STATE OF THE ART
State of the art in cystic fibrosis pharmacology optimization of antimicrobials in the treatment of cystic fibrosis pulmonary exacerbations: III. Executive summary
Quovadis J. Epps PharmD, MS, BCPS,
Kevin L. Epps PharmD, BCPS, BCNSP, BCIDP,
David C. Young PharmD,
Jeffery T. Zobell PharmD, BCPPS,
Quovadis J. Epps PharmD, MS, BCPS
Florida Agricultural and Mechanical University College of Pharmacy and Pharmaceutical Sciences, Jacksonville, Florida, USA
Search for more papers by this authorKevin L. Epps PharmD, BCPS, BCNSP, BCIDP
Department of Pharmacy, The Mayo Clinic, Jacksonville, Florida, USA
Search for more papers by this authorDavid C. Young PharmD
Department of Pharmacotherapy, L.S. Skaggs Pharmacy Institute, University of Utah College of Pharmacy, Salt Lake City, Utah, USA
Department of Pharmacy, University of Utah Adult Cystic Fibrosis Center, Salt Lake City, Utah, USA
Search for more papers by this authorCorresponding Author
Jeffery T. Zobell PharmD, BCPPS
Department of Pharmacy, Intermountain Primary Children's Hospital, Salt Lake City, Utah, USA
Department of Pharmacy, Primary Children's Cystic Fibrosis Center, Salt Lake City, Utah, USA
Correspondence Jeffery T. Zobell, PharmD, BCPPS, Intermountain Primary Children's Hospital, Department of Pharmacy, 100 North Mario Capecchi Dr., Salt Lake City, UT 84113, USA.
Email: [email protected]
Search for more papers by this authorQuovadis J. Epps PharmD, MS, BCPS,
Kevin L. Epps PharmD, BCPS, BCNSP, BCIDP,
David C. Young PharmD,
Jeffery T. Zobell PharmD, BCPPS,
Quovadis J. Epps PharmD, MS, BCPS
Florida Agricultural and Mechanical University College of Pharmacy and Pharmaceutical Sciences, Jacksonville, Florida, USA
Search for more papers by this authorKevin L. Epps PharmD, BCPS, BCNSP, BCIDP
Department of Pharmacy, The Mayo Clinic, Jacksonville, Florida, USA
Search for more papers by this authorDavid C. Young PharmD
Department of Pharmacotherapy, L.S. Skaggs Pharmacy Institute, University of Utah College of Pharmacy, Salt Lake City, Utah, USA
Department of Pharmacy, University of Utah Adult Cystic Fibrosis Center, Salt Lake City, Utah, USA
Search for more papers by this authorCorresponding Author
Jeffery T. Zobell PharmD, BCPPS
Department of Pharmacy, Intermountain Primary Children's Hospital, Salt Lake City, Utah, USA
Department of Pharmacy, Primary Children's Cystic Fibrosis Center, Salt Lake City, Utah, USA
Correspondence Jeffery T. Zobell, PharmD, BCPPS, Intermountain Primary Children's Hospital, Department of Pharmacy, 100 North Mario Capecchi Dr., Salt Lake City, UT 84113, USA.
Email: [email protected]
Search for more papers by this authorAbstract
Acute pulmonary exacerbations are complications of cystic fibrosis (CF) and are associated with increased morbidity and mortality. Methicillin-resistant Staphylococcus aureus (MRSA) and Aspergillus fumigatus are organisms that have been detected in the lungs of CF patients. The focus of this review is to provide an overview of the classes of antimicrobials used for MRSA and allergic bronchopulmonary aspergillosis (ABPA), a hypersensitivity reaction caused by A. fumigatus. The current anti-MRSA antibiotics and medications for ABPA dosing recommendations are discussed. This article also reviews the findings from the MRSA utilization surveys and the pharmacokinetic and pharmacodynamic differences between CF and non-CF patients. Antimethicillin S. aureus antibiotics include ceftaroline, clindamycin, fluoroquinolone derivatives (ciprofloxacin, levofloxacin), glycopeptide derivatives (telavancin, vancomycin), linezolid, rifampin, sulfamethoxazole/trimethoprim, and tetracycline derivatives (doxycycline, minocycline, tigecycline). Medications used for ABPA include corticosteroids, amphotericin B, azole antifungals (isavuconazole, itraconazole, posaconazole, voriconazole), and a monoclonal antibody, omalizumab.
CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.
Open Research
DATA AVAILABILITY STATEMENT
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
REFERENCES
- 1 Ramsey BW. Management of pulmonary disease in patients with cystic fibrosis. N Engl J Med. 1996; 335(3): 179-188.
- 2 Zobell JT, Epps KL, Young DC, et al. Utilization of antibiotics for methicillin-resistant Staphylococcus aureus infection in cystic fibrosis. Pediatr Pulmonol. 2015; 50(6): 552-559.
- 3 Elphick HE, Southern KW. Antifungal therapies for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. Cochrane Database Syst Rev. 2016; 11:CD002204.
- 4 Jubin V, Ranque S, Stremler Le Bel N, Sarles J, Dubus JC. Risk factors for Aspergillus colonization and allergic bronchopulmonary aspergillosis in children with cystic fibrosis. Pediatr Pulmonol. 2010; 45(8): 764-771.
- 5 Skov M, McKay K, Koch C, Cooper PJ. Prevalence of allergic bronchopulmonary aspergillosis in cystic fibrosis in an area with a high frequency of atopy. Respir Med. 2005; 99(7): 887-893.
- 6 Jennings MT, Dasenbrook EC, Lechtzin N, Boyle MP, Merlo CA. Antibiotic management of lung infections in cystic fibrosis. II. Nontuberculous mycobacteria, anaerobic bacteria, and fungi. Ann Am Thorac Soc. 2014; 11(8): 1298-1306.
- 7 Jennings MT, Dasenbrook EC, Lechtzin N, Boyle MP, Merlo CA. Risk factors for persistent methicillin-resistant Staphylococcus aureus infection in cystic fibrosis. J Cyst Fibros. 2017; 16(6): 681-686.
- 8 Epps QJ, Epps KL, Young DC, Zobell JT. 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(1): 33-57.
- 9 Teflaro. Approved package labeling. Forest Pharmaceuticals, Inc. 2016.
- 10 Kasten MJ. Clindamycin, metronidazole, and chloramphenicol. Mayo Clin Proc. 1999; 74(8): 825-833.
- 11 Champion EA, Miller MB, Popowitch EB, Hobbs MM, Saiman L, Muhlebach MS. Complex molecular epidemiology of methicillin-resistant staphylococcus aureus isolates from children with cystic fibrosis in the era of epidemic community-associated methicillin-resistant S aureus. Chest. 2008; 133(6): 1381-1387.
- 12 Moore ZS, Jerris RC, Hilinski JA. Antimicrobial susceptibility and molecular typing of MRSA in cystic fibrosis. Pediatr Pulmonol. 2014; 49(3): 230-237.
- 13 Moore ZS, Jerris RC, Hilinski JA. High prevalence of inducible clindamycin resistance among Staphylococcus aureus isolates from patients with cystic fibrosis. J Cyst Fibros. 2008; 7(3): 206-209.
- 14 Fusco NM, Toussaint KA, Prescott WA, Jr. Antibiotic management of methicillin-resistant Staphylococcus aureus-associated acute pulmonary exacerbations in cystic fibrosis. Ann Pharmacother. 2015; 49(4): 458-468.
- 15 Levison ME, Levison JH. Pharmacokinetics and pharmacodynamics of antibacterial agents. Infect Dis Clin North Am. 2009; 23(4): 791-815.
- 16 Cipro. Approved package labeling. Bayer HealthCare Pharmaceuticals Inc. 2016.
- 17 Levaquin. Approved package labeling. Janssen Pharmaceuticals, Inc. 2018.
- 18
Connors KPKJ, Nicolau DP. Optimizing antibiotic pharmacodynamics for clinical practice. Pharmaceut Anal Acta. 2013; 4(3): 1–8.
10.4172/2153-2435.1000214 Google Scholar
- 19 Vibativ. Approaved package labeling. Theravance Biopharma Antibiotics, Inc. 2016.
- 20 Vancomycin. Approved package labeling. Baxter Healthcare Corporation. 2015.
- 21 Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary. Clin Infect Dis. 2011; 52(3): 285-292.
- 22 https://wiley.eproofing.in/Proof.aspx?token=f801f2d026df4c7bb120a44605b09bfc113119275
- 23 Rothstein DM. Pharmacokinetics and pharmacodynamics of linezolid in children with cystic fibrosis. Pediatr Pulmonol. 2009; 44(2): 148-154.
- 24 Rothstein DM. Rifamycins, alone and in combination. Cold Spring Harb Perspect Med. 2016; 6(7): 1-19.
- 25 Rifampin injection. Approved Package Labeling. Mylan Institutional, LLC. 2018.
- 26 Rifampin capsule. Approved Package Labeling. Eon Labs, Inc. 2019.
- 27 Goutelle S, Bourguignon L, Maire PH, Van Guilder M, Conte JE, Jelliffe RW. Pharmacokinetics–pharmacodynamics of rifampin in an aerosol infection model of tuberculosis. Antimicrob Agents Chemother. 2003; 47(7): 2118-2124.
- 28 Goutelle S, Bourguignon L, Maire PH, Van Guilder M, Conte JE, Jr., Jelliffe RW. Population modeling and Monte Carlo simulation study of the pharmacokinetics and antituberculosis pharmacodynamics of rifampin in lungs. Antimicrob Agents Chemother. 2009; 53(7): 2974-2981.
- 29 Sulfamethoxazole and trimethoprim tablet. Approved Package Labeling. Sun Pharmaceutical Industries, Inc. 2018.
- 30 Sulfamethoxazole and trimethoprim injection. Mylan Institutional, LLC. 2018.
- 31 Smilack JD. Trimethoprim–sulfamethoxazole. Mayo Clin Proc. 1999; 74(7): 730-734.
- 32 Wormser GP, Keusch GT, Heel RC. Co-trimoxazole (trimethoprim–sulfamethoxazole): an updated review of its antibacterial activity and clinical efficacy. Drugs. 1982; 24(6): 459-518.
- 33 Vibramycin injection approved package labeling. Roerig. 2017.
- 34 Patterson PR. Minocycline in the antibiotic regimen of cystic fibrosis patients: weight gain and clinical improvement. Clin Pediatr (Phila). 1977; 16(1): 60-63.
- 35 Tygacil approved package labeling. Wyeth Pharmaceuticals LLC. 2018.
- 36 Molloy L, Snyder AH, Srivastava R, Rybak MJ, McGrath E. Ceftaroline fosamil for methicillin-resistant Staphylococcus aureus pulmonary exacerbation in a pediatric cystic fibrosis patient. J Pediatr Pharmacol Ther. 2014; 19(2): 135-140.
- 37 Clindamycin phosphate injection. Approved Package Labeling. Akorn, Inc. 2018.
- 38 Doring G, Flume P, Heijerman H, Elborn JS. Consensus Study Group. Treatment of lung infection in patients with cystic fibrosis: current and future strategies. J Cyst Fibros. 2012; 11(6): 461-479.
- 39 Mouton JW, Vinks AA. Pharmacokinetic/pharmacodynamic modelling of antibacterials in vitro and in vivo using bacterial growth and kill kinetics: the minimum inhibitory concentration versus stationary concentration. Clin Pharmacokinet. 2005; 44(2): 201-210.
- 40 Vibramycin oral. Approved package labeling. Pfizer Labs. 2017.
- 41 Minocin injection. Approved package labeling. Rempex Pharmaceuticals, Inc. 2018.
- 42 UK Cystic Fibrosis Trust Antibiotic Working Group. Antibiotic treatment for cystic fibrosis. 2009.
- 43 Autry EB, Rybak JM, Leung NR, et al. Ceftaroline pharmacokinetics and pharmacodynamics in patients with cystic fibrosis. J Cyst Fibros. 2018; 17(3): e25-e31.
- 44 Le J, Bradley JS, Hingtgen S, et al. Pharmacokinetic and pharmacodynamic analyses of ceftaroline in adults with cystic fibrosis. Pharmacotherapy. 2016; 36(1): 13-18.
- 45 Molloy L, Snyder AH, Srivastava R, Rybak MJ, McGrath E. Pharmacokinetics of single-dose ceftaroline fosamil in children with cystic fibrosis. Pediatr Pulmonol. 2017; 52(11): 1424-1434.
- 46 Raeburn JA, Devine JD. Clindamycin levels in sputum in a patient with purulent chest disease due to cystic fibrosis. Postgrad Med J. 1971; 47(548): 366-367.
- 47 Pleasants RA, Michalets EL, Williams DM, Samuelson WM, Rehm JR, Knowles MR. Pharmacokinetics of vancomycin in adult cystic fibrosis patients. Antimicrob Agents Chemother. 1996; 40(1): 186-190.
- 48 McDade EJ, Hewlett JL, Moonnumakal SP, Baker CJ. Evaluation of vancomycin dosing in pediatric cystic fibrosis patients. J Pediatr Pharmacol Ther. 2016; 21(2): 155-161.
- 49 Durham SH, Garza KB, Eiland LS. Relationship between vancomycin dosage and serum trough vancomycin concentrations in pediatric patients with cystic fibrosis. Am J Health Syst Pharm. 2016; 73(13): 969-974.
- 50 Amin RW, Guttmann RP, Harris QR, Thomas JW. Prediction of vancomycin dose for recommended trough concentrations in pediatric patients with cystic fibrosis. J Clin Pharmacol. 2018; 58(5): 662-665.
- 51 Bosso JA, Flume PA, Gray SL. Vancomycin dosing and monitoring in the treatment of cystic fibrosis: results of a national practice survey. J Pediatr Pharmacol Ther. 2017; 22(6): 406-411.
- 52 Bosso JA, Flume PA, Gray SL. Linezolid pharmacokinetics in adult patients with cystic fibrosis. Antimicrob Agents Chemother. 2004; 48(1): 281-284.
- 53 Fusco NM, Meaney CJ, Wells C, Frederick CA, Prescott WA. Linezolid-resistant ST36 methicillin-resistant Staphylococcus aureus associated with prolonged linezolid treatment in two paediatric cystic fibrosis patients. J Antimicrob Chemother. 2010; 65(3): 442-445.
- 54 Fusco NM, Meaney CJ, Wells C, Frederick CA, Prescott WA, Jr. Vancomycin versus vancomycin plus rifampin for the treatment of acute pulmonary exacerbations of cystic fibrosis. J Pediatr Pharmacol Ther. 2018; 23(2): 125-131.
- 55 Beringer PM, Owens H, Nguyen A, Benitez D, Rao A, D'Argenio DZ. Staphylococcus aureus small-colony variants are independently associated with worse lung disease in children with cystic fibrosis. Clin Infect Dis. 2013; 57(3): 384-391.
- 56 Clindamycin hydrochloride capsule. Approved Package Labeling. Greenstone, LLC. 2018.
- 57 López-Hernández I, Delgado Valverde M, Batista Díaz N, Pascual A. Pharmacokinetics of intravenous and oral linezolid in adults with cystic fibrosis. Antimicrob Agents Chemother. 2011; 55(7): 3393-3398.
- 58 Lopez-Hernandez I, Delgado Valverde M, Batista Diaz N, Pascual A. First report of linezolid dependence in methicillin-resistant Staphylococcus aureus. Clin Microbiol Infect. 2015; 21(7):650.
- 59 Román F, Roldán C, Trincado P, Ballesteros C, Carazo C, Vindel A. Emergence of linezolid-resistant Staphylococcus aureus after prolonged treatment of cystic fibrosis patients in Cleveland, Ohio. Antimicrob Agents Chemother. 2011; 55(4): 1684-1692.
- 60 Roman F, Roldan C, Trincado P, Ballesteros C, Carazo C, Vindel A. Detection of linezolid-resistant Staphylococcus aureus with 23S rRNA and novel L4 riboprotein mutations in a cystic fibrosis patient in Spain. Antimicrob Agents Chemother. 2013; 57(5): 2428-2429.
- 61 Tazi A, Chapron J, Touak G, et al. Rapid emergence of resistance to linezolid and mutator phenotypes in Staphylococcus aureus isolates from an adult cystic fibrosis patient. Antimicrob Agents Chemother. 2013; 57(10): 5186-5188.
- 62 Yu D, Stach LM, Newland JG. Linezolid-resistant Staphylococcus aureus in children with cystic fibrosis. J Pediatric Infect Dis Soc. 2015; 4(4): e163-e165.
- 63 Antonelli A, D'Andrea MM, Galano A, et al. Emergence of cfr-mediated linezolid resistance in a methicillin-resistant Staphylococcus aureus epidemic clone isolated from patients with cystic fibrosis. Antimicrob Agents Chemother. 2015; 60(3): 1878-1882.
- 64 Gales A, Sader H, Andrade S, Lutz L, Machado A, Barth A. Linezolid-resistant cfr-positive MRSA, Italy. J Antimicrob Chemother. 2016; 71(8): 2349-2351.
- 65 Gales AC, Sader HS, Andrade SS, Lutz L, Machado A, Barth AL. Emergence of linezolid-resistant Staphylococcus aureus during treatment of pulmonary infection in a patient with cystic fibrosis. Int J Antimicrob Agents. 2006; 27(4): 300-302.
- 66 Reed MD, Stern RC, Bertino JS, Jr., Myers CM, Yamashita TS, Blumer JL. Dosing implications of rapid elimination of trimethoprim–sulfamethoxazole in patients with cystic fibrosis. J Pediatr. 1984; 104(2): 303-307.
- 67 Wolter DJ, Emerson JC, McNamara S, et al. Increased Prevalence and resistance of important pathogens recovered from respiratory specimens of cystic fibrosis patients during a decade. Pediatr Infect Dis J. 2015; 34(7): 700-705.
- 68 Beringer PM, Owens H, Nguyen A, Benitez D, Rao A, D'Argenio DZ. Pharmacokinetics of doxycycline in adults with cystic fibrosis. Antimicrob Agents Chemother. 2012; 56(1): 70-74.
- 69 Epps QJ, Epps KL, Zobell JT, Young DC. Optimization of antimicrobials in the treatment of cystic fibrosis pulmonary exacerbations: II. Therapies for allergic bronchopulmonary aspergillosis. Pediatr Pulmonol. 2020; 55(12): 3541-3572.
- 70 Solu-Medrol. Approved package labeling. Pharmacia & Upjohn, LLC. 2020.
- 71 Amphotericin B injection. Approved package labeling. XGen Pharmaceuticals. 2010.
- 72 Abelect. Approved package labeling. Sigma-Tau Pharmasource, Inc. 2013.
- 73 Ambisome. Approved package labeling. Astellas Pharma US, Inc. 2020.
- 74 Cresemba. Approved package labeling. Astellas Pharma US, Inc. December 2019.
- 75 Sporanox. Approved package labeling. Pricara, Division of Ortho McNeil-Janssen Pharmaceuticals, Inc. 2001.
- 76 Noxafil. Approved package labeling. Merck, Inc. 2015.
- 77 Vfend. Approved package labeling. Pfizer, Inc. 2020.
- 78 Xolair. Approved package labeling. Genentech, Inc. 2019.
- 79 Sermet-Gaudelus I, Lesne-Hulin A, Lenoir G, Singlas E, Berche P, Hennequin C. Sputum itraconazole concentrations in cystic fibrosis patients. Antimicrob Agents Chemother. 2001; 45(6): 1937-1938.
- 80 Conway SP, Etherington C, Peckham DG, Brownlee KG, Whitehead A, Cunliffe H. Pharmacokinetics and safety of itraconazole in patients with cystic fibrosis. J Antimicrob Chemother. 2004; 53(5): 841-847.
- 81 Hennig S, Wainwright CE, Bell SC, Miller H, Friberg LE, Charles BG. Population pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole in paediatric cystic fibrosis and bone marrow transplant patients. Clin Pharmacokinet. 2006; 45(11): 1099-1114.
- 82 Patel D, Popple S, Claydon A, Modha DE, Gaillard EA. Treatment of Aspergillus fumigatus in patients with cystic fibrosis: a randomized, placebo-controlled pilot study. PLOS One. 2012; 7(4):e36077.
- 83 Patel D, Popple S, Claydon A, Modha DE, Gaillard EA. Posaconazole therapy in children with cystic fibrosis and Aspergillus-related lung disease. Med Mycol. 2020; 58(1): 11-21.
- 84 Bentley S, Gupta A, Balfour-Lynn IM. Pharmacokinetics of oral voriconazole in patients with cystic fibrosis. J Antimicrob Chemother. 2011; 66(10): 2438-2440.
- 85 Bentley S, Gupta A, Balfour-Lynn IM. Subtherapeutic itraconazole and voriconazole levels in children with cystic fibrosis. J Cyst Fibros. 2013; 12(4): 418-419.
- 86 Markantonis SL, Katelari A, Pappa E, Doudounakis S. Voriconazole pharmacokinetics and photosensitivity in children with cystic fibrosis. J Cyst Fibros. 2012; 11(3): 246-252.
- 87 Han K, Capitano B, Bies R, et al. Voriconazole pharmacokinetic variability in cystic fibrosis lung transplant patients. Transpl Infect Dis. 2009; 11(3): 211-219.
- 88 Stelzer D, Weber A, Ihle F, et al. Bioavailability and population pharmacokinetics of voriconazole in lung transplant recipients. Antimicrob Agents Chemother. 2010; 54(10): 4424-4431.
- 89 Gibson RL, Burns JL, Ramsey BW. Comparing azole plasma trough levels in lung transplant recipients: percentage of therapeutic levels and intrapatient variability. Ther Drug Monit. 2017; 39(2): 93-101.
- 90 Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med. 2003; 168(8): 918-951.
- 91 Touw DJ. Clinical pharmacokinetics of antimicrobial drugs in cystic fibrosis. Pharm World Sci. 1998; 20(4): 149-160.
- 92 Mouton JW, Dudley MN, Cars O, Derendorf H, Drusano GL. Standardization of pharmacokinetic/pharmacodynamic (PK/PD) terminology for anti-infective drugs: an update. J Antimicrob Chemother. 2005; 55(5): 601-607.
- 93 Minocin capsule. Approved package labeling. Patheon Pharmaceuticals. 2010.
- 94 Stevens DA, Moss RB, Kurup VP, et al. Allergic bronchopulmonary aspergillosis in cystic fibrosis—state of the art: Cystic Fibrosis Foundation Consensus Conference. Clin Infect Dis. 2003; 37(suppl 3): S225-S264.
Citing Literature
