accessed 2012 Sept 16).
10. Laohavaleeson S, Barriere SL, Nicolau DP, Kuti JL. Cost-effectiveness of telavancin versus
vancomycin for treatment of complicated skin and skin structure infections. Pharmacotherapy.
2008;28(12):1471-82.
11. Dellit TH, Owens RC, Mcgowan JE, et al. Infectious Diseases Society of America and the
Society for Healthcare Epidemiology of America guidelines for developing an institutional
program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44(2):159-77.
12. Centers for Disease Control and Prevention. Diagnosis and testing of MRSA infections.
Updated 2 Dec 2010. Accessed 17 Sept 2012.
13. Centers for Disease Control and Prevention. Vancomycin resistant enterococci (VRE) in
healthcare settings. Updated 10 May 2011. Accessed 16 Sept 2012.
14.Phillips JW, Goetz MA, Smith SK, et al. Discovery of kibdelomycin, a potent new class of
bacterial type II topoisomerase inhibitor by chemical-genetic profiling in Staphylococcus aureus.
Chem Biol. 2011;18(8):955-65.