prescribing antibiotics in the clinical setting

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

http://www.idosciety.org/

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

http://www.idosciety.org/

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


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


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)


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


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


Cephalosporins: 2nd generation Examples Cefoxitin, cefuroxime, cefotetan, cefaclor


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


Cephalosporins: 3rd generation Examples Ceftriaxone, cefotaxime, ceftazidime, cefdinir, cefpodoxime, cefixime


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


Cephalosporins: 4th generation

Examples Cefepime


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


Cephalosporins: 5th generation Examples Ceftaroline


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


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!


Monobactams: aztreonam


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


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


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


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


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


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


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


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


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


Tetracyclines Example Doxycycline, minocycline, tetracycline

Mechanism of action



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



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)


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


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



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


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®


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


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


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.

http://www.fda.gov/Drugs/DrugSafety/ucm265305.htm

Nitroimidazoles Example Metronidazole, tinidazole

Mechanism of action

Inhibit protein synthesis leading to cell death of susceptible organisms


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


Nitrofurans Example Nitrofurantoin

Mechanism of action

Inhibits several bacterial enzyme systems including acetyl coenzyme A interfering with metabolism and possibly cell wall synthesis


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.


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


Folate antagonists Example

Trimethoprim/sulfamethoxazole, dapsone, pyrimethamine, sulfadiazine

Mechanism of action

Inhibit folate synthesis pathway inhibit DNA synthesis


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


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


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


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


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


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

http://www.google.com/url?sa=i&rct=j&q=monurol&source=images&cd=&cad=rja&docid=M-956z9H3NyonM&tbnid=iowz9HOKjpdFZM:&ved=0CAUQjRw&url=https%3A%2F%2Fhealthy.kaiserpermanente.org%2Fhealth%2Fcare%2F!ut%2Fp%2Fc4%2FHYvRCsIwDEW_qGRMQdmb3zBE68sIaayBJinVCf79VrlP99xz4QF7DL-S8SNuWOAOUTkJiXEQe3rT_zKltubARj8qXncB4da_xQkLQ2QL67sDSRDH0zAOx95qw6wI0TwQ0othZluuM1TV80GXywbgmz-L%2F&ei=YNkvUZGaDe-w0AHb04DACA&bvm=bv.43148975,d.dmQ&psig=AFQjCNGFPWXikF-7tp6Op-003y8gegIj1A&ust=1362176734921729

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


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


http://www.google.com/url?sa=i&rct=j&q=colistimethate&source=images&cd=&cad=rja&docid=Ctn7zHk_FWecTM&tbnid=Ao3DY7qKEWhrDM:&ved=0CAUQjRw&url=http%3A%2F%2Fwww.dailymedplus.com%2Fmonograph%2Fview%2Fsetid%2Fab241809-0d2f-44ba-829c-26be67ee623f&ei=K-EvUfygFIi50AHCsYGgAg&bvm=bv.43148975,d.dmQ&psig=AFQjCNHmwxUV-4GUb6x70KzTaNaH8Rl-eQ&ust=1362178729578739

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


http://www.idsociety.org/

prescribing antibiotics in the clinical setting

Documents