Review Article| Volume 43, ISSUE 4, P667-676, December 2022

Novel Approaches to Multidrug-Resistant Infections in Cystic Fibrosis

  • Thomas S. Murray
    Corresponding authors.
    Department of Pediatrics, Section Infectious Diseases and Global Health, Yale University School of Medicine, PO Box 208064, 333 Cedar Street, New Haven, CT 06520-8064, USA
    Search for articles by this author
  • Gail Stanley
    Corresponding authors.
    Department of Internal Medicine, Section Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, PO Box 208057, 300 Cedar Street TAC-441 South, New Haven, CT 06520-8057, USA

    Adult Cystic Fibrosis Program

    Yale University Center for Phage Biology & Therapy
    Search for articles by this author
  • Jonathan L. Koff
    Corresponding authors.
    Adult Cystic Fibrosis Program

    Yale University Center for Phage Biology & Therapy

    Department of Internal Medicine, Section Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, PO Box 208057, 300 Cedar Street TAC-455A South, New Haven, CT 06520-8057, USA
    Search for articles by this author


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribers receive full online access to your subscription and archive of back issues up to and including 2002.

      Content published before 2002 is available via pay-per-view purchase only.


      Subscribe to Clinics in Chest Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


      1. Centers for disease control and prevention updated February 2017 Accessed July 7, 2022.

      2. Cystic Fibrosis Foundation Patient Registry 2020 Annual Data Report Bethesda, Maryland ©2021 Cystic Fibrosis Foundation.

        • Rogers G.B.
        • Taylor S.L.
        • Hoffman L.R.
        • et al.
        The impact of CFTR modulator therapies on CF airway microbiology.
        J Cyst Fibros. 2020; 19: 359-364
        • Saiman L.
        Improving outcomes of infections in cystic fibrosis in the era of CFTR modulator therapy.
        Pediatr Pulmonol. 2019; 54: S18-S26
        • Hisert K.B.
        • Heltshe S.L.
        • Pope C.
        • et al.
        Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function Reduces Airway Bacteria and Inflammation in People with Cystic Fibrosis and Chronic Lung Infections.
        Am J Respir Crit Care Med. 2017; 195: 1617-1628
        • Harris J.K.
        • Wagner B.D.
        • Zemanick E.T.
        • et al.
        Changes in Airway Microbiome and Inflammation with Ivacaftor Treatment in Patients with Cystic Fibrosis and the G551D Mutation.
        Ann Am Thorac Soc. 2020; 17: 212-220
        • Epps Q.J.
        • Epps K.L.
        • Young D.C.
        • et al.
        State of the art in cystic fibrosis pharmacology optimization of antimicrobials in the treatment of cystic fibrosis pulmonary exacerbations: III. Executive summary.
        Pediatr Pulmonol. 2021; 56: 1825-1837
        • Smith S.
        • Rowbotham N.J.
        • Regan K.H.
        Inhaled anti-pseudomonal antibiotics for long-term therapy in cystic fibrosis.
        Cochrane Database of Systematic Reviews. 2018;
        • Elborn J.S.
        • Vataire A.L.
        • Fukushima A.
        • et al.
        Comparison of Inhaled Antibiotics for the Treatment of Chronic Pseudomonas aeruginosa Lung Infection in Patients With Cystic Fibrosis: Systematic Literature Review and Network Meta-analysis.
        Clin Ther. 2016; 38: 2204-2226
        • Wenzler E.
        • Fraidenburg D.R.
        • Scardina T.
        • et al.
        Inhaled Antibiotics for Gram-Negative Respiratory Infections.
        Clinical microbiology reviews. 2016; 29: 581-632
        • Yahav D.
        • Giske C.G.
        • Grāmatniece A.
        • et al.
        New β-Lactam-β-Lactamase Inhibitor Combinations.
        Clin Microbiol Rev. 2020; 34
        • Parker A.C.
        • Pritchard P.
        • Preston T.
        • et al.
        Enhanced drug metabolism in young children with cystic fibrosis.
        Arch Dis Child. 1997; 77: 239-241
        • Kearns G.L.
        Hepatic drug metabolism in cystic fibrosis: recent developments and future directions.
        Ann Pharmacother. 1993; 27: 74-79
        • Prandota J.
        Clinical pharmacology of antibiotics and other drugs in cystic fibrosis.
        Drugs. 1988; 35: 542-578
        • Epps Q.J.
        • Epps K.L.
        • Young D.C.
        • et al.
        State of the art in cystic fibrosis pharmacology-Optimization of antimicrobials in the treatment of cystic fibrosis pulmonary exacerbations: I. Anti-methicillin-resistant Staphylococcus aureus (MRSA) antibiotics.
        Pediatr Pulmonol. 2020; 55: 33-57
        • Epps Q.J.
        • Epps K.L.
        • Zobell J.T.
        Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: II. Cephalosporins and penicillins latest update.
        Pediatr Pulmonol. 2021; 56: 1784-1788
        • Magreault S.
        • Roy C.
        • Launay M.
        • et al.
        Pharmacokinetic and Pharmacodynamic Optimization of Antibiotic Therapy in Cystic Fibrosis Patients: Current Evidences, Gaps in Knowledge and Future Directions.
        Clin Pharmacokinet. 2021; 60: 409-445
        • Prescott Jr., W.A.
        • Gentile A.E.
        • Nagel J.L.
        • et al.
        Continuous-infusion antipseudomonal Beta-lactam therapy in patients with cystic fibrosis.
        P T. 2011; 36: 723-763
        • Bensman T.J.
        • Wang J.
        • Jayne J.
        • et al.
        Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Determine Optimal Dosing of Ceftazidime-Avibactam for the Treatment of Acute Pulmonary Exacerbations in Patients with Cystic Fibrosis.
        Antimicrob Agents Chemother. 2017; 61
        • Garazzino S.
        • Altieri E.
        • Silvestro E.
        • et al.
        Ceftolozane/Tazobactam for Treating Children With Exacerbations of Cystic Fibrosis Due to Pseudomonas aeruginosa: A Review of Available Data.
        Front Pediatr. 2020; 8: 173
        • Forrester J.B.
        • Steed L.L.
        • Santevecchi B.A.
        • et al.
        Vitro Activity of Ceftolozane/Tazobactam vs Nonfermenting, Gram-Negative Cystic Fibrosis Isolates.
        Open Forum Infect Dis. 2018; 5: ofy158
        • Nguyen T.T.
        • Condren M.
        • Walter J.
        Ceftazidime-avibactam for the treatment of multidrug resistant Burkholderia cepacia complex in a pediatric cystic fibrosis patient.
        Pediatr Pulmonol. 2020; 55: 283-284
        • Nolan P.J.
        • Jain R.
        • Cohen L.
        • et al.
        In vitro activity of ceftolozane-tazobactam and ceftazidime-avibactam against Pseudomonas aeruginosa isolated from patients with cystic fibrosis.
        Diagn Microbiol Infect Dis. 2021; 99: 115204
        • Spoletini G.
        • Etherington C.
        • Shaw N.
        • et al.
        Use of ceftazidime/avibactam for the treatment of MDR Pseudomonas aeruginosa and Burkholderia cepacia complex infections in cystic fibrosis: a case series.
        J Antimicrob Chemother. 2019; 74: 1425-1429
        • Sader H.S.
        • Duncan L.R.
        • Doyle T.B.
        • et al.
        Antimicrobial activity of ceftazidime/avibactam, ceftolozane/tazobactam and comparator agents against Pseudomonas aeruginosa from cystic fibrosis patients.
        JAC Antimicrob Resist. 2021; 3: dlab126
        • Van Dalem A.
        • Herpol M.
        • Echahidi F.
        • et al.
        Vitro Susceptibility of Burkholderia cepacia Complex Isolated from Cystic Fibrosis Patients to Ceftazidime-Avibactam and Ceftolozane-Tazobactam.
        Antimicrob Agents Chemother. 2018; 62
        • Haidar G.
        • Philips N.J.
        • Shields R.K.
        • et al.
        Ceftolozane-Tazobactam for the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Infections: Clinical Effectiveness and Evolution of Resistance.
        Clin Infect Dis. 2017; 65: 110-120
        • Romano M.T.
        • et al.
        Ceftolozane/tazobactam for pulmonary exacerbation in a 63-year-old cystic fibrosis patient with renal insufficiency and an elevated MIC to Pseudomonas aeruginosa.
        IDCases. 2020; 21: e00830
        • Stokem K.
        • et al.
        Use of ceftolozane-tazobactam in a cystic fibrosis patient with multidrug-resistant pseudomonas infection and renal insufficiency.
        Respir Med Case Rep. 2018; 23: 8-9
        • Vickery S.B.
        • McClain D.
        • Wargo K.A.
        Successful Use of Ceftolozane-Tazobactam to Treat a Pulmonary Exacerbation of Cystic Fibrosis Caused by Multidrug-Resistant Pseudomonas aeruginosa.
        Pharmacotherapy. 2016; 36: e154-e159
        • Belcher R.
        • Zobell J.T.
        Optimization of antibiotics for cystic fibrosis pulmonary exacerbations due to highly resistant nonlactose fermenting Gram negative bacilli: Meropenem-vaborbactam and cefiderocol.
        Pediatr Pulmonol. 2021; 56: 3059-3061
        • Zeiser E.T.
        • Becka S.A.
        • Wilson B.M.
        • et al.
        Switching Partners": Piperacillin-Avibactam Is a Highly Potent Combination against Multidrug-Resistant Burkholderia cepacia Complex and Burkholderia gladioli Cystic Fibrosis Isolates.
        J Clin Microbiol. 2019; 57
        • Lopeman R.C.
        • Harrison J.
        • Rathbone D.L.
        • et al.
        Effect of Amoxicillin in combination with Imipenem-Relebactam against Mycobacterium abscessus.
        Sci Rep. 2020; 10: 928
        • Zhanel G.G.
        • Golden A.R.
        • Zelenitsky S.
        • et al.
        Cefiderocol: A Siderophore Cephalosporin with Activity Against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli.
        Drugs. 2019; 79: 271-289
        • Gavioli E.M.
        • Guardado N.
        • Haniff F.
        • et al.
        Does Cefiderocol Have a Potential Role in Cystic Fibrosis Pulmonary Exacerbation Management?.
        Microb Drug Resist. 2021 Dec; 27: 1726-1732
        • Warner N.C.
        • Bartelt L.A.
        • Lachiewicz A.M.
        • et al.
        Cefiderocol for the Treatment of Adult and Pediatric Patients With Cystic Fibrosis and Achromobacter xylosoxidans Infections.
        Clin Infect Dis. 2021; 73: e1754-e1757
        • Hurley M.N.
        • Ariff A.H.
        • Bertenshaw C.
        • et al.
        Results of antibiotic susceptibility testing do not influence clinical outcome in children with cystic fibrosis.
        J Cyst Fibros. 2012; 11: 288-292
        • Aaron S.D.
        • Vandemheen K.L.
        • Ferris W.
        • et al.
        Combination antibiotic susceptibility testing to treat exacerbations of cystic fibrosis associated with multiresistant bacteria: a randomised, double-blind, controlled clinical trial.
        Lancet. 2005; 366: 463-471
        • Choby J.E.
        • Ozturk T.
        • Satola S.W.
        • et al.
        Widespread cefiderocol heteroresistance in carbapenem-resistant Gram-negative pathogens.
        Lancet Infect Dis. 2021; 21: 597-598
        • Chalhoub H.
        • Saenz Y.
        • Nichols W.W.
        • et al.
        Loss of activity of ceftazidime-avibactam due to MexAB-OprM efflux and overproduction of AmpC cephalosporinase in Pseudomonas aeruginosa isolated from patients suffering from cystic fibrosis.
        Int J Antimicrob Agents. 2018; 52: 697-701
        • Barsky E.E.
        • Pereira L.M.
        • Sullivan K.J.
        • et al.
        Ceftaroline pharmacokinetics and pharmacodynamics in patients with cystic fibrosis.
        J Cyst Fibros. 2018; 17: e25-e31
        • Branstetter J.
        • Searcy H.
        • Benner K.
        • et al.
        Ceftaroline vs vancomycin for the treatment of acute pulmonary exacerbations in pediatric patients with cystic fibrosis.
        Pediatr Pulmonol. 2020; 55: 3337-3342
        • Molloy L.
        • Snyder A.H.
        • Srivastava R.
        • et al.
        Ceftaroline Fosamil for Methicillin-Resistant Staphylococcus aureus Pulmonary Exacerbation in a Pediatric Cystic Fibrosis Patient.
        J Pediatr Pharmacol Ther. 2014; 19: 135-140
        • Varela M.C.
        • Roch M.
        • Taglialegna A.
        • et al.
        Carbapenems drive the collateral resistance to ceftaroline in cystic fibrosis patients with MRSA.
        Commun Biol. 2020; 3: 599
        • Nichols D.P.
        • Durmowicz A.G.
        • Field A.
        • et al.
        Developing Inhaled Antibiotics in Cystic Fibrosis: Current Challenges and Opportunities.
        Ann Am Thorac Soc. 2019; 16: 534-539
        • Waterer G.
        • Lord J.
        • Hofmann T.
        • et al.
        Phase I, Dose-Escalating Study of the Safety and Pharmacokinetics of Inhaled Dry-Powder Vancomycin (AeroVanc) in Volunteers and Patients with Cystic Fibrosis: a New Approach to Therapy for Methicillin-Resistant Staphylococcus aureus.
        Antimicrob Agents Chemother. 2020; 64
        • Dezube R.
        • Jennings M.T.
        • Rykiel M.
        • et al.
        Eradication of persistent methicillin-resistant Staphylococcus aureus infection in cystic fibrosis.
        Journal of Cystic Fibrosis. 2019; 18: 357-363
        • Flume P.A.
        • VanDevanter D.R.
        • Morgan E.E.
        • Dudley M.N.
        • Loutit J.S.
        • Bell S.C.
        • et al.
        A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients.
        J Cyst Fibros. 2016; 15: 495-502
        • Cystic Fibrosis Foundation
        Drug development pipeline: inhaled levofloxacin (Quinsair).
        (Available at:) (Accessed July 7 ,2022)
        • Banaschewski B.
        • Verma D.
        • Pennings L.J.
        • et al.
        Clofazimine inhalation suspension for the aerosol treatment of pulmonary nontuberculous mycobacterial infections.
        J Cyst Fibros. 2019; 18: 714-720
        • Waterer G.
        Beyond antibiotics for pulmonary nontuberculous mycobacterial disease.
        Curr Opin Pulm Med. 2020; 26: 260-266
        • Bogdan C.
        Nitric oxide synthase in innate and adaptive immunity: an update.
        Trends Immunol. 2015; 36: 161-178
        • Meng Q.H.
        • Springall D.R.
        • Bishop A.E.
        • et al.
        Lack of inducible nitric oxide synthase in bronchial epithelium: a possible mechanism of susceptibility to infection in cystic fibrosis.
        J Pathol. 1998; 184: 323-331
        • Zheng S.
        • De B.P.
        • Choudhary S.
        • et al.
        Impaired innate host defense causes susceptibility to respiratory virus infections in cystic fibrosis.
        Immunity. 2003; 18: 619-630
        • Bogdanovski K.
        • Chau T.
        • Robinson C.J.
        • et al.
        Antibacterial activity of high-dose nitric oxide against pulmonary Mycobacterium abscessus disease.
        Access Microbiol. 2020; 2 (acmi000154)
        • Goldbart A.
        • Gatt D.
        • Golan Tripto I.
        Non-nuberculous mycobacteria infection treated with intermittently inhaled high-dose nitric oxide.
        BMJ Case Rep. 2021; 14
        • Yaacoby-Bianu K.
        • Gur M.
        • Toukan Y.
        • et al.
        Compassionate Nitric Oxide Adjuvant Treatment of Persistent Mycobacterium Infection in Cystic Fibrosis Patients.
        Pediatr Infect Dis J. 2018; 37: 336-338
        • Bentur L.
        • Gur M.
        • Ashkenazi M.
        • et al.
        Pilot study to test inhaled nitric oxide in cystic fibrosis patients with refractory Mycobacterium abscessus lung infection.
        J Cyst Fibros. 2020; 19: 225-231
      3. Cystic Fibrosis Foundation Accessed July 7, 2022.

        • Scott J.P.
        • Ji Y.
        • Kannan M.
        • et al.
        Inhaled granulocyte-macrophage colony-stimulating factor for Mycobacterium abscessus in cystic fibrosis.
        Eur Respir J. 2018; 51
      4. Cystic Fibrosis Foundation. Accessed July 7, 2022.

        • Chitambar C.R.
        • Narasimhan J.
        Targeting iron-dependent DNA synthesis with gallium and transferrin-gallium.
        Pathobiology. 1991; 59: 3-10
        • Goss C.H.
        • Kaneko Y.
        • Khuu L.
        • et al.
        Gallium disrupts bacterial iron metabolism and has therapeutic effects in mice and humans with lung infections.
        Sci Transl Med. 2018; 10
        • Kaneko Y.
        • Thoendel M.
        • Olakanmi O.
        • et al.
        The transition metal gallium disrupts Pseudomonas aeruginosa iron metabolism and has antimicrobial and antibiofilm activity.
        J Clin Invest. 2007; 117: 877-888
        • Abdalla M.Y.
        • Switzer B.L.
        • Goss C.H.
        • et al.
        Gallium Compounds Exhibit Potential as New Therapeutic Agents against Mycobacterium abscessus.
        Antimicrob Agents Chemother. 2015; 59: 4826-4834
        • Kortright K.E.
        • Chan B.K.
        • Koff J.L.
        • et al.
        Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria.
        Cell Host & Microbe. 2019; 25: 219-232
        • Wommack K.E.
        • Colwell R.R.
        Virioplankton: viruses in aquatic ecosystems.
        Microbiology and molecular biology reviews : MMBR. 2000; 64: 69-114
        • Oh J.
        • Byrd A.L.
        • Deming C.
        • et al.
        Biogeography and individuality shape function in the human skin metagenome.
        Nature. 2014; 514: 59-64
        • Reyes A.
        • Haynes M.
        • Hanson N.
        • et al.
        Viruses in the faecal microbiota of monozygotic twins and their mothers.
        Nature. 2010; 466: 334-338
        • Abedon S.T.
        Bacteriophage Clinical Use as Antibacterial "Drugs": Utility and Precedent.
        Microbiol Spectr. 2017; 5
        • Abdelkader K.
        • Gerstmans H.
        • Saafan A.
        • et al.
        The Preclinical and Clinical Progress of Bacteriophages and Their Lytic Enzymes: The Parts are Easier than the Whole.
        Viruses. 2019; 11
        • Dedrick R.M.
        • Guerrero-Bustamante C.A.
        • Garlena R.A.
        • Russell D.A.
        • et al.
        Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus.
        Nat Med. 2019; 25: 730-733
        • Luong T.
        • Salabarria A.-C.
        • Roach D.R.
        Phage Therapy in the Resistance Era: Where Do We Stand and Where Are We Going?.
        Clinical Therapeutics. 2020; 42: 1659-1680
        • Dufour N.
        • Delattre R.
        • Ricard J.D.
        • et al.
        The Lysis of Pathogenic Escherichia coli by Bacteriophages Releases Less Endotoxin Than by β-Lactams.
        Clin Infect Dis. 2017; 64: 1582-1588
        • Chan B.K.
        • Stanley G.
        • Modak M.
        • et al.
        Bacteriophage therapy for infections in CF.
        Pediatr Pulmonol. 2021; 56 (S4–s9)
        • Wright R.C.T.
        • Friman V.P.
        • Smith M.C.M.
        • et al.
        Resistance Evolution against Phage Combinations Depends on the Timing and Order of Exposure.
        mBio. 2019 Sep 24; 10 (e01652–19)
        • Dennehy J.J.
        • Turner P.E.
        Reduced fecundity is the cost of cheating in RNA virus phi6.
        Proc Biol Sci. 2004; 271: 2275-2282
        • Labrie S.J.
        • Samson J.E.
        • Moineau S.
        Bacteriophage resistance mechanisms.
        Nat Rev Microbiol. 2010; 8: 317-327
        • Chan B.K.
        • Sistrom M.
        • Wertz J.E.
        • et al.
        Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa.
        Sci Rep. 2016; 6: 26717
        • Chan B.K.
        • Turner P.E.
        • Kim S.
        • et al.
        Phage treatment of an aortic graft infected with Pseudomonas aeruginosa.
        Evol Med Public Health. 2018; 2018: 60-66
        • Dedrick R.M.
        • Freeman K.G.
        • Nguyen J.A.
        • et al.
        Potent antibody-mediated neutralization limits bacteriophage treatment of a pulmonary Mycobacterium abscessus infection.
        Nat Med. 2021; 27: 1357-1361