Post on 03-Dec-2021
Prescribing antibiotics in the clinical setting Nicole Srivastava, Pharm D, BCPS
Clinical Pharmacy Specialist, Infectious Diseases
Christiana Care Health System
Objectives
Review general principles in antimicrobial therapy
◦ Common organisms
◦ Antibiogram
◦ Bactericidal vs bacteriostatic
◦ Duration of therapy
Review the pharmacology of common antimicrobials
◦ Mechanism of action
◦ Spectrum of activity
◦ Place in therapy
◦ Adverse effects
◦ Key points
Gram positive organisms
Gram negative organisms
Anaerobic organisms
Atypical organisms
Legionella
Mycoplasma
Chlamydophila
Multi Drug Resistant Organisms
E = Enterococcus faecium
S = Staphylococcus aureus
K = *ESBL producing-Klebsiella and E. coli
A = Acinetobacter baumannii
P = Pseudomonas aeruginosa
E = Enterobacter species
Boucher HW, et al. Clin Infect Dis. 2009;48:1-12.
Common organisms Site Common organisms
Meningitis (dependent on age)
< 1 month: S. agalactiae, E. coli, L. monocytogenes, Klebsiella
1-23 months: S. pneumoniae, N. meningitidis, S. agalactiae, H. influenzae, E. coli
2-50 years: N. meningitidis, S. pneumoniae
> 50 years: N. meningitidis, S. pneumoniae, L. monocytogenes, aerobic GNB
Post neurosurgery: aerobic GNB, P. aeruginosa, S. aureus, coag-neg staph
Skin Coag-neg staph, S. aureus, Streptococcus , Corynebacterium, Propionibacterium
Oral cavity Viridans streptococci, Peptococcus, Peptostreptococcus, Eikenella, Haemophilus
Pneumonia
CAP: S. pneumoniae, H. influenzae, M. pneumoniae, C. pneumoniae, Legionella +/- S. aureus and aerobic GNB
HAP: S. pneumoniae, H. influenzae, E. coli, K. pneumoniae, Enterobacter, Proteus, Serratia, S. aureus, P. aeruginosa, Acinetobacter
HCAP: HAP organisms + atypical organisms
Available from: www.idosciety.org. Accessed on: 12 September 2012
Common organisms
Site Common organisms
Endocarditis Viridans group streptococcus, S. bovis, enterococcus, S. aureus, coag-neg staph, HACEK, GNB
Intra-abdominal infections
E. coli, K. pneumoniae, streptococcus, anaerobes +/- enterococcus, candida, P. aeruginosa, MRSA
Urinary tract infections
E. coli, K. pneumoniae, P. aeruginosa
Diabetic foot infections
β-hemolytic streptococcus, S. aureus, Enterobacteriaceae, P. aeruginosa
Available from: www.idosciety.org. Accessed on: 12 September 2012
Antibiogram
See attached
Bactericidal vs bacteriostatic
Bactericidal
β-lactams
Glycopeptides
Fluoroquinolones
Aminoglycosides
Metronidazole
Daptomycin
Sulfamethoxazole/ trimethoprim
Bacteriostatic
Macrolides
Clindamycin
Tetracyclines
Linezolid
Bergman SJ, et al. Infect Dis Clin N Am. 2007;21:821-46. Finberg FW, et al. Clin Infect Dis. 2004;39:1314-20.
Bactericidal preferred for endocarditis, neutropenic fever and meningitis +/- osteomyelitis
Duration of therapy Infection Duration
Meningitis Organism specific: 7-21 days
CAP ≥ 5 days
HAP 7 days
HAP – non lactose fermenter >8-14 days
Complicated intra-abdominal infection 4-7 days
Cystitis FQ: 3 days Bactrim: 3-5 days *beta lactams
Pyelonephritis Levofloxacin 750 mg x 5 days Ciprofloxacin 7 days *beta lactams and Bactrim
Cellulitis 7-14 days
Endocarditis Organism specific: 4-6 weeks
Osteomyelitis ~ 6 weeks
Hayashi Y and Paterson DL. Clin Infect Dis. 2011;52(10):1232-40.
Beta lactams
MOA: ◦ Inhibit penicillin binding proteins interferes
with cell wall synthesis cell wall death
Hypersensitivity reactions ◦ Anaphylaxis/hives (IgE mediated) ◦ Rash ◦ Fever ◦ Acute interstitial nephritis ◦ Cross-reactivity: Cephalosporins: 5-10% Carbapenems: 1-50%* Aztreonam: about 0%
Beta lactams
β-lactams
Penicillins Cephalosporins Carbapenems Monobactams-
aztreonam
Penicillins
Natural penicillins
Antistaphylococcal penicillins
Amino-penicillins
Antipseudomonal penicillins
β-lactam/β-lactamase inhibitor combinations
Penicillin G Penicillin V
Nafcillin Oxacillin Dicloxacillin
Amoxicillin Ampicillin
Piperacillin Ticarcillin
Ampicillin/sulbactam (Unasyn®) Amoxicillin/clavulanate (Augmentin®) Piperacillin/tazobactam (Zosyn®) Ticarcillin/clavulanate (Timentin®)
Natural penicillins
Examples Penicillin G and V
Spectrum of activity Good: Treponema pallidum, most streptococci Moderate: S. pneumoniae, enterococci Poor: everything else
Place in therapy Neurosyphilis GAS pharyngitis Endocarditis
Adverse effects Hypersensitivity reactions Seizures
Key points Penicillin V = oral Penicillin G = intravenous Penicillin G benzathine = IM shots for syphilis
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Anti-staphylococcal penicillins Examples Oxacillin, dicloxacillin, nafcillin
Spectrum of activity Good: MSSA, penicillin sensitive streptococci Poor: Gram negative bacilli, enterococci, anaerobes, MRSA, listeria, penicillin resistant streptococci
Place in therapy MSSA bacteremia/endocarditis Skin and skin structure infections
Adverse effects
Oxacillin: hepatitis, rash Nafcillin: phlebitis Hypersensitivity reactions , seizures, acute interstitial nephritis
Key points
• Beta lactams are more rapidly cidal against staphylococci compared to vancomycin, consider desensitization in patients with severe beta lactam allergy
• Eliminated by liver, do not warrant renal dose adjustment
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Aminopenicillins Examples Ampicillin, amoxicillin
Spectrum of activity Good: streptococci, enterococci Moderate: Gram negative bacilli, Haemophilus Poor: staphylococci, anaerobes
Place in therapy Enterococci infections (ie: UTI, endocarditis) Amoxicillin is frequently used for OM, URI, GAS
Adverse effects Hypersensitivity reactions Diarrhea
Key points
• resistance among Gram negative bacilli • Ampicillin can be given orally however
amoxicillin is more bioavailable, better tolerated, administered less frequently • (IV = amp; PO = amox)
• Ampicillin is static must combine with gentamicin/streptomycin to achieve bactericidal activity for enterococcus endocarditis
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Antipseudomonal penicillins
Examples Piperacillin, ticarcillin
Spectrum of activity Good: P. aeruginosa, streptococci, enterococci Moderate: Gram negative bacilli, Haemophilus Poor: anaerobes, staphylococci
Place in therapy Not on formulary
Adverse effects Hypersensitivity reactions Seizures
Key points • Use in combination with beta-lactamase inhibitor
(ie: tazobactam or clavulanate)
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
β lactam/ β lactamase inhibitor combinations
Examples
Ampicillin/sulbactam Amoxicillin/clavulanate Piperacillin/tazobactam Ticarcillin/clavulanate
Spectrum of activity
Good: MSSA, streptococci, enterococci, anaerobes, Gram negative bacilli, *Pseudomonas aeruginosa (pip/tazo, ticar/clav only) Poor: MRSA, extended spectrum beta-lactamase (ESBL) producing Gram negative bacilli
Place in therapy
Empiric therapy: intra-abdominal infections**, diabetic foot ulcers, nosocomial/aspiration pneumonia
Adverse effects
Hypersensitivity reaction Seizures
Key points
• Sulbactam active against Acinetobacter baumannii use high doses of ampicillin/sulbactam
• Increase in amp/sul resistant E. coli not ideal for empiric therapy of intra-abdominal infections
• Prolonged infusion with piperacillin/tazobactam
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Cephalosporins
Generations with variable spectrum of activity
All lack activity against enterococci
Anaerobic coverage: cefoxitin, cefotetan
Pseudomonas coverage: cefepime, ceftazidime
MRSA coverage: ceftaroline
Cross reactivity with penicillins: 5-10%
◦ Varies with generation, based on side chain
Cephalosporins: 1st generation Examples Cefazolin, cephalexin
Spectrum of activity Good: MSSA, streptococci Moderate: Gram negative bacilli Poor: enterococci, anaerobes, MRSA, P. aeruginosa
Place in therapy Pre-operative surgical prophylaxis MSSA bacteremia/endocarditis Skin and skin structure infections
Adverse effects Hypersensitivity reaction
Key points
• Good alternative to oxacillin/nafcillin for MSSA bacteremia as less frequent dosing and less phlebitis
• Do NOT cross BBB • Cephalexin = oral • Cefazolin = intravenous
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Cephalosporins: 2nd generation Examples Cefoxitin, cefuroxime, cefotetan, cefaclor
Spectrum of activity
Stronger Gram - , weaker gram + coverage Good: some Gram negative bacilli, Haemophilus, Neisseria Moderate: streptococci, staphylococci, anaerobes* Poor: enterococci, MRSA, P. aeruginosa
Place in therapy Pre-operative surgical prophylaxis URI, CAP
Adverse effects Hypersensitivity reaction MTT side chain (ie: cefotetan): can inhibit vitamin K production bleeding; disulfiram reaction
Key points
• Least utilized • Do NOT cross BBB • Cefoxitin = intravenous • Cefuroxime = oral, intravenous
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Cephalosporins: 3rd generation Examples Ceftriaxone, cefotaxime, ceftazidime, cefdinir, cefpodoxime, cefixime
Spectrum of activity
Good: streptococci, Gram negative bacilli Moderate: MSSA Poor: enterococci, Pseudomonas , anaerobes, MRSA
Place in therapy
Respiratory infections, pyelonephritis, meningitis, skin and skin structure infections, neutropenic fever/nosocomial infections (ceftazidime), Lyme’s disease and gonorrhea (ceftriaxone)
Adverse effects
Hypersensitivity reaction
Key points
• Ceftazidime covers P. aeruginosa at the expense of Gram positive coverage
• 3rd GC have been highly associated with C. difficile • Ceftriaxone, cefotaxime, ceftazidime cross BBB
• Ceftriaxone preferred for S. pneumoniae meningitis (q12hrs) • Ceftriaxone interacts with calcium products forms crystals that
can precipitate in lungs and kidneys • Ceftriaxone has been associated with biliary sludging in neonates ,
cefotaxime preferred • Induce Gram negative resistance
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Cephalosporins: 4th generation
Examples Cefepime
Spectrum of activity
Broadest spectrum Good: MSSA, streptococci, P. aeruginosa, Gram negative bacilli Moderate: Acinetobacter Poor: enterococci, anaerobes, MRSA
Place in therapy Febrile neutropenia, nosocomial pneumonia, post-neurosurgical meningitis
Adverse effects Hypersensitivity reaction CNS toxicity
Key points • FDA warning with risk of seizures in patients with
renal impairment in which the dose was not adjusted correctly
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Cephalosporins: 5th generation Examples Ceftaroline
Spectrum of activity
Good: MRSA and MSSA, streptococci, Gram negative bacilli Moderate: Acinetobacter Poor: enterococci, anaerobes, P. aeruginosa
Place in therapy Skin and skin structure infections (including MRSA) Community acquired pneumonia (excluding MRSA)
Adverse effects Hypersensitivity reaction
Key points Off label/case reports: complicated MRSA bacteremia in which vancomycin or daptomycin MIC are elevated
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Carbapenems
“big guns”
◦ Broadest spectrum: MSSA, streptococci, Gram negative bacilli including ESBL’s, anaerobes
ESBL GNR
Pseudomonas Acinetobacter E. faecalis E. faecium Anaerobes
Ertapenem + - - - - +
Imipenem + + +* + +/-* +
Doripenem + +* + +/- - +
Meropenem + + + +/- - +
Carbapenems
Examples Ertapenem, doripenem, imipenem, meropenem
Place in therapy
Infections caused by ESBL producing organisms, febrile neutropenia, intra-abdominal infections, nosocomial infections
Adverse effects
Hypersensitivity reaction, seizures, C. difficile colitis
Key points
• Seizures: possible with all, however in clinical trials the reported incidence with imipenem 3.8% vs 1.1% with doripenem vs 0.5% with ertapenem • Risk increased in renal impairment, h/o seizures
• CNS infections: meropenem preferred • Cross-reactivity: 1-50% reported however more likely < 1% • Prolonged infusion • Renally dose adjust!
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Monobactams: aztreonam
Spectrum of activity
Good: P. aeruginosa, Gram negative bacilli Moderate: Acinetobacter Poor: Gram positive organisms, anaerobes
Place in therapy
Gram negative infections including nosocomial infections in patients with beta-lactam allergies
Adverse effects
Similar to other beta lactams except for hypersensitivity reaction
Key points • Available to be given as a nebulized treatment in CF patients • Ceftazidime: side chain similar, potential for cross reactivity
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Glycopeptides
Example Vancomycin
Mechanism of action
inhibits bacterial cell wall synthesis by blocking glycopeptide polymerization through biding tightly to D-alanyl-D-alanine portion of cell wall precursor
Spectrum of activity
Streptococci, enterococci, S. aureus C. difficile (oral vancomycin)
Place in therapy
Gram positive infections: meningitis, endocarditis, pneumonia, skin and skin structure infections, sepsis, bacteremia
Adverse effects
Nephrotoxicity, red man syndrome, ototoxicity
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Vancomycin : key points
MRSA vs MSSA bacteremia
MRSA pneumonia
Dosing and therapeutic drug monitoring
S. aureus and MIC creep
MRSA vs MSSA bacteremia
MSSA treatment of choice = anti-staphylococcal beta-lactam (ie: oxacillin/nafcillin or cefazolin)
Vancomycin Oxacillin/nafcillin Cefazolin
Pros •Dosing convenience (ie: HD) •Ease of administration in penicillin allergic patient
•Superior anti-staphylococcal killing when compared to glycopeptides for MSSA
•Superior anti-staphylococcal killing when compared to glycopeptides for MSSA •IDSA has dosing recommendations for HD
Cons
•Less rapidly cidal •Has been associated with poor patient outcomes – nephrotoxicity, persistent bacteremia, treatment failures
•Frequent dosing administration •Warrants allergy assessment, desensitization, graded challenge in the penicillin allergic
•Warrants allergy assessment, desensitization, graded challenge in the penicillin allergic
Schweizer ML, et al. BMC Infectious Diseases. 2011;11:279-86.
MRSA pneumonia ZEPHyR study: Linezolid in MRSA nosocomial pneumonia: a randomized, controlled study
Study design
Prospective, double-blind, controlled, multicenter
Treatment •Linezolid 600 mg IV q 12 hours OR vancomycin 15 mg/kg IV q 12 hours for 7-14 days
Patients •Linezolid N= 224; Vancomycin N= 224 •Concomitant bacteremia: linezolid N= 9; vancomycin N= 19
Outcomes •Clinical success rates at EOT: 80.1% vs 67.8% (95% CI: 4.0 to 20.7) •Clinical success rates at EOS: 54.8% vs 44.9% (95% CI: 0.1 to 19.8) •All-cause 60 day mortality rate : 15.7% vs 17%
Conclusion •Clinical success rate significantly better with linezolid compared with vancomycin however no difference in 60 day mortality rate
Wunderink RG, et al. Clin Infect Dis. 201;54:621-9.
EOT: end of therapy, EOS: end of study
MRSA pneumonia
ZEPHyR study
Number of patients with suspected HAP needed to be treated with linezolid rather than vancomycin to prevent on additional clinical failure
NNT = 1/[0.159 (95/597) – 0.137 (81/587)] ≈ 45
Wunderink RG, et al. Clin Infect Dis. 201;54:621-9. MacDougall C. CE presentation. Treatment of MRSA infections: Can we improve outcomes? Available from: http://medassetsce.rxschool.com/. Accessed on 28 June 2012.
Dosing In order to achieve optimal trough concentrations
doses of 15-20 mg/kg based on ABW given every 8-12 hours is recommended in patient with normal renal function
In seriously ill patients, a loading dose of 25-30 mg/kg based on ABW can be used to facilitate rapid attainment of target trough concentrations
Continuous infusion regimens are unlikely to substantially improve patient outcomes compared to intermittent dosing
Ryback M. Am J Health-Syst Pharm. 2009; 66:82-98.
Therapeutic drug monitoring
WHAT Vancomycin TROUGH concentrations
WHY Most accurate and practical method for measuring EFFICACY
WHEN Just prior to FOURTH dose (at steady state)
HOW
•P&T approved pharmacists the ability to order vancomycin trough levels •Nursing order •Lab order
Ryback M. Am J Health-Syst Pharm. 2009; 66:82-98.
Therapeutic drug monitoring Vancomycin trough Indication Comments
< 10 mcg/mL None May produce resistant strains
10-15 mcg/mL
Skin and skin structure infections Urinary tract infections Intra-abdominal infections
15-20 mcg/mL
Sepsis Bacteremia Endocarditis Osteomyelitis Meningitis Pneumonia
May improve penetration, increase the probability of optimal target serum vancomycin concentrations, and improve clinical outcomes for complicated infections Should achieve an AUC/MIC of ≥ 400 in most patients if the MIC is ≤ 1 mg/dL
Ryback M. Am J Health-Syst Pharm. 2009; 66:82-98.
Staphylococcus aureus
Penicillin resistant S. aureus
Daptomycin Vancomycin Methicillin Penicillin
Methicillin resistant S. aureus
Vancomycin resistant S. aureus
Daptomycin resistant S. aureus
19
45
19
61
20
02
19
85
20
05
Boucher HW, et al. CID. 2007;45:601-8.
S. aureus and vancomycin MIC creep
VSSA = vancomycin sensitive S. aureus; hVISA = heteroresistant vancomycin intermediate S. aureus; VISA = vancomycin intermediate S. aureus; VRSA = vancomycin resistant S. aureus
Boucher HW, et al. CID. 2007;45:601-8.
MIC
0 2 1 ≥16 8 4
hVISA
VSSA
VISA
VRSA
Question
Which of the following are TRUE?
A. The target vancomycin trough for severe infections is 10-15 mcg/mL
B. Vancomycin trough levels should be obtained prior to the 5th dose
C. Vancomycin dosing is dependent on a patients actual body weight and CrCl
D. A and C
Fluoroquinolones
Example Ciprofloxacin, levofloxacin, moxifloxacin
Mechanism of action
Inhibits DNA-gyrase leading to relaxation of supercoiled DNA and promotes breakage of double stranded DNA
Place in therapy
UTI, prostatitis, intra-abdominal infections, H. pylori, SBP prophylaxis, pneumonia, COPD exacerbations, skin and skin structure infections, bone and joint infections, febrile neutropenia, mycobacterial infections
Adverse effects
CNS: dizziness, drowsiness, headache, confusion, tremors, seizures QTc prolongation Tendinoplasty Clostridium difficile associated diarrhea Phototoxicity Alteration in glucose levels GI upset
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Fluoroquinolones: spectrum
Ciprofloxacin Levofloxacin Moxifloxacin
MSSA +/- ++ ++
MRSA - - -
Streptococci - ++ ++
Enterococci - +/- +/-
Gram negative rods ++ ++ ++
Pseudomonas ++ ++ -
Anaerobes - - ++
Atypicals + ++ ++
2011 CCHS antibiogram
Organisms Levofloxacin % susceptible
Ciprofloxacin % susceptible
E. coli 78 78
K. oxytoca 95 95
K. pneumoniae 92 92
P. aeruginosa 78 78
S. pneumoniae (non-sterile)
100 --
Fluoroquinolones: key points
• Moxifloxacin ≠ UTI
• Pseudomonas dosing
• Levofloxacin 750 mg
• Ciprofloxacin 400 mg IV q 8 hrs or 750 mg PO q 12 hrs
• Drug interactions
• Warfarin
• Antacids, mineral supplements, enteral feeds, sucralfate
• Duration of therapy
• CAP: levofloxacin x 5 days
• Uncomplicated UTI: levofloxacin/ciprofloxacin x 3 days
• Complicated UTI/pyelonephritis: levofloxacin 750 mg x 5 days/ciprofloxacin 500 mg PO q 12 hrs x 7 days
• IV to PO conversion
• Renally dose adjust (except for moxifloxacin)
Aminoglycosides
Example Gentamicin, tobramycin, amikacin, streptomycin
Mechanism of action
Inhibits protein synthesis by binding to 30s ribosomal subunit
Spectrum of activity
Gram negative bacilli, P. aeruginosa, Acinetobacter
Place in therapy
Serious Gram positive infections (synergy with cell wall agent), Gram negative infections, febrile neutropenia, cystic fibrosis exacerbations (nebs), pneumonia (combination therapy), mycobacterial infections (amikacin, streptomycin)
Adverse effects
Nephrotoxicity: dose related oliguric acute renal failure • Increased risk with concomitant nephrotoxins Ototoxicity: dose related cochlear and vestibular toxicity • Increased risk with prolonged therapy • Irreversible • streptomycin > gentamicin > tobramycin > amikacin
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Aminoglycosides: key points
Synergy with gentamicin/streptomycin
Once daily vs conventional dosing
TROUGH
PEAK
PEAK
Gentamicin Tobramycin Amikacin
Pk Tr Pk Tr Pk Tr
OD n/a <1 n/a <1 n/a <2
CD 4-10 <1.5 4-10 <1.5 20-30 <6
SD 3-4 <1 na na na na
Dosing weight = ideal body weight (IBW) If actual body weight (ABW) < IBW, dose based on ABW If morbidly obese (>20% over ideal body weight) dose based on adjusted body weight (Adj BW) • Males: IBW = 50 kg + 2.3 kg for each inch over 60 inches • Females: IBW = 45.5 kg + 2.3 kg for each inch over 60 inches • Adj BW = 0.4 (ABW - IBW) + IBW
Aminoglycosides: key points
Neuromuscular blocking agents: possible enhanced action of nondepolarizing muscle relaxant respiratory depression
Monotherapy vs synergy vs combination therapy
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Tetracyclines Example Doxycycline, minocycline, tetracycline
Mechanism of action
Inhibits protein synthesis by binding to 30s ribosomal subunit
Spectrum of activity
Good: Atypicals, rickettsia, spirochetes, Plasmodium sp (malaria) Moderate: staphylococci (MRSA), S. pneumoniae +/-: Gram negative bacilli, enterococci Poor: anaerobes
Place in therapy
URI, CAP (non-ICU), tick-borne illness, skin and skin structure infections, acne, malaria, STD’s (ie: syphilis, chlamydia), enterococci UTI, ESBL UTI
Adverse effects
• GI upset (nausea, diarrhea) • Photosensitivity • Esophageal irritation take with water while standing up • Tooth discoloration in children < 8 years of age
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012. Rapp RP, et al. Pharmacotherapy. 2012;32:399-407. Heintz BH, et al. Pharmacotherapy. 2010;30:1136-49.
Tetracyclines: key points
Pregnancy category D
IV to PO (1:1) for doxycycline and minocycline
Chelate cations: separate from calcium, iron, antacids by at least 2 hours
Doxycycline: no need for renal or hepatic adjustment
Doxycycline C. difficile protectant?
Doernberg SB, et al. Clin Infect Dis. 2012;55:615-20.
Tigecycline (tetracycline)
Example Tigecycline
Mechanism of action
Inhibits protein synthesis by binding to 30s ribosomal subunit
Spectrum of activity
Good: atypicals, enterococci (including VRE), staphylococci (including MRSA), S. pneumoniae Acceptable: Gram negative bacilli, anaerobes Poor: Pseudomonas sp, Proteus sp, Providencia sp
Place in therapy
Intra-abdominal infections, complicated skin and skin structure infections, MDR Gram negative infections
Adverse effects
Nausea, vomiting Pancreatitis (rare)
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Tigecycline: key points
Urinary excretion 33% not ideal for UTI
Static
Dose limiting toxicity nausea and vomiting
Intravenous formulation only
Treatment of carbapenem resistant Enterobacteriaceae (CRE/KPC)
Does not cover Pseudomonas sp, Proteus sp, Providencia sp
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Tigecycline: bacteremia
Large Vd poor serum concentrations
Static
Meta-analysis of safety and efficacy of tigecycline in subjects with SECONDARY bacteremia from 8 phase III clinical trials
◦ IAI, cSSSI, and CAP
◦ Not ideal for PRIMARY bacteremia Endocarditis, CLABSI
Gardiner D, et al. Clin Infect Dis. 2010;50:229-38.
Tigecycline: mortality
FDA Drug Safety Communication: September 1, 2010 ◦ Pooled analysis of 13 trials increased mortality
◦ Greatest risk of death VAP
Prasad P et al: ◦ Tigecycline was associated with increased
mortality (risk difference 0.7%; 95% CI 0.1-1.2%, p = 0.01)
◦ Tigecycline was associated with increased non-cure rates (risk difference 2.9%; 95% CI 0.6-5.2%, p = 0.01)
Available from: http://www.fda.gov/Drugs/DrugSafety/ucm224370.htm. Accessed on: 30 June 2012. Prasad P, et al. Clin Infect Dis. 2012;54:1699-709.
Macrolides
Example Azithromycin, clarithromycin, erythromycin
Mechanism of action
Inhibits protein synthesis by binding to 50s ribosomal subunit
Spectrum of activity
Good: atypicals, H. influenzae, M. catarrhalis, H. pylori, Mycobacterium avium Moderate: S. pneumoniae, S. pyogenes Poor: staphylococci, Gram negative bacilli, anaerobes, enterococci
Place in therapy
Respiratory tract infections*, chlamydia, atypical mycobacterial infections, travelers diarrhea (azithromycin) Erythromycin: GI prokinetic Clarithromycin: H. pylori cocktail
Adverse effects
GI upset Cardiac: QT prolongation
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Macrolides: key points
Drug interactions: CYP450 inhibitors
◦ Erythromycin, clarithromycin
Prolonged half-life
◦ Azithromycin x 3-5 days = 7-10 day course
Bacteriostatic
IV to PO conversion
◦ Azithromycin 1:1
Overprescribing of Z-pak®
2011 CCHS antibiogram
Ceftriaxone Azithromycin Levofloxacin
S. pneumoniae (non-sterile)
30/34 88%
45/74 (61%)
73/73 (100%)
Azithromycin and risk of CV death
Ray WA, et al. N Engl J Med. 2012; 366:1881-90.
NEJM 2012
Study design
Cohort: Tennessee Medicaid patients who received azithromycin between 1992-2006 Matched controls: no antibiotic, amoxicillin, levofloxacin, ciprofloxacin
Outcomes
CV death: •Azithromycin vs no antibiotic HR 2.88 (95% CI: 1.79-4.63, p < 0.001) •Azithromycin vs amoxicillin HR 2.49 (95% CI: 1.38-4.50, p = 0.002) •Azithromycin vs ciprofloxacin HR 3.49 (95% CI: 1.32-9.26, p = 0.01) •Azithromycin vs levofloxacin HR 1.75 (95% CI: 0.91-3.37, p = 0.09)
Conclusion 5 days of azithromycin was associated with a small absolute increase in CV deaths
Take home point
Azithromycin may be associated with increased CV death Commonly prescribed for the treatment of CAP-consider doxycycline for outpatients? Assess each individual patient for comorbidities, electrolyte abnormalities, concurrent drug therapy-increased monitoring for inpatients?
Oxazolidinones
Example Linezolid
Mechanism of action
Inhibits protein synthesis by binding to 23s ribosomal RNA of the 50Sribosomal subunit. Prevents the formation of functional 70s initiation complex necessary for bacterial translation process
Spectrum of activity
Good: MSSA, MRSA, streptococci (MDR S. pneumoniae), enterococci (VRE), Nocardia Moderate: some atypicals Poor: Gram negative bacilli, anaerobes
Place in therapy
Nosocomial pneumonia, skin and skin structure infections
Adverse effects
Bone marrow suppression > 2 weeks Peripheral neuropathy with prolonged therapy
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Linezolid: key points
Bacteriostatic against enterococci and staphylococci; Bacteriocidal against streptococci
IV to PO conversion = 1:1
$$
Linezolid for MRSA pneumonia ZEPHyR study
Wunderink RG, et al. Clin Infect Dis. 201;54:621-9.
Linezolid and serotonin syndrome
Linezolid = inhibits monoamine oxidase A
◦ Inhibits break down of serotonin in the brain
◦ Risk for serotonin syndrome when used in combination with serotonergic psychiatric medications
FDA Drug Safety Communication: October 20, 2011
◦ Not all serotonergic psychiatric drugs have equal capacity to cause serotonin syndrome
◦ Most reported cases occurred with SSRIs and SNRIs
◦ Unclear risk with alternative agents: TCAs, MAOIs, mirtazapine, trazodone, bupropion, buspirone
http://www.fda.gov/Drugs/DrugSafety/ucm276251.htm
Linezolid and serotonin syndrome
Discontinuation of anti-depressant not always practical
Consider therapeutic alternatives If linezolid must be continued in combination with
serotonergic psychiatric medication monitor for serotonin syndrome ◦ Confusion, hyperactivity, memory problems ◦ Muscle twitching ◦ Excessive sweating ◦ Shivering or shaking ◦ Diarrhea ◦ Fever
http://www.fda.gov/Drugs/DrugSafety/ucm265305.htm Boyer EW and Shannon S. N Engl J Med. 2005;352:1112-20.
Nitroimidazoles Example Metronidazole, tinidazole
Mechanism of action
Inhibit protein synthesis leading to cell death of susceptible organisms
Spectrum of activity
Good: Gram negative and Gram positive anaerobes (ie: Bacteroides spp, Fusobacterium, and Clostridium spp); protozoa (ie: Trichomoniasis, Entamoeba, and Giardia) Moderate: H. pylori Poor: aerobic Gram negative and positive organisms; oral anaerobes (ie: Peptostreptococcus, Actinomyces, Propionibacterium)
Place in therapy
Intra-abdominal infections, mild-moderate C. difficile infection, vaginal trichomoniasis
Adverse effects
Peripheral neuropathy (dose related, prolonged exposure) GI upset Metallic taste Hepatitis and pancreatitis (rare) Confusion and seizures (rare)
Key points Metronidazole and disulfiram reaction (inhibits aldehyde dehydrogenase) Metronidazole and warfarin increase INR IV to PO conversion = 1: 1
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Nitrofurans Example Nitrofurantoin
Mechanism of action
Inhibits several bacterial enzyme systems including acetyl coenzyme A interfering with metabolism and possibly cell wall synthesis
Spectrum of activity
Good: E. coli; Staphylococcus saprophyticus Moderate: Citrobacter spp, Klebsiella spp, enterococci Poor: Pseudomonas spp, Proteus spp, Acinetobacter spp, Serratia
Place in therapy
Uncomplicated cystitis
Adverse effects
Nausea and vomiting (take with food) Pulmonary toxicity (rare, acute pneumonitis or chronic pulmonary fibrosis) Peripheral neuropathy
Key points
Only used for lower urinary tract infections Caution in patients with CrCl < 60 ml/min decrease efficacy/insufficient accumulation in bladder; increase toxicity/possible accumulation Macrodantin® vs Macrobid® 2 different dosing schedules VRE UTI- in vitro data
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012. Heintz BH, et al. Pharmacotherapy. 2010;30:1136-49.
Cyclic lipopeptide Example Daptomycin
Mechanism of action
Binds to cell membrane and causes rapid depolarization, inhibiting synthesis of intracellular synthesis of DNA, RNA and protein.
Spectrum of activity
Good: MSSA, MRSA, streptococci Moderate to good: enterococci including VRE Poor: Gram negative bacilli, anaerobes
Place in therapy
Skin and skin structure infections, S. aureus bacteremia including right sided endocarditis
Adverse effects
Rhabdomyolysis Eosinophilic pneumonia
Key points
• Bactericidal • Concentration dependent • Inactivated by pulmonary surfactant do NOT use for pneumonia • Higher doses have been considered for high grade S. aureus bacteremia
and enterococcal bacteremia • CK monitoring should be considered in patients receiving high doses,
concurrent statin therapy, or with renal impairment (ie: HD) • Not part of standard panel at CCHS, may request sensitivities from the
microbiology lab
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Folate antagonists Example
Trimethoprim/sulfamethoxazole, dapsone, pyrimethamine, sulfadiazine
Mechanism of action
Inhibit folate synthesis pathway inhibit DNA synthesis
Spectrum of activity
Good: S. aureus, H. influenzae, Stenotrophomonas maltophilia, Listeria, Pneumocystis jiroveci, Toxoplasma gondii Moderate: Gram negative bacilli, S. pneumoniae, Salmonella, Shigella, Nocardia Poor: P. aeruginosa, enterococci, S. pyogenes, anaerobes
Place in therapy
Urinary tract infections, listerial meningitis (PCN allergic), PJP treatment and prophylaxis, treatment of Toxoplasma gondii encephalitis, prostatitis, MRSA skin and skin structure infections
Adverse effects
Rash common, can be severe (ie: SJS, TEN) Bone marrow suppression Renal failure Hyperkalemia
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Folate antagonists : key points
Excellent bioavailability utilize oral in setting of shortage, salvage therapy for S. aureus bacteremia
Drug interaction with warfarin increase INR
IV compounded in large volumes as fairly insoluble
Renal failure with TMP/SMX
◦ Blockade of creatinine secretion by TMP Scr without in GFR
◦ Crystalluria and AIN
Cross reactivity to other sulfonamide containing drugs?
◦ Furosemide, celecoxib, glipizide
2011 CCHS antibiogram
Cefazolin Ceftriaxone TMP/SMX Levofloxacin
E. coli 88% 95% 74% 78%
Lincosamides Example Clindamycin
Mechanism of action
Inhibits protein synthesis by reversibly binding to the 50s ribosomal subunit
Spectrum of activity
Good: Gram positive anaerobes, Plasmodium spp (malaria) Moderate: S. aureus (including MRSA), S. pyogenes, Gram negative anaerobes, Chlamydia trachomatis, Pneumocystic jiroveci, Actinomyces, Toxoplasma Poor: enterococci, C. difficile, Gram negative bacilli
Place in therapy
Skin and skin structure infections, oral cavity infections, anaerobic intra-abdominal infections, PJP in sulfa allergic, Toxoplasmosis in sulfa allergic, malaria in combination with other drugs, bacterial vaginosis
Adverse effects
GI upset Diarrhea, C. difficile superinfection Rash
Key points • D-test
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
Clindamycin: key point
Streptococcal Toxic Shock Syndrome
◦ Eagle effect:
Penicillin failure when used alone, most effective against rapidly growing bacteria
beta-lactam + clindamycin for suppression of toxin inhibition of protein synthesis and activity against organisms in the stationary growth phase
Fosfomycin Example Fosfomycin
Mechanism of action
Inhibits bacterial cell wall synthesis
Spectrum of activity
Gram negative bacilli: E. coli, K. pneumoniae, Enterobacter* Enterococcus faecalis*
Place in therapy
Cystitis, prostatitis Do not use for: pyelonephritis, bacteremia
Adverse effects
GI upset Diarrhea
Key points
• Oral sachet reconstitute with 90-120 mL of cool water • Normal dose: 3g PO x 1 • Complicated UTI: 3g PO q 48 hours x 3 doses • May consider for ESBL or CRE cystitis • Must request additional testing (KB), established breakpoints
only for E. coli and E. faecalis
Polymixin Example Colistin, polymixin B
Mechanism of action
Colistimethate (prodrug) colistin which acts as cationic detergent that damages the bacterial cytoplasmic membrane causing leaking of intracellular substances and cell death
Spectrum of activity
Good: many Gram negative bacilli including MDR Acinetobacter, Pseudomonas, K. pneumoniae Moderate: Stenotrophomonas maltophilia Poor: all Gram positive organisms, Burkholderia, Serratia
Place in therapy
MDR GN infections often in combination with other agents
Adverse effects
Nephrotoxicity – acute tubular necrosis Neurotoxicity – weakness, dizziness, paresthesias, mental status changes
Key points
• Dose based on IBW • Inhaled: administer dose promptly following preparation to decrease
possibility of high concentrations of colistin from forming which may lead to potentially life-threatening pulmonary toxicity
• Optimal dosing? • Europe= international units, US = milligrams
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.
VRE UTI
Heintz B, et al. Pharmacotherapy. 2010;30(11):1136-49.
VRE UTI
Heintz B, et al. Pharmacotherapy. 2010;30(11):1136-49.
MDR Gram negative: ESBL and CRE
Kanj SS and Kanafani ZA. Mayo Clin Proc. 2011;86(3):250-9.
Question
Which of the following cover MRSA?
A. Tigecycline
B. Linezolid
C. Ceftaroline
D. Daptomycin
E. All of the above
Question
Which of the following could be considered for an ESBL cystitis?
A. Imipenem
B. Fosfomycin
C. Cefepime
D. Ceftriaxone
E. A and B
Question
Which of the following covers VRE?
A. Daptomycin
B. Linezolid
C. Tigecycline
D. Vancomycin
E. A, B and C
Summary
Understanding the general principles of antimicrobials allows for more appropriate prescribing
Understanding the pharmacology of antimicrobials allows for more appropriate prescribing
Recommended references
www.idsociety.org
Johns Hopkins ABX guide
EMRA antibiotic guide
Sanford antibiotic guide
Gallagher JC and MacDougall C. Antibiotics Simplified, 2nd edition. Jones and Bartlett Learning. 2012.