Antimicrobial agents with primary activity against gram-positive bacteria

Therapeutic drug monitoring

Routine monitoring of vancomycin serum concentrations has become a highly debated issue over the years. Those who advocate routine monitoring cite the need to ensure therapeutic concentrations and to minimize toxicities.

Studies have shown that peak concentrations of vancomycin are not associated with safety or clinical efficacy. Therefore monitoring peak serum concentrations has largely fallen out of favor. On the other hand, vancomycin troughs have been heavily studied for their correlation with efficacy and toxicity. And although a few publications found improved outcomes when targeting vancomycin troughs of 15–20 μg/mL for serious MRSA infections, mounting evidence suggests that vancomycin troughs of this magnitude (greater than or equal to 15 μg/mL) are associated with an increased risk of nephrotoxicity. Because of this, greater attention has been given to AUC-based dosing strategies, with recent literature finding that an AUC/MIC target ratio of ≥400 was associated with decreased mortality and clinical failure while at the same time lower rates of nephrotoxicity and overall vancomycin exposure. Unfortunately, AUC monitoring is not routinely performed in clinical practice, and most critically ill patients are inappropriate for AUC-based dosing. Thus it still remains prudent to measure serum trough concentrations until more definitive guidance is provided to address these patient populations.

Intravenous administration in adults

In nonobese adults with normal renal function, the usual dose of vancomycin is 1 g (~15 mg/kg actual body weight) intravenously (IV) every 12 hours. For severe MRSA infections, 15–20 mg/kg every 8–12 hours has been recommended to achieve serum trough concentrations of 15–20 μg/mL, and loading doses of 25–30 mg/kg are proposed for critically ill patients in order to achieve higher concentrations sooner (both grade IIIB recommendations). Several dosing nomograms using body weight and CrCl have been developed to accurately and easily dose vancomycin; however, significant interpatient variability exists in both volume of distribution and renal clearance estimation in the critically ill population, so use of these nomograms is limited. Similarly, use of continuous infusion has been proposed, but with limited data on its benefit over intermittent infusion. ^, Table 108.1 lists dosing regimens for the antimicrobials discussed in this chapter.

Dosing in the setting of obesity

Morbidly obese, critically ill patients are difficult to dose given the lack of pharmacokinetic studies. Although actual body weight and CrCl continue to be the best correlate to volume of distribution and vancomycin clearance in the obese population, use of traditional weight-based dosing has led to overexposure and toxicity. This has prompted various alternative dosing strategies, including AUC-targeted nomograms, but these have yet to be studied in the combined critically ill and obese cohort. Because of this, therapeutic drug monitoring (TDM) remains a key tool in managing vancomycin dosing in this population. ^,

Dosing in renal failure/dialysis

Dose reduction is recommended for patients with renal dysfunction. In patients receiving intermittent hemodialysis, vancomycin pharmacokinetics vary depending on the patient’s actual body weight, timing of administration, residual renal function, and type of dialysis membrane used. With older, low-flux membranes, less frequent and lower postdialysis supplemental doses are required. With high-flux membranes, as much as 50% of vancomycin is removed. In these situations, common practice involves administration of a weight-based loading dose followed by maintenance doses given during the last hour of each dialysis session. Use of trough levels before each dialysis session may further guide dosing.

When continuous renal replacement therapy (CRRT) is being used, vancomycin dosing again depends on patient- and dialysis modality–related factors. Continuous venovenous hemodialysis (CVVHD) and continuous venovenous hemodiafiltration (CVVHDF) result in a greater total body clearance of vancomycin than does continuous venovenous hemofiltration (CVVH); therefore dosing every 12–24 hours and every 24–48 hours has been proposed for each modality, respectively. ^, For patients receiving sustained low-efficiency dialysis (SLED), a newer modality combining intermittent hemodialysis and CRRT, it appears that an initial weight-based loading dose followed by maintenance doses coupled with TDM may be appropriate. Overall, a review of several pharmacokinetic studies in patients receiving various forms of CRRT showed an association between effluent flow rate and vancomycin clearance. However, these findings require additional validation. Based on the variability in clearances achieved with each of these methods depending on blood flow rate, ultrafiltration rate, and the membranes used, TDM remains an effective method of ensuring appropriate vancomycin dosing when CRRT is used.

Dosing in cardiopulmonary bypass/extracorporeal membrane oxygenation

Cardiopulmonary bypass (CPB) was found to significantly affect the pharmacokinetic parameters of vancomycin in several small studies over the past 20 years. For example, Ortega and colleagues observed an immediate decrease in vancomycin serum concentration by 7 μg/mL after initiation of CBP, followed by gradual and steady decreases over the next 30 minutes. However, a recent prospective, comparative evaluation of vancomycin pharmacokinetics found no difference in maximum plasma concentration (C _max ), area under the curve (AUC _0–8 ), V _d , and clearance (Cl) between patients undergoing cardiac surgery with and without CBP.

Three studies in adult patients receiving extracorporeal membrane oxygenation (ECMO) found no significant differences in pharmacokinetic parameters compared with matched controls, reflecting vancomycin’s relative stability in ECMO circuits.

Oral administration

Oral administration of vancomycin is only for treating C. difficile colitis. The dose is 125–500 mg orally every 6 hours depending on severity and is not adjusted for renal dysfunction. Two oral formulations (capsules or liquid) can be used, or the IV solution can be administered orally to treat C. difficile . In cases of ileus or toxic megacolon, administration via rectal tube (as a retention enema) or ileostomy can be considered.

Adverse effects

The most notable adverse effects associated with vancomycin include nephrotoxicity, ototoxicity, and infusion-related reactions.

Initial reports of nephrotoxicity were thought to be related to impurities in the early formulations. After improved purification methods, the rate is generally accepted to be between 5% and 10% when vancomycin is not administered with other nephrotoxic agents and trough concentrations are less than 10 μg/mL. Factors that may increase the risk of nephrotoxicity include trough concentrations >15 μg/mL, higher total daily doses (≥4 g/day), larger patient weight, prolonged durations (>7 days), and concomitant nephrotoxins (i.e., aminoglycosides). ^, Recently, piperacillin-tazobactam in combination with vancomycin has also been associated with increased risk of acute kidney injury when compared with either agent alone and when compared with combinations of vancomycin with other beta-lactams. ^, On the other hand, use of continuous infusion appears to lower these risks. Although vancomycin-associated nephrotoxicity is usually reversible, it can lead to increased hospital length of stay, healthcare costs, and even mortality.

Ototoxicity is rare and ranges from vertigo and tinnitus to hearing loss. ^, Correlation between vancomycin exposure and risk of ototoxicity is lacking, suggesting that early reports of toxicity may have been caused by either another drug or the combination of another drug with vancomycin. ^, In the majority of cases, ototoxicity symptoms disappear within a month of discontinuing vancomycin.

Red man syndrome comprises erythema, pruritus, and flushing of the upper torso and is often associated with too rapid an infusion of the drug. In general, the infusion rate should not exceed 1 g/hr. Less frequently, hypotension and angioedema can occur. It is thought that increased histamine release is the cause of this syndrome, and the effects can be relieved by antihistamines. ^{, ,}

Other toxicities associated with vancomycin include maculopapular or erythematous rashes (2%–8%) ^{, ,} and anecdotal reports of neutropenia and thrombocytopenia. ^,

Dosing in renal failure/dialysis

Teicoplanin is not removed by hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). ^, The amount removed by high-flux membranes such as CVVH, CVVHD, and CVVHDF can be significant. For renal dysfunction, several dosing regimens exist, with doses even as high as 600–1800 mg/day during CVVH. Even with such high doses, therapeutic drug monitoring is still recommended, given the variability in protein binding and ultrafiltration rates when using CRRT.

Dosing in venoarterial extracorporeal membrane oxygenation

Limited data are available on the use of teicoplanin in patients receiving venoarterial extracorporeal membrane oxygenation (VA-ECMO). Eleven patients received a median loading dose of 11.6 mg/kg every 12 hours × 3 then a fourth dose 24 hours after the third dose. The range of trough concentrations was 14.85–44.84 μg/mL.