Imipenem/Cilastatin/Relebactam Pharmacokinetics, Safety, and Outcomes in Adults and Adolescents With Cystic Fibrosis

Inclusion Criteria:

• Documented diagnosis of CF defined based on medical history of two or more clinicalfeatures of CF and a documented sweat chloride >60 mEq/L by quantitative pilocarpineiontophoresis test or a genotype showing two well characterized disease causingmutations

• Hospitalized with an acute pulmonary exacerbation (APE), defined as an exacerbationof respiratory symptoms that requires intravenous antibiotics for any 4 of thefollowing 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; decreasein pulmonary function by 10 percent or more from a previously recorded value; orradiographic changes indicative of pulmonary infection.

• APE documented or suspected (based on prior surveillance cultures) to be caused byP. 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 uneventfulre-exposure is not a contraindication);

• At the time of enrollment, known or suspected infection caused bymethicillin-resistant Staphylococcus aureus, Non-tuberculosis mycobacteria (NTM),Burkholderia cepacia complex, Achromobacter species, Stenotrophomonas maltophilia,or moulds; if these pathogens are identified AFTER enrollment, participants maycontinue to complete the study for objectives 1 and 2; additional treatment will beat the discretion of the treating clinician and discussion with the principalinvestigator;

• Receiving or intent to receive any other intravenous antibiotic therapy exceptconcomitant aminoglycosides or fluoroquinolones (concomitant azithromycinadministered as chronic suppression therapy to increase duration betweenexacerbations is permitted); combination therapy to treat CF APE is consideredstandard of care with aminoglycosides and fluoroquinolones typically prescribed assecond antibiotic; the use of combination therapy will not influence objective 1 andwill 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 pharmacokineticsampling;

• Inability to perform pulmonary function tests (PFT) at baseline or 2 weeks after endof therapy;

• For ADULT Participants (18 years or older): Renal dysfunction defined as acreatinine clearance < 60 mL/min (calculated by the Cockcroft-Gault equation);

• For ADOLESCENT Participants (12-17 years): Renal dysfunction defined as a creatinineclearance <90 mL/min/1.73m2 (calculated by the Revised Bedside Schwartz Equation) (Note. Imipenem/cilastatin/relebactam has not been studied in adolescent patientswith creatinine clearance (CrCL) < 90 ml/min/1.73m2);

• Has used or plans to use any of the following medications, which are organic aniontransporter (OAT) 1 or OAT3 inhibitors, within 1 week prior to screening or at anypoint 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), andketorolac;

• Has used or plans to use imipenem or valproic acid within 7 days before study druginfusion;

• Acute liver injury, defined as aspartate aminotransferase (AST) or alanineaminotransferase (ALT) > 5 times the upper limit of normal, or AST or ALT > 3 timesthe upper limit of normal with an associated total bilirubin > 2 times upper limitof normal;

• Any rapidly-progressing disease or immediately life-threatening illness (defined asimminent death within 48 hours in the opinion of the investigator);

• Any condition or circumstance that, in the opinion of the investigator, wouldcompromise the safety of the patient or the quality of study data