CF WELL Pharmacology: Microbiology & Antibiotics Bradley E. McCrory, PharmD, BCPS Clinical Pharmacy Specialist Pulmonary Medicine Cincinnati Children s Hospital Medical Center January 26, 2017
Disclosure I have nothing to disclose regarding the content of this presentation
Objectives Describe the prevalence of bacteria that grow in the lungs of CF patients Given a CF patient, develop a treatment regimen (interactive) Describe the recommended monitoring for antibiotics used with CF patients
Presentation Outline Cystic fibrosis bacteria prevalence Antibiotics commonly used to treat cystic fibrosis exacerbations Dosing recommendations Monitoring recommendations
CYSTIC FIBROSIS BACTERIA PREVALENCE
Bacteria Prevalence Cystic Fibrosis Foundation Patient Registry Data: 2014 Annual Patient Report
Bacteria Prevalence Cystic Fibrosis Foundation Patient Registry Data: 2014 Annual Patient Report
Bacteria Prevalence Top 3 bacteria encountered in cystic fibrosis patients Staphylococcus aureus Methicillin-susceptible Methicillin-resistant Thymidine-dependent Haemophilus influenzae Non-typeable Pseudomonas aeruginosa Non-mucoid Mucoid
Staphylococcus aureus Gram positive cocci Most common organism found in respiratory tract of young children with CF Transmission is from person-to-person Members of the same household likely have the same strain Wong et al. Pediatr Pulmonol 2013;48:1151-9
Staphylococcus aureus Upper airway colonization believed to precede lower airway infection Once reaches lower airway, infection often persists Children culture positive for S. aureus in first 2 years of life have shown lower FEV 1 and FVC by age 5 Compared to uninfected, matched CF patients Wong et al. Pediatr Pulmonol 2013;48:1151-9
Staphylococcus aureus Prophylaxis: Not routinely recommended in the US Studies have linked prophylaxis to increase prevalence of P. aeruginosa infections Studies show no difference in outcomes Weight, radiographic findings, lung function Eradication: Not routinely recommended in the US Eradication is difficult, various rates of efficacy Wong et al. Pediatr Pulmonol 2013;48:1151-9
Pseudomonas aeruginosa Gram negative rod Most common organism found in respiratory tract of older CF patients Transmission can be either environmental or person-to-person Usually begins with intermittent isolation from the airways Bendiak G, et al. Semin Respir Crit Care Med 2009;30:587-95
Pseudomonas aeruginosa Risk factors for Pseudomonas infection Female gender Homozygous for Phe508-del mutation Decreased lung function Lack of Staphylococcus aureus on recent sputum cultures Little effect on lung function with acquisition of non-mucoid Pseudomonas Significant decline in lung function with development of mucoid Pseudomonas Bendiak G, et al. Semin Respir Crit Care Med 2009;30:587-95 Li, et al. JAMA 2005;293:581-8
Pseudomonas aeruginosa Prevention: Not Recommended Vaccine against P. aeruginosa has shown variable results Eradication: Recommended Prevent infection with mucoid Pseudomonas Several treatment regimens studied Inhaled antibiotics alone Inhaled antibiotics with oral antibiotics Bendiak G, et al. Semin Respir Crit Care Med 2009;30:587-95
Patient Case 4 year old, newly diagnosed patient with cystic fibrosis will be treated for an exacerbation with intravenous antibiotics at home What organism would you want to make sure is empirically treated in this patient? A. Pseudomonas aeruginosa B. Staphylococcus aureus C. Haemophilus influenzae D. Stenotrophomonas maltophilia
CYSTIC FIBROSIS ANTIBIOTICS
Concentration Dependent
Minimal Concentration Dependent
Patterns of Bactericidal Activity Concentration-dependent Aminoglycosides Fluoroquinolones Metronidazole Daptomycin Telithromycin Minimal concentrationdependent Penicillins Cephalosporins Carbapenems Monobactams Clindamycin Vancomycin Azithromycin Clarithromycin Linezolid Doxycycline Tigecycline Beta-lactams
Choosing Antibiotics in Cystic Fibrosis Pseudomonas aeruginosa Two antipseudomonal antibiotics combination of an aminoglycoside with an antipseudomonal β-lactam In 2009, CF Foundation concluded there is insufficient evidence to support the use of monotherapy for chronic infections Flume et al. Am J Respir Crit Care Med. 2009; 180:802 8 Gibson et al. Am J Respir Crit Care Med. 2003; 168:918-51
Choosing Antibiotics in Cystic Fibrosis Pseudomonas aeruginosa Antibiotic susceptibility testing found to not be clinically relevant No correlation found between tobramycin or ceftazidime susceptibilities and clinical response Routine synergy testing is not recommended even for multi-drug resistant (MDR) bacteria Smith et al. Chest. 2003; 123:1495-502 Aaron et al. Lancet. 2005; 366:463-71 Flume et al. Am J Respir Crit Care Med. 2009; 180:802-8.
Dosing in Cystic Fibrosis Patients have increased volume of distribution Patients have increased total body clearance Different dosing not limited to antibiotics Most studied class of medications Zobell, et al. Pediatr Pulmonol 2013;48:525-37
Aminoglycosides
Aminoglycosides Spectrum of activity Burkholderia cepacia Escherichia coli Klebsiella species Enterobacter species Serratia species Citrobacter species Morganella Morganii Acinetobacter species Providencia species Proteus mirabilis Proteus vulgaris Pseudomonas aeruginosa Staphylococcus aureus Synergy with β-lactams or vancomycin Long, et al. Principles and Practice of Pediatric Infectious Diseases, 3rd ed., 2009. Pg.1430
Aminoglycosides Tissue penetration (percentage of serum) CNS: 5-10% Lungs (epithelial lining fluid): ~30% of peak serum concentrations Urine: 100% Optimal microbiologic efficacy occurs when peak concentration is 8-10 times the MIC Also exhibit a post-antibiotic effect, where activity against bacteria persists when concentration is below the MIC
Aminoglycosides Dosing strategies Conventional: every 8 hours Once Daily Dosing: every 24 hours Utilize higher peak concentrations and postantibiotic effect to overcome higher MICs and reduce toxicities 2009: CF Foundation recommends once daily dosing of aminoglycosides is preferred to 3 times daily dosing Flume et al. Am J Respir Crit Care Med 2009;180:802 8
Amikacin Pharmacodynamics and pharmacokinetics similar to gentamicin and tobramycin Higher MICs than gentamicin and tobramycin NOT appropriate for once daily dosing PAE only 1-2 hours Typically reserved for bacteria that are resistant to gentamicin and tobramycin Craig et al. J Antimicrob Chemother 1991: Suppl 27:29-40
Aminoglycosides Adverse effects Nephrotoxicity Risk increases with elevated trough concentrations Risk increases with dehydration status Ototoxicity Risk increases with prolonged/repeated exposure Risk increases with elevated peak concentrations Electrolyte wasting Potassium and Magnesium
Fluoroquinolones Ciprofloxacin Levofloxacin
Fluoroquinolones Systemic fluoroquinolones studied in pediatric patients Ciprofloxacin Levofloxacin Ciprofloxacin and levofloxacin have similar spectrums of activities
Fluoroquinolones Spectrum of activity Acinetobacter species Escherichia coli Klebsiella pneumoniae Enterobacter species Citrobacter species Proteus species Serratia marcescens Pseudomonas aeruginosa Haemophilus species Moraxella catarrhalis Streptococcus species Enterococcus faecalis Bacillus anthracis Bradley, et al. Principles and Practice of Pediatric Infectious Diseases, 292, 1453-84
Fluoroquinolones Tissue penetration Penetrates most tissues Ciprofloxacin: minimal penetration into CSF For treatment of CF exacerbations, need to get antibiotic into the lungs Epithelial lining fluid concentrations (ELF) Differences exist between ciprofloxacin and levofloxacin
Concentration (mg/l) Fluoroquinolones Lung Penetration 12 10 ELF/Plasma = 1.879 8 6 4 ELF/Plasma = 0.914 2 0 Ciprofloxacin ELF Plasma Levofloxacin Schuler P, et al. Eur Respir J 1997;10:1130-6 Drusano GL, et al. Antimicrob Agents Chemother 2002;46:586-9
Fluoroquinolones Dosing strategies Ciprofloxacin Oral: 40 mg/kg/day divided Q12H Max dose 1000 mg Q12H IV: 30 mg/kg/day divided Q8 to 12H Max dose 400 mg Q8H Levofloxacin (IV and oral dosing) <10 years: 20 mg/kg/day divided Q12H 10 years: 10 mg/kg/day Q24H Max dose 750 mg Q24H Taketomo et al. Pediatric and Neonatal Dosing Handbook, 22nd ed. Lexi-comp 2015 Courter et al. J Pediatric Infect Dis Soc Feb 2016. DOI:10.1093/jpids/piw006
Fluoroquinolones Adverse effects Bone and joint disorders Use with caution in patients who are: <18 years of age or >60 years of age, requiring concomitant corticosteroids, strenuous physical activity, and renal impairment QTc prolongation Baseline EKG, especially with concomitant medications that prolong the QTc interval
Beta Lactams Penicillins Cephalosporins Carbapenems Monobactams
Beta Lactams Activity Penicillins Gram positive activity Beta-lactamase inhibitor combos Adds Gram negative activity Extended spectrum PCNs Ex: Piperacillin Adds Pseudomonas activity Cephalosporins Generations 1 3 Gram positive progressing to mostly Gram negative activity Ceftazidime: Pseudomonas coverage Fourth Generation Gram positive and negative activity with Pseudomonas coverage Fifth Generation Gram positive and negative activity with MRSA coverage Carbapenems Gram positive and negative activity with Pseudomonas coverage Monobactams Gram negative activity only including Pseudomonas Bradley, et al. Principles and Practice of Pediatric Infectious Diseases, 292, 1453-84
Beta Lactams Tissue penetration Penetrates most tissues, with most reaching the CSF Dosing CF patients mostly require maximal dosing listed in dosing references Watch for different dosing when need to cover for Pseudomonas Meropenem 40 mg/kg/dose Q8H (max 2000 mg Q8H) vs 20 mg/kg/dose Q8H (max 1000 mg Q8H)
Beta Lactams Dosing strategies Intermittent infusion (conventional infusions) Extended infusion Prolonged infusion of antibiotic Typical duration is ½ of the dosing interval Goal is to keep serum concentrations high Continuous infusion Usually given via CADD pumps, or other device Goal is to keep serum concentrations high Can adjust doses based on serum concentrations and MIC of bacteria treating Need to interrupt infusions when aminoglycosides are needed Zobell, et al. Pediatr Pulmonol 2013;48:525-37
Beta Lactams Adverse effects Seizures Mostly in renal failure Drug fevers Usually with prolonged therapy Increased AST and ALT Interstitial nephritis
Vancomycin Spectrum of activity Streptococcus species Enterococcus species Staphylococcus species Actinomyces species Bradley, et al. Principles and Practice of Pediatric Infectious Diseases, 292, 1453-84
Vancomycin Tissue penetration (percentage of serum) CNS: <10% Sternal Bone: 57% Heart Valve: 12% ELF: 18% Lung tissue: 17-24% Bone: 7-13% Fat:14% Muscle: 9% Massias et al. Antimicrob Agents Chemother 1992;36:2539-41; Cruciani et al. J Antimicrob Chemother 1996;38:865-9; Lamer et al Antimicrob Agents Chemother 1993;37:281-6; Daschner et al J Antimicrob Chemother 1987;19:359-62; Graziani et al. Antimicrob Agents Chemother 1988;32:1320-2
Vancomycin Dosing 15-20 mg/kg/dose Q6-8H Dose adjusted based on serum concentrations Dose may start higher if historical dosing information shows the patient requires higher dosing
Vancomycin Adverse effects Ototoxicity Associated with serum concentrations >40 mg/l Not seen much any more since compound purified Nephrotoxicity Associated with trough concentrations >10 mg/l No longer considered nephrotoxic since compound purified Increased risk for nephrotoxicity when used in combination with other nephrotoxic medications E.g. aminoglycosides, loop diuretics, etc. Red man syndrome Infusion related reaction
Vancomycin Red man syndrome Skin reaction associated with infusion of vancomycin Faster rates of infusion associated with Histamine release Treat initial reaction with diphenhydramine Q6H until symptoms resolved prophylaxis is to slow down rate of infusion Extending infusion duration to 2 hours If still with significant reaction during infusion Give diphenhydramine premedication prior to vancomycin doses
Patient Case 10 year old CF patient with history of Pseudomonas aeruginosa, susceptible to tobramycin in cultures. The patient will be started on ceftazidime and another antibiotic to treat the exacerbation. Which of the following is the best choice for this patient? A. Amikacin Q24H B. Tobramycin Q24H C. Tobramycin Q8H D. Piperacillin/Tazobactam Q6H
CF ANTIBIOTIC MONITORING
Pharmacokinetics Aminoglycosides Peak Goal 8-10 x MIC Trough Low enough to prevent toxicities Typically administered over 30 minutes Monitor serum concentrations regularly
Pharmacokinetics Aminoglycosides Conventional dosing Reach steady state concentrations with 3rd dose Peaks and troughs Peak 30 minutes after dose is infused Trough prior to dose Repeat trough concentrations every 5-7 days High Dose Once Daily dosing Never reach steady state concentrations Obtain 2 post-dose serum concentrations, after 1 st or 2 nd dose Repeat serum concentrations every 5-7 days
Pharmacokinetics Vancomycin Goal trough is 4-5 x MIC Typically given over 1 hour If dose gets to be >1000 mg/dose (or greater than 25 mg/kg/dose) extend infusion time Monitor serum concentrations regularly Goal trough concentration 10-20 mcg/ml Goal AUC:MIC of >400
Pharmacokinetics Vancomycin Neonates, Infants, Children, Adolescents and Adults Trough levels only Checked around the 3 rd or 4 th dose of the regimen Different if monitoring AUC
Antibiotic Monitoring Serum creatinine Ex: Aminoglycosides, vancomycin, piperacillin/tazobactam, ceftazidime, colistimethate Complete blood counts (CBC) Ex: Linezolid, sulfamethoxazole/trimethoprim, meropenem, ceftazidime Liver function tests (LFT) Ex: Piperacillin/tazobactam, rifampin, sulfamethoxazole/trimethoprim, ceftazidime
Patient Case 9 year old with cystic fibrosis, admitted for a pulmonary exacerbation. Will be treated with intravenous tobramycin and ceftazidime. Which of the following are the best options for monitoring this patient? A. Serum creatinine only B. Serum creatinine and CBC C. Serum creatinine, CBC, and LFT D. No monitoring required
PUTTING IT ALL TOGETHER
Patient Case 18 year old with cystic fibrosis, to be treated with antibiotics for pulmonary exacerbation. History of growing Staphylococcus aureus and Pseudomonas aeruginosa. Based on prior admissions, the patient has responded well to intravenous tobramycin, ceftazidime, and sulfamethoxazole/trimethoprim therapy. The following are the most recent culture with susceptibilities:
Patient Case Sputum Staphylococcus aureus Antibiotic MIC (mcg/ml) Susceptibility Clindamycin 1 R Erythromycin 8 R Nafcillin 4 R Doxycycline 0.25 S Sulfamethoxazole/trimethoprim 0.25 S Rifampin 0.06 S Vancomycin 1 S
Patient Case Sputum Pseudomonas aeruginosa Antibiotic MIC (mcg/ml) Susceptibility Amikacin 2 S Aztreonam 256 R Ceftazidime 256 R Cefepime 256 R Piperacillin/Tazobactam 256 R Ticarcillin/Clavulanate 256 R Meropenem 256 R Colistin 0.5 S Levofloxacin 256 R Tobramycin 1.5 S
Patient Case Which of the following is the best option for treatment of this patient s pulmonary exacerbation? A. Intravenous tobramycin, ceftazidime, and sulfamethoxazole/trimethoprim B. Intravenous tobramycin, intravenous colistimethate, and clindamycin C. Intravenous amikacin, ceftazidime, and sulfamethoxazole/trimethoprim D. Intravenous tobramycin, intravenous colistimethate, and intravenous vancomycin
Patient Case Based on the treatment regimen of intravenous tobramycin, ceftazidime, and sulfamethoxazole/trimethoprim, which of the following is the best option for monitoring this patient while on these antibiotics? A. Serum creatinine B. CBC C. LFT D. All of the above
CF WELL Pharmacology: Microbiology & Antibiotics Bradley E. McCrory, PharmD, BCPS Clinical Pharmacy Specialist Pulmonary Medicine Cincinnati Children s Hospital Medical Center January 26, 2017