Cotrimoxazole - optimal dosing in the critically ill

Annals of Intensive Care Cotrimoxazole - optimal dosing in the critically ill Glen R Brown 0 0 Pharmacy Department, St. Paul's Hospital , 1081 Burrard St, Vancouver, BC V6Z 1Y6 , Canada The optimum dosage regimen for cotrimoxazole in the treatment of life threatening infections due to susceptible organisms encountered in critically ill patients is unclear despite decades of the drug's use. Therapeutic drug monitoring to determine the appropriate dosing for successful infection eradication is not widely available. The clinician must utilize published pharmacokinetic, pharmacodynamic, and effective inhibitory concentration information to determine potential dosing regimens for individual patients when treating specific pathogens. Using minimum inhibitory concentrations known to successfully block growth for target pathogens, the pharmacokinetics of both trimethoprim and sulfamethoxazole can be utilized to establish empiric dosing regimens for critically ill patients while considering organ of clearance impairment. The author's recommendations for appropriate dosing regimens are forwarded based on these parameters. Cotrimoxazole; Trimethoprim; Sulfamethoxazole; Pharmacokinetics; Pharmacodynamics - Review Cotrimoxazole, the combination of trimethoprim (TMP) and sulfamethoxazole (SMX), is frequently required for the treatment of critically ill patients with infections caused by sensitive pathogens, such as Pneumocystis jovenii or Stenotrophomonas maltophilia. As with other antibiotics, TMP/SMX must be given in a sufficient dose at a proper frequency to produce adequate concentrations at the site of infection for successful eradication of the pathogen. TMP/ SMX also has concentration-dependent toxicities, necessitating avoidance of excessive dosage. The determination of the appropriate dosing regimen requires optimum application of the drugs pharmacokinetics and pharmacodynamic characteristics. Data from clinical trials of various dosages of TMP/SMX in the critically ill population are generally lacking, forcing the clinician to prescribe the drug without clear knowledge of the appropriate regimen. This paper will review the available pharmacodynamic and pharmacokinetic data necessary for the clinician to determine the optimum dosage of TMP/SMX for selected infections in the critically ill. Relevant electronic databases of published literature (Embase, Medline) containing studies of the pharmacokinetics, pharmacodynamics, and inhibitory concentrations of TMP/SMX were searched to end date of 16 September 2013. References of selected manuscripts were reviewed for relevant citations. References in tertiary information sources, and the authors personal information files were searched for relevant data. The preliminary search yielded few studies focused specifically on the critically ill population. Therefore, studies outlining the pharmacokinetics in normal and altered organ clearance populations (renal and/ or liver impairment); the pharmacodynamics of TMP/SMX in any setting; and the minimum inhibitory concentrations, determined either in vitro or in vivo, were selected. Data from the selected publications were reviewed to allow an assessment of the applicability to the critically ill population and to determine potential dosing regimens for specific pathogens in critically ill patients. Pharmacokinetics The volume of distribution (Vd) for each drug has been determined in healthy subjects with TMP having a much larger volume of distribution than SMX based on differences in lipid solubility [1]. There are only very limited data available on the impact of critical illness on the Vd of the two drugs, despite the widely recognized changes that occur with other antibiotics. In critically ill patients requiring mechanical ventilation for Pneumocystis carinii pneumonia, the Vd of TMP was 1.6 L/kg versus 1.4 L/kg for non-ventilated patients, and the Vd for SMX was 0.5 L/kg versus 0.4 L/kg [2]. In trauma patients, although reporting low Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of 1 to 24, the Vd of TMP was found to be 2.1 L/kg and for SMX was 0.5 L/kg [3]. No studies have reported the magnitude of change in Vd of the drugs in patients with septic shock requiring large volume resuscitation or vasopressors. Data are also lacking on the impact of obesity on the Vd, and resulting dosing of the drug. Therefore, dosing regimens should be based on actual body weight. Both TMP and SMX are eliminated from the body predominantly by renal excretion [1,4]. Approximately 20% of SMX is metabolized in the liver to N4-acetylsulfamethoxazole which is subsequently excreted in the urine [5]. N4-acetylsulfamethoxazole lacks relevant antibacterial activity [1]. The remainder of SMX is cleared by the kidney as unchanged drug [4]. The renal excretion of SMX is increased when the urine is alkaline [5]. Similarly, only a small portion of TMP (10 to 20%) is metabolized by the liver to inactive metabolites, which are subsequently conjugated and excreted in the urine [1]. The remaining portion of TMP elimination is via renal secretion of unchanged drug [4]. Unlike SMX, TMP renal clearance is increased with acid urine [1]. Achievable concentrations for various dosages are described in Table 1. The commercially available tablet contains 80 mg TMP with 400 mg SMX (single strength) or 160 mg TMP with 800 mg SMX (double strength). An intravenous preparation is commercially available containing 16 mg TMP with 80 mg SMX per ml. Both intravenous (IV) and oral (PO) dosages of 15 mg/kg/day of TMP produced Cmax concentrations within the target range for treatment of Pneumocystis jovenii (5 to 8 mcg/ml) [2,6]. Oral dosages of 20 mg/kg/day of TMP produced higher concentrations which resulted in a high incidence of toxicities [7]. For pathogens with lower target concentrations (see Target concentrations; Table 2), Cmin concentrations for TMP of above 2 mcg/ml can be maintained with a dosage of 160 mg TMP twice daily. Renal dysfunction Despite the availability of TMP/SMX for a number of decades, published data on the optimum dosage of the drug in patients with renal impairment are unavailable, similar to many widely used treatments [18]. Early work demonstrated a linear relationship between the elimination rate of both unchanged SMX (weak correlation) or TMP (significant correlation) and renal function (as measured by inulin clearance) [8]. The strongest correlation between renal function and pharmacokinetics was seen with the clearance of SMX metabolites (inactive), while the unchanged SMX concentrations remained constant over a wide range of renal impairment [8,19]. These studies involved patients with renal impairment resulting in creatinine clearance rates of 3 to 72 ml/min/1.73 m2 [8,19]. Using the dosage recommended for normal renal function, similar concentrations of unchanged active SMX from patients with normal renal function were achieved in patients with severe renal impairmen (...truncated)