Clinical Trial Finder

Inclusion Criteria:

• - Documented diagnosis of CF defined based on medical history of two or more clinical features of CF and a documented sweat chloride >60 mEq/L by quantitative pilocarpine iontophoresis test or a genotype showing two well characterized disease causing mutations.

• - Hospitalized with an acute pulmonary exacerbation (APE), defined as an exacerbation of respiratory symptoms that requires intravenous antibiotics for any 4 of the following signs or symptoms: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue, or lethargy; temperature above 38C; anorexia or weight loss; change in physical examination of the chest; decrease in pulmonary function by 10 percent or more from a previously recorded value; or radiographic changes indicative of pulmonary infection.

• - APE documented or suspected (based on prior surveillance cultures) to be caused by P.

aeruginosa.

Exclusion Criteria:

• - If female, currently pregnant or breast feeding; - History of any moderate or severe hypersensitivity or allergic reaction to any β-lactam agent (a history of mild rash to a β-lactam followed by uneventful re-exposure is not a contraindication); - At the time of enrollment, known or suspected infection caused by methicillin-resistant Staphylococcus aureus, Non-tuberculosis mycobacteria (NTM), Burkholderia cepacia complex, Achromobacter species, Stenotrophomonas maltophilia, or moulds; if these pathogens are identified AFTER enrollment, participants may continue to complete the study for objectives 1 and 2; additional treatment will be at the discretion of the treating clinician and discussion with the principal investigator; - Receiving or intent to receive any other intravenous antibiotic therapy except concomitant aminoglycosides or fluoroquinolones (concomitant azithromycin administered as chronic suppression therapy to increase duration between exacerbations is permitted); combination therapy to treat CF APE is considered standard of care with aminoglycosides and fluoroquinolones typically prescribed as second antibiotic; the use of combination therapy will not influence objective 1 and will be considered in assessment of objective 2; - Receiving or intent to receive any inhaled antibiotics; - Unlikely to remain hospitalized for at least 4 days to ensure pharmacokinetic sampling; - Inability to perform pulmonary function tests (PFT) at baseline or 2 weeks after end of therapy; - For ADULT Participants (18 years or older): Renal dysfunction defined as a creatinine clearance < 60 mL/min (calculated by the Cockcroft-Gault equation); - For ADOLESCENT Participants (12-17 years): Renal dysfunction defined as a creatinine clearance <90 mL/min/1.73m2 (calculated by the Revised Bedside Schwartz Equation) (Note.

Imipenem/cilastatin/relebactam has not been studied in adolescent patients with creatinine clearance (CrCL) < 90 ml/min/1.73m2); - Has used or plans to use any of the following medications, which are organic anion transporter (OAT) 1 or OAT3 inhibitors, within 1 week prior to screening or at any point between screening and the last PK sample collection: cimetidine, probenecid, indomethacin, mefenamic acid, furosemide or other loop diuretics (eg, bumetanide, torsemide, ethacrynic acid), angiotensin receptor blockers (eg, valsartan), and ketorolac; - Has used or plans to use imipenem or valproic acid within 7 days before study drug infusion; - Acute liver injury, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 times the upper limit of normal, or AST or ALT > 3 times the upper limit of normal with an associated total bilirubin > 2 times upper limit of normal; - Any rapidly-progressing disease or immediately life-threatening illness (defined as imminent death within 48 hours in the opinion of the investigator); - Any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the patient or the quality of study data

Participants will receive 10-14 days of imipenem/cilastatin/relebactam every 6 hours with dose determined per renal function, with or without adjunctive aminoglycoside or fluoroquinolone therapy as determined by local study site. After receiving at least 3 doses (i.e. steady-state), a total of eight blood samples will be collected over one dosing interval to measure imipenem and relebactam concentrations. Data will be fit to a population pharmacokinetic model. The final model will be utilized in a Monte Carlo simulation to determine the probability of several different dosing regimens retaining both

• (1) free imipenem concentrations above the minimum inhibitory concentration (MIC) for at least 40% of the dosing interval and (2) free relebactam area under the concentration-time curve at least eight times greater than the MIC.

These data will be utilized to determine an optimized dosing regimen for adults and adolescents with CF. Additionally, two weeks after treatment, as part of the exploratory clinical endpoint, patients will complete follow-up pulmonary function tests to determine relative percent increase in FEV1 and return to baseline FEV1 after treatment. These outcomes will be reported descriptively.

Arms

Experimental: Imipenem/cilastatin/relebactam

Adult participants will receive intravenous imipenem/cilastatin/relebactam at a dosing regimen consistent with the current prescribing information and according to estimated renal function. Adolescent participants will receive intravenous imipenem/cilastatin/relebactam at a dosing regimen consistent with Phase I data [37.5 (15/15/7.5) mg/kg, up to a maximum dose of 1.25g]. Each dose will be infused over 30 minutes.

Interventions

Drug: - Imipenem/Cilastatin/Relebactam

Patients will receive intravenous imipenem/cilastatin/relebactam every 6 hours for 10-14 days.