P&T News: August 2002
Jessica L. Lewis, Pharm.D.
Peer Review Status: Internally Peer Reviewed bu
by Bradley E. Britigan, M.D., Professor and Head, Division of
Infectious Diseases, Department of Internal Medicine and the
Antibiotic Advisory Subcommittee
The discovery of the fluoroquinolone class of antibiotics revealed antibiotics with a broad spectrum of activity, efficacy, general safety, good bioavailability, favorable pharmacokinetics, and convenient dosing. 2-4 This favorable profile has led to broad acceptance within both hospital and community settings. 2,3 The use of fluoroquinolones over the years has increased nationwide and within UIHC. 2,5 As the number of flouroquinolone prescriptions increases, the degree of fluoroquinolone resistance may also rise. 6 Overuse of antimicrobial medications, such as fluoroquinolones, has the potential to breed resistant microbial organisms and cause the medical management of the patient to be more challenging and, oftentimes, more expensive.
Alterations in drug target and permeation of the drug are the proposed mechanisms for fluoroquinolone resistance. Fluoroquinolones directly inhibit bacterial DNA synthesis by interacting with either DNA gyrase or topoisomerase IV, the enzymes required for DNA replication. The entrapment of these enzymes halts the movement of the DNA replication fork. Disruption of the replication fork and rapid inhibition of DNA synthesis ultimately results in bacterial cell death. All fluoroquinolones are active, to some extent, against both DNA gyrase and topoisomerase IV, but the degree of affinity for each enzyme differs between fluoroquinolones. 1,2,7 For example, if the fluoroquinolone has a higher affinity for DNA gyrase and a spontaneous mutation occurs in this enzyme, the drug's activity becomes dependent on topoisomerase IV. If this drug has a low affinity for topoisomerase IV, then the mutant strain may continue to replicate. 1 Resistance is more likely to develop if mutations are present in both DNA gyrase and topoisomerase IV for a particular species. However, if a mutation occurs in just one of the enzymes, alterations in the primary target will lead to a greater degree of resistance than if the secondary target was changed.
The second theorized mechanism of fluoroquinolone resistance is alteration in permeation of the drug. Mutations may occur in the outer and inner bacterial protein membranes resulting in altered expression of porin proteins which limits the ability of fluoroquinolones to permeate bacterial membranes. Thirdly, all bacteria are thought to contain efflux pumps. Expression or overexpression of these pumps can actively remove antimicrobials from the cell resulting in antibiotic ineffectiveness and drug resistance. The ideal fluoroquinolone would possess equal activity against both DNA gyrase and topoisomerase IV, and also remain unaffected by membrane mutations and efflux pumps. 1,2,7
The Centers for Disease Control and Prevention (CDC) have employed a campaign to increase awareness and prevent antimicrobial resistance in healthcare settings. 6 They state that treating infections effectively and using antimicrobials wisely are key in a drug resistance prevention program. Additionally, discontinuing antimicrobials when the infection is treated and avoiding antimicrobial treatment if infection is not diagnosed or when infection is unlikely will also help to ensure appropriate use of antibiotics. The CDC state that by engaging in local antimicrobial appropriate-use programs care providers can accurately combat antimicrobial resistance because information is specific for the healthcare organization's patient population, formulary, and antibiogram. 6 The challenge put forth by the CDC is to "transform this increasingly urgent threat into a manageable problem."6
What can we do to prevent resistance? In order to preserve fluoroquinolone efficacy and prevent the spread of resistant organisms, the use of levofloxacin (the UIHC formulary fluoroquinolone) has been approved at UIHC for specific conditions (see Algorithm). By restricting the use of levofloxacin to the approved indications illustrated in the algorithm, the development of resistance may be slowed or prevented. Other antimicrobial regimens may be more appropriate and/or cost-effective for other indications. For example, gentamicin should be used in place of levofloxacin in patients without high risk for renal dysfunction for the treatment of nosocomial pneumonia and pseudomonas infection as synergy is consistently attained with gentamicin but not with levofloxacin. In the outpatient setting where E. coli resistance to it is low (<20%), trimethoprim/sulfamethoxazole is a good cost-effective alternative for treating urinary tract infections.
Intravenous levofloxacin use at UIHC is restricted to designated indications that are outlined on a Protocol Drug Order Form. The indications include: 1) serious gram negative infections with organisms documented to be resistant to aminoglycosides, third or fourth generation cephalosporins, and extended spectrum penicillins; 2) as monotherapy of a serious gram negative infection in which there is an intolerance and/or a contraindication to aminoglycosides, third or fourth generation cephalosporins and extended spectrum penicillins; 3) as combination therapy with a beta-lactam antibiotic for treatment of a serious gram negative infection for patients who have a contraindication and/or intolerance to aminoglycosides; 4) community-acquired pneumonia; 5) formal Infectious Diseases recommendation. This form is available on all the patient care units or from the pharmacy satellites. This form must be completed within 24 hours of the start of therapy. If this form is not received by Pharmacy within 24 hours of the written order, the order will be discontinued and subsequent doses will be withheld until a completed protocol order form has been received.
References
One of the major causes of medication errors is the ongoing use of potentially dangerous abbreviations and dose designations. While many drug name and medical abbreviations have been associated with medication errors, the designation "U" for unit/units has been especially problematic. This was noted by the Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) in its September, 2001, Sentinel Event ALERT entitled, "Medication Errors Related to Potentially Dangerous Abbreviations." In this document the JCAHO points out that when "U" is poorly handwritten, it can often look like a zero (0), potentially leading to ten-fold overdoses or greater. There have been numerous case reports from around the U.S. where the root cause of sentinel events related to insulin dosage has been the interpretation of a "U" as a zero (e.g., "6 U" mistakenly interpreted as 60 units). See examples of potentially misread orders below.
Several other national safety organizations, including the Institute for Safe Medication Practices (ISMP) and the National Coordinating Council for Medication Error Reporting and Prevention (NCCMERP), have also recommended that "U" not be designated as an approved medical abbreviation for unit/units. , These organizations point out that besides the confusion with zero, other error reports have described situations in which "U" has been misinterpreted as "4" or "cc."
Because of the safety concerns outlined above, the Pharmacy and Therapeutics Subcommittee and the Health Information Management Subcommittee have approved the deletion of the abbreviation "U" for unit/units from the UIHC's list of Approved Medical Abbreviations. Prescribers and other clinicians should spell out the complete word unit (or units) when ordering medication or other treatments designated in this manner. Prescribers will be notified to clarify orders using the "U" designation.
Two new alternative medicine databases (AltMedDex and AltMed-REAX for Professionals) are now available on Micromedex. These databases can be accessed by doing a search on the main screen in the Integrated Index System and scrolling down the results to the Complementary and Alternative Medicine Information heading. You can also select 'Search by database' on the main menu and then select Alternative Medicine.
AltMed-REAX for Professionals provides information to healthcare professionals on interactions related to herbal medicines and other dietary supplements. This includes information on:
For each type of interaction, the following information is given:
AltMedDex provides evidence-based, clinical information on herbal, vitamin, mineral and other dietary supplements. AltMedDex contains two sections: Alternative Medicine Evaluations and Alternative Medicine Consults.
Alternative Medicine Evaluations monographs appear in a standardized format that allows you to easily find the information you need. Specific topics include the following:
Alternative Medicine Consults provide crucial information of interest to those needing information on herbal medicines and other dietary supplements. Topics include FDA warnings, pregnancy risk categories, and guidelines on dosing, safety and efficacy issues.
DRUGS ADDED TO STOCK
ETHINYL ESTRADIOL WITH NORETHINDRONE ACETATE
Tablets: 5 mcg/1 mg
This combination product (femhrt® - Pfizer) is indicated for the
treatment of moderate to severe vasomotor symptoms associated with
menopause and the prevention of osteoporosis.
FLUVESTRANT
Injection: 50 mg per ml
Fluvestrant (Faslodex® - Astra-Zeneca) is an estrogen receptor
antagonist indicated for the treatment of metastatic breast cancer in
post menopausal women with disease progression following antiestrogen
therapy.
LOVASTATIN
Tablets: 10 mg, 20 mg
Lovastatin (generic, Mevacor® - Merck) is an HMG-CoA reductase
inhibitor indicated for the primary prevention of coronary heart
disease, slowing the progession of coronary heart disease, and the
management of hypercholesterolemia.
VORICONAZOLE
Injection: 200 mg
Tablets: 50 mg, 200 mg
Voriconazole (Vrend® - Pfizer) is an antifungal indicated for the
treatment of invasive aspergillosis and serious fungal infections
caused by Scedosporium apiospermum and Fusarium Spp.
Note: Voriconazole is a protocol drug with its use restricted to: 1)
documented or high clinical index of suspicion of invasive
aspergillosis; 2) documented or high clinical index of suspicion of
an invasive mold infection; and 3) formal Infectious Diseases
recommendation.
ADDITIONAL ACTIONS
FEXOFENADINE (ALLEGRA®) TABLETS
A 180 mg strength has been added to stock.
ESTRADIOL TRANSDERMAL PATCHES
The Climera® brand has been deleted. It will be replaced by the
Esclim® brand which is dosed twice weekly.
Note: The cost following each monograph is the UIHC inpatient
acquisition cost.
DRUGS DELETED FROM STOCK
AUROTHIOGLUCOSE (SOLGANAL®) INJECTION
Discontinued by all manufacturers.
BECLOMETHASONE 0.084% (VANCENASE AQ DS®) NASAL SPRAY
Discontinued by the manufacturer. The single-strength (0.042%) nasal
spray (Beconase AQ®) is available.
CHLORAMPHENICOL OTIC SOLUTION
Discontinued by all manufacturers.
DIHYDROTACHYSTEROL 0.2 MG TABLET (DHT)
Discontinued by all manufacturers. The 0.4 mg tablets and oral
solution are available.
ESTRADIOL WITH NORETHINDRONE ACETATE (COMBIPATCH®) TRANSDERMAL
PATCH
Deleted by Pharmacy and Therapeutics Subcommittee action. Less costly
alternatives include femhrt® and Ortho-Prefest®.
ESTRADIOL TRANSDERMAL PATCHES
The Climera® brand which is dosed once-weekly has been deleted
from stock. It has been replaced with the Esclim® brand which is
dosed twice weekly.
GLIPIZIDE (GLUCOTROL® XL) SUSTAINED-RELEASE TABLETS
Deleted due to markedly increased cost compared to regular-release
glipizide. Glipizide 5 mg and 10 mg regular-release tablets are
available.
HISTOPLASMIN SKIN TEST
Discontinued by all manufacturers.
LORATADINE (CLARITIN®) TABLETS AND SYRUP
Deleted by Pharmacy and Therapeutics Subcommittee action. Less costly
alternatives include fexofenadine (Allegra®) and cetirizine
(Zyrtec®).
LORATADINE WITH PSEUDOEPHEDRINE (CLARITIN-D® 24 HOUR)
TABLETS
Deleted by Pharmacy and Therapeutics Subcommittee action. Less costly
alternatives include fexofenadine with pseudoephedrine or single
component products.
NANDROLONE DECONOATE INJECTION
Discontinued by all manufacturers.
OCTREOTIDE ACETATE SUSPENSION FOR INJECTION
The 10 mg strength (Sandostatin® LAR Depot) has been discontinued
by the manufacturer. The 20 mg and 30 mg strengths are still
available.
POLYMIXIN B INJECTION
Discontinued due to low use.
THIOTHIXENE ORAL LIQUID
Discontinued by all manufacturers. The capsule formulation is still
available.
TUBERCULIN TINE TEST
Discontinued by all manufacturers. Tuberculin purified protein
derivative (PPD) skin test is available.