Antimicrobial Dosing for Empiric and Documented Pseudomonas

Pseudomonas is a genus of aerobic, Gram-negative bacilli consisting of about 200 species. Pseudomonas aeruginosa (P aeruginosa) is the species most commonly associated with serious hospital-acquired infections and is commonly found in moist environments in hospitals, such as sinks, showers, and machinery/equipment. The symptoms of an infection by this bacterium are variable based on the site of infection and can manifest in various sites, such as the respiratory tract, urinary tract, ears, eyes, heart, skin, and soft tissue.¹ General risk factors for infection with P aeruginosa include immunosuppression, history of lung disease, hospitalization lasting at least 5 days, history of repeated antibiotic use within 90 days, and a history of pseudomonal colonization/infection.

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Pseudomonas aeruginosa is a challenging organism to manage, as it is inherently resistant to many antibiotics. Furthermore, antibiotics effective against infections caused by P aeruginosa often require specific regimens as a result of the high minimum inhibitory concentration (MIC) of the organism. Two specific strategies that have been analyzed for proper coverage of P aeruginosa include the use of higher than usual doses and extended infusions. Due to significant challenges associated with obtaining patient outcomes data in human clinical trials, researchers often use Monte Carlo simulations, which are computational algorithms that simulate the variables of a study (ie, patient demographics) to be as real as possible to accurately predict therapeutic responses in patients.

Analyzing pharmacokinetic (PK) and pharmacodynamic (PD) indexes is valuable for determining therapeutic efficacy, as these indexes consider both the antibiotic dose/concentration and its effect over time in relation to response to therapy. The free-drug area under the concentration time curve (fAUC/MIC) ratio is a PK/PD value commonly used to describe the free-drug concentration over 24 hours that is above the MIC.² The fAUC is dependent on creatinine clearance (CrCl) and, therefore, is specific to each patient. A threshold value for the fAUC/MIC is determined for an antibiotic, and a therapeutic regimen is dosed accordingly to assure fAUC/MIC attainment above the minimum threshold. The probability of target attainment (PTA), which is the probability that the threshold value of a PD index is achieved at a certain MIC, and the probability of cure (POC) for a given antibiotic regimen are used to determine the efficacy of an antibiotic in Monte Carlo simulations.²

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A study by Zelenitsky and colleagues evaluated the efficacy of 3 ciprofloxacin dosing regimens using Monte Carlo simulations (400 mg IV every 12 hours [standard dose], 400 mg IV every 8 hours [high dose], and a PD-targeted regimen dosed to attain an fAUC/MIC value > 86).³ An fAUC/MIC value of 86 was previously determined to predict cure rates of at least 90%.⁴ The Clinical and Laboratory Standards Institute defines a P aeruginosa MIC of ≤ 1 μg/mL to be susceptible and an MIC of ≥ 4 μg/mL to be resistant to ciprofloxacin.⁵

The researchers determined PTA and POC values for each regimen based on various MICs. The in vitro laboratory simulations revealed the PTA and POC values approached 100% for all 3 regimens when the MIC was 0.125 μg/mL. However, when the MIC was 1 μg/mL, the PTA for the standard and high dose was 0%, and the PD-targeted regimen was 40%. The POC was 27%, 40%, and 72% for the standard dose, high dose, and the PD-targeted regimen, respectively. Although the PD-targeted regimen was the most efficacious, it took doses exceeding 1,300 mg and 1,800 mg daily to achieve similar results. In addition, PD-targeted regimens are not practical for dosing due to patient variability in CrCl. From these simulations, it was concluded that the high dose of ciprofloxacin 400 mg IV every 8 hours should be recommended for treating Pseudomonas infections in patients with normal renal function.

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In another study by Lodise and colleagues, researchers examined the clinical implications of an extended-infusion dosing strategy for piperacillin-tazobactam in the critically ill.⁶ The 2 piperacillin- tazobactam regimens evaluated were 3.375 g IV over 30 minutes given every 4 or 6 hours and 3.375 g IV over 4 hours given every 8 hours. The 14-day mortality rate in critically ill patients who received the extended- and intermittent-infusion regimens was 12.2% and 31.6%, respectively (P = .04). Additionally, patients receiving the extended-infusion regimen had a decreased in-house length of stay compared with the intermittent-infusion group (21 vs 38 days, P = .02). Despite having a lower drug concentration peak, the extended-infusion regimen maintains steady drug concentrations above the MIC for a greater period, resulting in prolonged therapeutic efficacy. Other antibiotics (cefepime⁷ and ceftazidime⁸) have been studied by using the same methodology of comparing intermittent and extended infusions and have had similar results.