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Ceftriaxone and Ceftazidime IV-IV Dosage Stepdown Initiative

Amy Wai, B.Sc. (Pharm), VHHSC Home IV Antibiotic Program
December 1997 Drug & Therapeutics Newsletter
(C) 1997, CSU-Pharmaceutical Sciences
Vancouver Hospital & Health Sciences Centre

The ceftriaxone and ceftazidime IV-IV dosage stepdown initiative was launched by the CSU Pharmaceutical Sciences in January 1997. A similar program for BMT/leukemia patients has been in place since April 1995. The initiative promotes the stepdown of select intravenous (IV) antibiotics from an initial aggressive dose to a moderate dose for the treatment of serious infections in patients who are clinically stable and still require parenteral therapy. This initiative reduces drug costs while maintaining equivalent patient outcomes. Stepdown from 2g to 1g per dosage interval of ceftriaxone or ceftazidime will save approximately $35.00 in drug costs per day.

What is the rationale for IV-IV dosage stepdown therapy?

While initial aggressive antibiotic dosage regimens are often prescribed for the treatment of serious bacterial infections, subsequent stepdown to moderate doses will achieve adequate serum concentrations for the eradication of most bacterial pathogens. Figures 1 and 2 show typical serum concentrations over time following 1g and 2g IV doses of ceftriaxone and ceftazidime.

A single 30-minute infusion of ceftriaxone 1g will yield a peak serum concentration of approximately 150 mg/L.1 At the end of a typical 24-hour dosing interval, the serum concentration remains greater than 10 mg/L which is in excess of the MIC90 of most susceptible organisms.1-3

Figure 1. Ceftriaxone serum concentrations versus time

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A single 1g dose of ceftazidime will yield a peak serum concentration of approximately 100mg/L.4 At the end of a typical 8-hour dosing interval, the serum concentration remains greater than 2 mg/L which is in excess of the MIC90 of most susceptible organisms except pseudomonas species. Studies have also shown that tissue and fluid concentrations of both ceftriaxone and ceftazidime at 1g per dosage interval exceed the MIC90 for sensitive organisms.1,5

Figure 2. Ceftazidime serum concentrations versus time

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Based upon a 1995 review of ceftazidime treatment courses in BMT/leukemia patients, IV-IV stepdown was initiated in 67% of the treatment courses. There was no evidence of any negative impact on patient outcome and an annual cost avoidance of $26,822 was projected.

Which patients are candidates for IV-IV dosage stepdown?

Patients are considered to be potential candidates for stepdown if they are clinically stable, afebrile for 48 hours and show signs of resolving infection. If the patient is able to tolerate oral therapy, stepdown to an appropriate oral antibiotic (IV-PO) is recommended. Patients being treated for central nervous system infections and severe pseudomonas infections should generally not receive stepdown therapy.

How is the IV-IV stepdown initiative promoted?

All ceftazidime and ceftriaxone treatment courses for non-BMT/leukemia patients are identified daily using the pharmacy computer. All 2g per dosage interval treatment courses are then reviewed daily by a clinical pharmacist in collaboration with the primary health care team to look for opportunities for stepdown.

What are the results of the IV-IV dosage stepdown initiative to date?

Ceftriaxone

A summary of the outcome of the ceftriaxone IV-IV dosage stepdown initiative is shown in Figure 3. During the first 6 months, there were 220 treatment courses involving initial regimens of 2g per dosage interval initiated in non-BMT/leukemia patients. Of the 96 treatment courses considered eligible for stepdown, 52 (54%) were successfully stepped down in collaboration with the primary health care team, 21 (22%) were discontinued, 13 (14%) were changed to another antibiotic, and 10 (11%) remained on the original regimen.

Figure 3. Ceftriaxone treatment course outcomes

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Of the 52 stepdown treatment courses, 13 (25%) were IV-IV dosage stepdown only, 11 (21%) were further stepped down to oral (IV-IV-PO) step-down), and 28 (54%) were converted directly to oral therapy. Stepdown was directly facilitated under the initiative in 60% of these treatment courses. Fifty-one (98%) of the stepdown treatment courses resulted in clinical cure or improvement. This was similar to the outcomes for non-stepdown patients. The treatment course duration for IV-IV stepdown patients was 8.3 days (range 3-21 days), similar to the mean treatment duration of non-stepdown courses (8.7 days, range 4-16 days).

Ceftazidime

A summary of the outcome of the ceftazidime IV-IV dosage stepdown initiative is shown in Figure 4. During the first 6 months, there were 50 treatment courses involving initial regimens of 2g per dosage interval initiated in non-BMT/leukemia patients. Of the 11 treatment courses considered eligible for stepdown, 6 (55%) were successfully stepped down in collaboration with the primary health care team, 1 (9%) was discontinued, and 4 (36%) remained on the original regimen.

Figure 4. Ceftazidime treatment course outcomes

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Of the 6 stepdown treatment courses, 3 (50%) were IV-IV dosage stepdown only, and 3 (50%) were converted directly to oral therapy. Stepdown was directly facilitated under the initiative in 67% of these treatment courses. Five (83%) of the stepdown treatment courses resulted in clinical cure or improvement. This was similar to the outcomes for non-stepdown patients. The treatment course duration of IV-IV stepdown patients was 12.7 days (range 8-20 days), and the mean treatment duration of non-stepdown courses was 8.7 days ( range 6-10 days).

What are the estimated savings from this initiative?

Estimated drug treatment acquisition, preparation and delivery cost avoidance directly attributed to the IV-IV dosage stepdown initiative for both ceftriaxone and ceftazidime during the 6-month period was $9900.00. This initiative also resulted in further streamlining of antibiotic therapy by switching to another antibiotic when warranted or by facilitating timely discontinuation of the target antibiotics. Savings associated with these latter treatment modifications have not been quantified.

This latest IV-IV dosage stepdown initiative has proven to be a safe, effective and cost efficient process.

References

1. Brogden RN, Ward A. Ceftriaxone. A reappraisal of its antibacterial activity and pharmacokinetic properties, and an update on its therapeutic use with particular reference to once-daily administration. Drugs 1988;35:604-45.

2. Low DE, Mandell LA. A prospective open-label multicentre trial on the use of 1g, once daily cetriaxone in lower respiratory tract infections. Can J Infect Dis 1994;5 Suppl C:3C-7C.

3. Richards DM et al. Ceftriaxone. A review of its antibacterial activity, pharmacological properties and therapeutic use. Drugs 1984;27:469-586.

4. Smith BR. Cefsulodin and ceftazidime, two antipseudomonal cephalosporins. Clin Pharm 1984;3:373-83.

5. Rains CP, Bryson HM, Peters DM. Ceftazidime. An update of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy. Drugs 1995;49:577-617.