piperacillin--tazobactam-drug-combination and Cystic-Fibrosis

Acute pulmonary exacerbations (APE) are well-described complications of cystic fibrosis (CF) and are associated with progressive morbidity and mortality. Despite aggressive management with two or more intravenous anti-pseudomonal agents, approximately 25% of exacerbations will result in a loss of lung function. The aim of this review is to provide an evidence-based summary of pharmacokinetic/pharmacodynamic (PK/PD), tolerability, and efficacy studies utilizing anti-pseudomonal cephalosporins (i.e., ceftazidime and cefepime) and penicillins (i.e., piperacillin-tazobactam and ticarcillin-clavulanate) in the treatment of APE and to identify areas where further study is warranted. The ceftazidime and cefepime dosing ranges from the literature are 200-400 mg/kg/day divided every 6-8 hr, maximum 8-12 g/day, and 150-200 mg/kg/day divided every 6-8 hr, up to 6-8 g/day, respectively. The literature supported dosing ranges for piperacillin and ticarcillin are 350-600 mg/kg/day divided every 4 hr, maximum 18-24 g/day of piperacillin component, and 400-750 mg/kg/day divided every 6 hr, up to 24-30 g/day of ticarcillin component, respectively. As a large portion of CF patients will not regain their lung function following an APE, we suggest the need to optimize antibiotic dosing and dosing regimens used to treat an APE in efforts to improve outcomes for CF patients infected with Pseudomonas aeruginosa. Future studies are needed to determine the clinical efficacy of higher than FDA-approved doses of ceftazidime, cefepime, and ticarcillin-clavulanate in APE. The usefulness of high dose piperacillin (>600 mg/kg/day) may be limited due to treatment-related adverse effects. Further understanding of these adverse effects in CF patients is needed.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; Cefepime; Ceftazidime; Cephalosporins; Clavulanic Acids; Cystic Fibrosis; Disease Progression; Drug Therapy, Combination; Humans; Microbial Sensitivity Tests; Penicillanic Acid; Penicillins; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Ticarcillin

Given the high frequency of acute pulmonary exacerbations due to Pseudomonas aeruginosa in patients with cystic fibrosis (CF), piperacillin/tazobactam is commonly used in empirical regimens. While extended-infusion piperacillin/tazobactam has been employed as one strategy to optimize this agent's pharmacodynamics, this approach has not been well characterized in patients with CF. The objectives of this study were to characterize the pharmacokinetics and pharmacodynamics of extended-infusion piperacillin/tazobactam in adult patients with CF and derive optimized piperacillin/tazobactam dosing recommendations.. Six serum samples were collected from nine adult patients with CF hospitalized for acute pulmonary exacerbations who received 3/0.375 g of piperacillin/tazobactam intravenously for 4 h every 8 h. Population pharmacokinetic models were fitted to the data utilizing first-order, Michaelis-Menten (MM) and parallel first-order/MM clearance. Monte Carlo simulations were performed to determine the probability of target attainment (PTA) for regimens where free piperacillin concentrations were above the MIC for at least 50% of the dosing interval.. The model incorporating MM clearance best described the data. Results of our simulation revealed that piperacillin/tazobactam dosed at 3-4 g for 30 min every 6-8 h led to <90% PTA against MIC values >4 mg/L. More intensive prolonged infusion regimens than are commonly used in practice, such as continuous infusions or 3 h infusions every 6 h, were needed to maximize the PTA for MICs ≥ 8 mg/L.. Intensive prolonged infusion regimens are the best option to ensure optimal exposures against most susceptible isolates in adult patients with CF.

Topics: Adult; Anti-Bacterial Agents; Cystic Fibrosis; Female; Humans; Infusions, Intravenous; Male; Microbial Sensitivity Tests; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Serum; Time Factors; Treatment Outcome; Young Adult

Patients with cystic fibrosis (CF) may be treated with piperacillin-tazobactam (PZT) for acute pulmonary exacerbations. Extending the infusion of PZT is one strategy to increase efficacy. Direct comparison, with respect to the incidence of acute kidney injury (AKI), between these two strategies has not been evaluated in pediatric patients with CF. The primary objective of this study was to compare the incidence of AKI in pediatric CF patients receiving extended infusion (EI) PZT versus traditional infusion (TI).. This IRB-approved, retrospective analysis included patients ages 30 days to 18 years that received PZT for at least 48 h between January 1, 2008, and January 1, 2020. PZT was infused over 30 min (TI group) or 4 h (EI group).. Two hundred and four patients were included (TI: 109, EI: 95). Median age was 8 years (4-13) and 7 years (3-12) in the TI and EI groups (p = 0.15). The groups did not differ significantly in their baseline characteristics. There were 12 (11%) AKIs in the TI group and 8 (8.4%) in the EI group (p = 0.53). There was one occurrence of serum sickness in the TI group and none in the EI group. The incidence of thrombocytopenia was similar between the two groups. Median treatment duration was 8 days (5-11) and 9 days (5-13) for the TI and EI groups, respectively (p = 0.24).. There was no significant increase in AKI in pediatric patients with CF receiving PZT by EI compared with TI. EI may be utilized to optimize the pharmacokinetics of PZT in pediatric CF patients.

Topics: Acute Kidney Injury; Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Cystic Fibrosis; Drug Therapy, Combination; Humans; Infant, Newborn; Infusions, Intravenous; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Retrospective Studies

Colistimethate sodium and tobramycin are important systemic antibiotics for treatment of cystic fibrosis (CF) pulmonary exacerbations but can induce acute kidney injury (AKI). We characterize the rate of AKI in CF patients treated with systemic colistimethate sodium compared with tobramycin.. This single-centre, retrospective cohort study included hospitalized CF patients treated with IV colistimethate sodium or tobramycin. The primary outcome was AKI defined using the RIFLE criteria. Multivariate logistic regression using a mixed model was performed to identify variables that were independently associated with AKI.. Overall, 156 patients representing 507 care encounters were included. The OR of AKI was not increased with IV colistimethate sodium relative to IV tobramycin after adjusting for other potential predictor variables (aOR 1.00; 95% CI 0.16-6.03). The frequency of AKI was 9.5% across all encounters, 6.9% with IV colistimethate sodium and 9.9% with IV tobramycin, with RIFLE category R (risk) being the most common stage, accounting for 4.2% of encounters with IV colistimethate sodium and 9.2% with IV tobramycin. The concomitant use of another nephrotoxin (aOR 2.51; 95% CI 1.27-4.95) or the combination of vancomycin and piperacillin/tazobactam (aOR 5.95; 95% CI 2.05-17.3) were both associated with increased odds of AKI.. Systemic treatment with colistimethate sodium or tobramycin in the CF patient population is associated with a similar rate of nephrotoxicity. However, clinicians should be mindful of the increased risk for AKI in patients treated with either IV colistimethate sodium or IV tobramycin when used concurrently with other nephrotoxic agents, particularly the combination of vancomycin and piperacillin/tazobactam.

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Drug Therapy, Combination; Humans; Piperacillin, Tazobactam Drug Combination; Retrospective Studies; Tobramycin; Vancomycin

Cystic fibrosis (CF) patients, with Pseudomonas aeruginosa infection, often require repeated aminoglycoside courses for the management of acute pulmonary exacerbations (APEs). Acute kidney injury (AKI) due to aminoglycosides has been reported; little data exist regarding long-term nephrotoxicity with repeated exposure. The objective of this study was to describe the incidence of acute and chronic nephrotoxicity due to cumulative intravenous (IV) aminoglycoside exposure. This is a retrospective, observational study of pediatric and adult CF patients admitted to an academic medical center between January 1, 2006 and October 1, 2018 for APE management. Patients were eligible for inclusion if they received at least five courses of an IV aminoglycoside for at least 7 days each. Cumulative weight-based aminoglycoside dose was reported in milligrams per kilogram. For each admission, baseline and highest serum creatinine were collected to assess the incidence of AKI. The baseline and final estimated glomerular filtration rate (eGFR) were calculated to assess long-term effects on renal function. Sixty-six patients, representing greater than 700 courses, were included in the final analysis. The median cumulative weight-based aminoglycoside dose was 1183 mg/kg of tobramycin or tobramycin equivalent. Twenty percent of courses resulted in AKI; 86% were Stage 1. A repeated measure multivariate model showed colistin, piperacillin/tazobactam, vancomycin, and age were significant AKI risk factors. There was no correlation between cumulative aminoglycoside dose and change in eGFR. AKI from IV aminoglycoside exposure occurred in 20% of courses. Cumulative exposure to IV aminoglycosides in APE management was not correlated with long-term renal dysfunction.

Topics: Acute Kidney Injury; Adolescent; Adult; Age Factors; Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Cystic Fibrosis; Female; Humans; Incidence; Infant; Male; Middle Aged; Piperacillin, Tazobactam Drug Combination; Pseudomonas Infections; Retrospective Studies; Risk Factors; Tobramycin; Vancomycin; Young Adult

Empirical models to predict β-lactam pharmacokinetics (PK) using information from routine aminoglycoside therapeutic drug monitoring (TDM) have been proposed for critically ill patients; however, no such models exist for patients with cystic fibrosis (CF).. To investigate whether PK parameters of tobramycin could be used to predict those of piperacillin.. A non-interventional, open-label PK study was conducted in hospitalized adults treated with piperacillin/tazobactam and tobramycin for acute pulmonary exacerbations of CF. Six serum samples per patient were collected and analysed. One- and two-compartment population PK models with linear, Michaelis-Menten or mixed elimination were evaluated for both drugs within the PmetricsTM package for R. Models were developed and compared iteratively using the log-likelihood and Akaike information criterion (AIC) objective functions.. Nine primarily female (n = 8) and Caucasian (100%) adult CF patients were enrolled. The median (IQR) age, height, weight and serum creatinine of included patients was 31 (27-32) years, 51.4 (49.9-55.8) kg, 162.6 (160.0-165.1)  cm and 0.6 (0.5-0.6) mg/dL, respectively. The final model with the lowest objective function values consisted of one compartment with first-order elimination for tobramycin and two compartments with mixed-order elimination for piperacillin with the elimination rate constant of piperacillin modelled as a linear function of the elimination rate constant of tobramycin.. A relationship was identified between the elimination rate constants of tobramycin and piperacillin. Validation of this relationship in larger studies of adult patients with CF is needed before application to the precision dosing of piperacillin/tazobactam in this patient population.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacterial Infections; beta-Lactamase Inhibitors; Cystic Fibrosis; Female; Humans; Male; Middle Aged; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Tobramycin; Young Adult

Pseudomonas aeruginosa is one of the most important pathogens in cystic fibrosis. This study was conducted to analyse the genetic basis and phylogenetic profile of resistance to ceftazidime/avibactam, ceftolozane/tazobactam and carbapenems in cystic fibrosis P. aeruginosa isolates. Whole genome sequence analysis was conducted of isolates resistant to piperacillin/tazobactam collected from seven hospitals in Scotland since the introduction of these two cephalosporin/β-lactamase inhibitor combinations. Ceftazidime resistance was primarily related to AmpC induction, as tested by cloxacillin inhibition assays, while high-level ceftazidime resistance not reversed by cloxacillin was associated with amino acid variations in AmpC. Only isolates resistant to both ceftazidime/avibactam and ceftolozane/tazobactam carried AmpD mutations, likely resulting in ampC overexpression. All isolates resistant to ceftazidime/avibactam and/or ceftolozane/tazobactam were resistant to carbapenems and showed inactivating mutations in the chromosomal oprD gene. None of the isolates bore class A, B, D plasmid-encoded carbapenemases. This study showed that mutational resistance emerged in phylogenetically distant lineages, which indicates the mutations occur independently without conferring a selective advantage to any phylogenetic lineage. These findings confirm the strong contribution of mutation-driven evolution to the population structure of P. aeruginosa.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; beta-Lactamase Inhibitors; beta-Lactamases; Carbapenems; Ceftazidime; Cephalosporins; Cystic Fibrosis; Drug Combinations; Drug Resistance, Bacterial; Female; Hospitals; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Piperacillin, Tazobactam Drug Combination; Porins; Pseudomonas aeruginosa; Pseudomonas Infections; Scotland; Tazobactam; Whole Genome Sequencing

Cystic fibrosis (CF) patients often receive prolonged courses of broad spectrum antibiotics, such as piperacillin-tazobactam or cefepime in combination with vancomycin and tobramycin. The objective of this study was to determine the difference in AKI for pediatric CF patients receiving piperacillin-tazobactam or cefepime in combination with vancomycin and tobramycin.. IRB approval from a single CF center was obtained for this retrospective cohort study. Charts were evaluated from December 1, 2008 to June 30,2015. Patients were included if they had a diagnosis of CF, age 30 days to 18 years, and received intravenous vancomycin, tobramycin, and piperacillin-tazobactam or cefepime. The primary outcome was difference of AKI incidence in patients receiving piperacillin-tazobactam or cefepime, as defined by modified pediatric risk, injury, failure, loss, end stage renal disease (pRIFLE) criteria.. Seventy-one patients were included with a median (interquartile range) age 11 years (7-16) and weight 36.2 kg (22.7-50). AKI was identified in 54.5% (18/33) of patients receiving piperacillin-tazobactam and 13.2% (5/38) of patients receiving cefepime (P ≤ 0.0001). One patient receiving piperacillin-tazobactam experienced acute renal failure. There was a slight difference in length of admission (13 vs 10 days, P = 0.042), but no difference in days to maximum SCr (6 vs 3, P = 0.127) nor FEV1 percent predicted on admission (69% vs 65%, P = 1.00).. AKI occurred in nearly 55% of patients with piperacillin-tazobactam therapy versus 13% of patients with cefepime therapy, which suggests cefepime may be preferred in combination with vancomycin and tobramycin for pediatric CF patients.

Topics: Acute Kidney Injury; Adolescent; Anti-Bacterial Agents; Cefepime; Cephalosporins; Child; Cystic Fibrosis; Drug Therapy, Combination; Female; Hospitalization; Humans; Incidence; Male; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Retrospective Studies; Tobramycin; Vancomycin

Topics: Achromobacter denitrificans; Anti-Bacterial Agents; Ceftazidime; Cephalosporins; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Humans; Meropenem; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Stenotrophomonas maltophilia; Tazobactam; Thienamycins

Topics: Anti-Bacterial Agents; Cystic Fibrosis; Dose-Response Relationship, Drug; Humans; Infusions, Intravenous; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination

Piperacillin-tazobactam is an antipseudomonal antibiotic frequently used in patients with cystic fibrosis (CF) to treat pulmonary exacerbations. Drug-induced immune haemolytic anaemia is a rare complication during treatment with piperacillin. So far, piperacillin-induced immune haemolytic anaemia (PIHA) is regarded as an acute and severe haemolytic anaemia resulting into life-threatening events. Here we report on a patient with mild PIHA, which did not result in any clinical symptoms or necessity for treatment. To the best of our knowledge, this is the first case report of PIHA without an acute severe haemolytic anaemia. Further research is needed to clarify if this case is a solitary clinical manifestation of PIHA or if mild clinical courses of PIHA might be under-reported. Cases of PIHA have been largely reported in patients with CF. This unequal distribution maybe due to the frequent administration of piperacillin for pulmonary exacerbation in patients with CF or due to CF-related cofactors of yet unknown aetiology.

Topics: Adult; Anemia, Hemolytic; Anti-Bacterial Agents; Cystic Fibrosis; Female; Humans; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination

Topics: Anti-Bacterial Agents; Cystic Fibrosis; Humans; Male; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Young Adult

We present a 24-year-old man with a history significant for cystic fibrosis and insulin-dependent diabetes mellitus who developed anaemia in the setting of piperacillin-induced immune haemolysis. This case provided a diagnostic challenge, a rare association of piperacillin-induced haemolysis in those suffering from cystic fibrosis.

Topics: Anemia, Hemolytic, Autoimmune; Anti-Bacterial Agents; Cystic Fibrosis; Humans; Male; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Young Adult