Vancomycin Lecture 5 PDF

Therapeutic Drug Monitoring Lecture 5: Vancomycin Department of Clinical Pharmacy/fifth stage Introduction: It is a glycopeptide antibiotic used to treat 1/ severe gram-positive infections due to organisms that are resistant to other antibiotics such as methicillin-resistant staphylococci and ampici...

Therapeutic Drug Monitoring Lecture 5: Vancomycin Department of Clinical Pharmacy/fifth stage Introduction: It is a glycopeptide antibiotic used to treat 1/ severe gram-positive infections due to organisms that are resistant to other antibiotics such as methicillin-resistant staphylococci and ampicillin-resistant enterococci. 2/ It is also used to treat infections caused by other sensitive gram-positive organisms in patients that are allergic to penicillins. It is bactericidal and exhibits time-dependent or concentration-independent bacterial killing, i.e. kill bacteria most effectively when drug concentrations are a multiple (usually three to five times) of the minimum inhibitory concentration (MIC) for the bacteria. 2 THERAPEUTIC AND TOXIC CONCENTRATIONS: 1/ Vancomycin is administered as a short-term (1-1.5hour) intravenous infusion and exhibit a distribution phase so that drug in the blood and in the tissues are not yet in equilibrium. Because of this, a 1/2–1 hour waiting period is allowed for distribution to finish before maximum or “peak” concentrations are measured. 2/ A peak vancomycin concentration is obtained after 1.5 hr. or 2 hr. 3/ Infusion rate related side effects have been noted when shorter infusion times (~30 minutes or less) have been used, includes: Urticarial or erythematous reactions, intense flushing (known as the “redman” or “red-neck” syndrome) Tachycardia, hypotension All can be largely avoided with the longer infusion time. 3 4/ Ototoxicity has been reported when vancomycin serum concentrations exceed 80 μg/mL, so the therapeutic range for steady-state peak concentrations is usually considered to be 20–40 μg/mL. 5/ Because vancomycin does not enter the central nervous system in appreciable amounts when given intravenously, steady-state peak concentrations of 40–60 μg/mL or direct administration into the cerebral spinal fluid may be necessary. 6/ Ototoxicity can be permanent if appropriate changes in vancomycin dosing are not made. 7/ Trough concentrations (pre-dose or minimum concentrations usually obtained within 30 minutes of the next dose) are usually related to therapeutic outcome for vancomycin because the antibiotic follows time-dependent bacterial killing. 4 8/ Optimal bactericidal effects are found at concentrations three to five times the organism’s MIC. Because the average vancomycin MICs for Staphylococcus aureus and Staphylococcus epidermidis are 1–2 μg/mL, minimum pre-dose or trough steadystate concentrations equal to 10–15 μg/mL are usually adequate to resolve infections with susceptible organisms. 9/ The need for higher trough concentrations in institutions with antibiograms that include MRSA with higher MIC values lead to the expansion of the therapeutic trough concentration range to 15–20 μg/mL. 10/ Vancomycin penetrates into lung tissue poorly (average serum: tissue ratio of 6:1) and pulmonary concentrations are highly variable among patients. Based on these findings and reports of therapeutic failures, recent treatment guidelines for hospital-aquired pneumonia recommend vancomycin steady-state trough concentrations equal to 15–20 μg/mL. 5 11/ Trough vancomycin steady-state concentrations above 15 μg/mL are related to an increased incidence of nephrotoxicity. 12/ Many patients receiving vancomycin are critically ill, so other sources of renal dysfunction, such as hypotension or other nephrotoxic drug therapy (such as aminoglycosides, amphotericin B, or immune-supressants), should be ruled out before the diagnosis of vancomycin-induced renal damage is made in a patient. 13/ Compared to aminoglycoside antibiotics, vancomycin is usually considered to have less nephrotoxicity potential. 14/ In contrast to ototoxicity, vancomycin-related nephrotoxicity is usually reversible with a low incidence of residual damage if the antibiotic is withdrawn or doses appropriately adjusted soon after renal function tests change. With adequate patient monitoring, the only result of vancomycin nephrotoxicity may be transient serum creatinine increases of 0.5–2.0 mg/dL. 6 7 CLINICAL MONITORING PARAMETERS 1/ Antibiotic therapy is prescribed for patient depending on current microbiologic cultures and sensitivities; in addition, antibiograms should be consulted regularly to note changes in resistance patterns and minimum inhibitory concentrations for pathogens. 2/ Favorable response to antibiotic treatment is usually indicated by high white blood cell counts decreasing toward the normal range, the trend of body temperatures (plotted as body temperature vs. time, also known as the “fever curve”) approaching normal, and any specific infection site tests or procedures resolving. 3/ Vancomycin steady-state serum concentrations should be measured in 3–5 estimated half-lives. Since prolongation of the dosage interval is often used in patients with decreased elimination, a useful clinical rule is to measure serum concentrations after the third dose which typically occurs 1–3 days after dosing has commenced and this is a good time to also assess clinical efficacy of the treatment. 8 4/ Most individuals advocate the measurement of just a steady-state trough concentration. The reasoning behind this approach is that vancomycin follows timedependent bacterial killing, and the efficacy of the drug should be most closely related to the minimum serum concentration encountered over the dosage interval. Since nephrotoxicity is related to high trough concentrations, measurement of this value should ensure therapeutic, non-nephrotoxic drug concentrations. 5/ Clinicians should consider measuring peak concentrations when large doses are given (>1500 mg/dose) or for infections that require high peak concentrations (such as central nervous system infections) in order not to have a steady-state peak concentration that would be above the accepted toxic range (>80 μg/mL) in which could developed ototoxicity while receiving vancomycin. 6/ When high vancomycin concentrations are needed for therapeutic reasons (trough >15 μg/mL, peak >40 μg/mL), assessment of renal function and auditory/vestibular function should be conducted on a daily basis. 7/ Vancomycin can also cause allergic symptoms such as chills, fever, skin rashes, and anaphylactoid reactions. 9 BASIC CLINICAL PHARMACOKINETIC PARAMETERS 1/ Vancomycin is almost completely eliminated unchanged in the urine primarily by glomerular filtration (≥90%). 2/ Intramuscular administration is usually avoided because this route has been reported to cause tissue necrosis at the site of injection. 3/ Oral bioavailability is poor (