E-DRUG: Cloxacillin, dicloxacillin or flucloxacillin? (2)
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[In response to the request for information posted 7/6/05]
Dear Wilbert,
You have identified the major considerations when selecting antibiotics for an EML, including:
1. Antibiotic class and antibacterial spectrum of activity for each antibiotic within the particular class
2. Dosage form availability for each antibiotic
3. Bioavailability of each antibiotic
4. Side effect profile for each antibiotic
5. Cost and cost-effectiveness of comparable antibiotics within a class
1. Antibiotic class and antibacterial spectrum of activity
Flucoxacillin, dicloxacillin, and cloxacillin all belong to the class of penicillinase-resistant penicillins (along with oxacillin and nafcillin).
Unlike other classes of penicillins, antibiotics within this particular class are very similar in terms of spectrum of activity and offer no clinical comparative advantage over one another in terms of spectrum.
All the penicillinase-resistant penicillins are active against gram-positive bacteria, specifically Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus milleri, and Streptococcus Groups A, B, C, and G as well as the peptostreptococcus anaerobe.
They are marginally active against Viridans streptococcus and Staph. epidermidis, however, other antibiotics show much greater activity against these organisms.
2. Dosage form availability
It is important to have penicillinase-resistant penicillins available in three dosage forms: oral tablet/capsule, oral powder for suspension, and injectable.
This presents a problem, however, as many of these drugs are not available in all 3 dosage forms in all countries.
For example, in the US, only 3 (dicloxacillin, oxacillin, and nafcillin) of the 5 penicillinase-resistant penicillins are marketed and they are available in limited dosage forms. Dicloxacillin is only available in oral formulations, whereas nafcillin and oxacillin are only available as injectable formulations. Therefore, US formularies tend to list 2 different antibiotics in this class: dicloxacillin as the oral formulation and either nafcillin or oxacillin as the injectable formulation. Typically, US institutions allow pharmacists to interchange nafcillin and oxacillin without permission of the prescriber.
3. Bioavailability
Micromedex states the following rates of absorption for these drugs:
cloxacillin 50-75%
dicloxacillin 60-80%
oxacillin 67-88%
nafcillin 50%
flucoxacillin (no data available)
The reality is that absorption is relatively similar between all these drugs. If you collected all the pharmacokinetic studies ever conducted on these drugs, absorption rates for all would likely fall in the 50-80% range, depending on conditions and number of subjects. All drugs are best absorbed on an empty stomach. The clinical implications of differences in absorption
are likely negligible.
4. Side effect profile
The side effect profiles of all drugs within this class are fairly comparable.
5. Cost and Comparable cost-effectiveness.
Because dosage, frequency of administration, duration of treatment, efficacy and safety are similar among drugs in this class, the cost of the drug itself becomes important in selection. Of course, costs vary within and among countries for all of these drugs and formulations, so this needs to be analyzed on a case-by-case basis.
The ideal EML:
In my opinon, in the ideal situation, an EML would list only one penicillinase-resistant penicillin and this antibiotic would be available in 3 dosage forms: tablet/capsule, suspension, and injection.
The 2005 WHO Model EML:
As you stated, The 2005 WHO Model EML contains only one penicillinase-resistant penicillin, cloxacillin. It is listed in 3 dosage forms. A square box next to cloxacillin in the WHO Model EML indicates countries should consider other alternatives within this class, if appropriate.
Advantages to listing only 1 antibiotic:
Listing only one antibiotic would, theoretically, lead to simpler standard treatment guidelines and facilitate training and practices of prescribers and dispensers. It could also facilitate procurement, stocking, etc.
Reasons to consider listing more than 1 antibioitc in this class:
1. Unavailability of all dosage forms in country
2. Cost: Significant cost differences exist between drugs and various formulations. Hypothetically, in a particular country, cloxacillin and dicloxacillin may both be available in all 3 dosage forms. But, cloxacillin injection may be the least expensive injectable drug, while dicloxacillin may be the least expensive oral drug. In this case, countries need to determine if the benefit of listing (and procuring) only 1 drug is worth the additional acquisiton costs.
Conclusion: In my opinion, clinically speaking, there is no need for more than one penicillinase-resistant penicillin on EMLs. Practically speaking, however, 2 drugs may need to be listed because of in-country unavailability of dosage forms and/or cost issues.
Brenda Waning, MPH, RPh
Center for International Health and Development
Boston University School of Public Health
85 East Concord Street, 5th floor
Boston, MA 02118 USA
Tel: +1 617-414-1278 Fax: +1 617-414-1261
Email: bwaning@bu.edu