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  • Influence of Age on Frequency of Vancomycin Dosing



Vancomycin is the drug of choice for hospital inpatients with severe methicillin-resistant Staphylococcus aureus (MRSA) infections. Although vancomycin is an effective bactericidal agent, literature reports of antibiotic failure with this drug are relatively common. Efforts to minimize the risk of antibiotic failure have led to a focus on how best to opti­mize vancomycin pharmacokinetics.
The predose level of vancomycin in the serum is believed to be the most relevant clinically measurable pharmacokinetic parameter because the killing of susceptible organisms by this drug is time-dependent. As such, the bactericidal effect is related to the time above the minimum inhibitory concentra­tion (MIC). Although target predose serum levels have tradi­tionally been 5—15 mg/L, there has been a trend among clini­cians and in guidelines to target higher predose levels. For example, higher levels (15—20 mg/L) and more frequent dosing for patients with normal renal function were endorsed by the recent guidelines of the Infectious Diseases Society of America.

Theoretical rationales for higher targets include known poor tissue penetration of vancomycin into the lung, central nervous system, and bone. Also of concern is the apparently greater rate of treatment failure among patients with S. aureus isolates having a higher MIC. However, the results of recent clinical studies have been mixed. Jeffres and others found that targeting higher predose serum levels did not seem to improve outcomes in patients with health-care-associated pneumonia. Conversely, Hidayat and others observed a 20% lower response rate among patients with MRSA pneumonia or bacteremia who did not initially achieve the target predose serum level (> 15 mg/L). In addition, patients infected with high-MIC MRSA strains (MIC > 2 mg/L) and those with inva­sive infections were less likely to have a response to treatment. viagra 50 mg

The debate about vancomycin target levels is particularly relevant at the authors’ institution because of the high prevalence of invasive MRSA infections in the patient population. At the time that this study was conducted, most clinicians at the study institution had adopted the higher target predose levels for vancomycin (mostly 10—15 mg/L) for severe infections such as meningitis, pneumonia, endocarditis, osteomyelitis, and sepsis. Interestingly, despite the general practice of targeting higher predose serum levels in the past 7 or 8 years, the approach to initial vancomycin dosing had remained largely unchanged. Anecdotal observation suggested that by far the most common initial regimen prescribed was 1 g IV every 12 h (q12h); however, clinical pharmacists at this institution usually corrected the dose to reflect the patient’s weight, using 15 mg/kg to guide empiric dosing.
It was observed that lower-than-desired initial steady- state predose serum levels (less than 10 mg/L, and often less than 5 mg/L) occurred more frequently in adult patients in their 20s and 30s than in patients in their 40s and older. In most cases, the only logical way to achieve the target predose levels was to change the dosing frequency to every 8 h (q8h), rather than adjusting the dose. As a result, for a high proportion of this patient group, q8h dosing was ultimately continued for the management of their infection. The challenge lies in promptly identifying the patients who will ultimately require q8h dosing.

Although it would seem logical to empirically adjust the dosing interval according to the patient’s renal function, by calculating the creatinine clearance (for which the modified Cockcroft—Gault equation is used at the authors’ institution), there are difficulties with this approach. Serum creatinine can fluctuate significantly within the “normal range” for patients admitted with these acute infections. Furthermore, serum creatinine is often somewhat elevated at the time of admission because of volume depletion and acute illness. It usually normalizes with volume replacement, but this is not usually confirmed until 24 h after admission. In addition, serum creatinine can be altered by diet, muscle mass, and acute illness. Many patients admitted to the authors’ institution have comorbidities, such as HIV infection or poor nutritional status, that can contribute to muscle wasting. In those patients, serum creatinine may not provide a good measure of renal function, since it typically overestimates creatinine clear­ance. Finally, the hospital’s vancomycin dosing nomogram (like many nomograms used elsewhere) did not suggest dosing intervals any more frequent than q12h, regardless of creatinine clearance. This made it difficult for clinicians to know when empiric q8h dosing was indicated. For these reasons, the authors believed that age might be a more reliable predictor of appropriate vancomycin dosing frequency for patients with apparently normal renal function.
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The hypothesis was that adult patients under 40 years of age eliminate vancomycin more quickly than older patients and are more likely to require q8h dosing to achieve target predose serum levels. The age of 40 years was arbitrarily chosen as the cut-off between older and younger patients on the basis of clinical experience and observation. It was believed that patients less than 40 years of age might be at risk for suboptimal outcomes through delays in achieving adequate serum levels of the drug, as a result of insufficient initial dosing. This factor is even more relevant now that recommended targets have been increased to 15—20 mg/L for the infections discussed in this paper. Therefore, this study was undertaken to determine whether younger patients (less than 40 years of age) were more likely than patients 40 years of age or older to need q8h dosing and whether recommendations could be made to alter prescribing practices as a way to optimize vancomycin therapy.

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