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
< 1 month: S. agalactiae, E. coli, L. monocytogenes, Klebsiella
Meningitis
(dependent on age)
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
CAP: S. pneumoniae, H. influenzae, M. pneumoniae, C. pneumoniae, Legionella
+/- S. aureus and aerobic GNB
Pneumonia
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, coagneg 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

Bacteriostatic

β-lactams
Glycopeptides
Fluoroquinolones
Aminoglycosides
Metronidazole
Daptomycin
Sulfamethoxazole/
trimethoprim

Macrolides
Clindamycin
Tetracyclines
Linezolid









Bactericidal preferred for endocarditis, neutropenic
fever and meningitis +/- osteomyelitis
Bergman SJ, et al. Infect Dis Clin N Am. 2007;21:821-46. Finberg FW, et al. Clin Infect Dis. 2004;39:1314-20.
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
Monobactamsaztreonam
Penicillins
Natural
penicillins
Antistaphylococcal
penicillins
Penicillin G
Penicillin V
Nafcillin
Oxacillin
Dicloxacillin
Aminopenicillins
Amoxicillin
Ampicillin
Antipseudomonal
penicillins
β-lactam/β-lactamase inhibitor
combinations
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, postneurosurgical 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 antistaphylococcal killing when
compared to glycopeptides
for MSSA
•Superior antistaphylococcal 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
EOT: end of therapy, EOS: end of study
Wunderink RG, et al. Clin Infect Dis. 201;54:621-9.
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
Ryback M. Am J Health-Syst Pharm. 2009; 66:82-98.
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
Vancomycin
resistant S. aureus
Boucher HW, et al. CID. 2007;45:601-8.
Vancomycin
Daptomycin
2005
Methicillin
2002
1961
1945
Penicillin
Daptomycin
resistant S. aureus
1985
Methicillin
resistant S. aureus
S. aureus and vancomycin MIC creep
0
1
2
4
8
≥16
MIC
VSSA
hVISA
VISA
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.
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
Levofloxacin
Ciprofloxacin
% susceptible
% susceptible
E. coli
K. oxytoca
78
95
78
95
K. pneumoniae
P. aeruginosa
S. pneumoniae
(non-sterile)
92
78
92
78
100
--
Organisms
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

PEAK
PEAK
TROUGH
Gentamicin
Tobramycin
Pk
Pk
Tr
Tr
Amikacin
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 noncure 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
Mechanis
m of
Inhibits protein synthesis by binding to 50s ribosomal subunit
action
Good: atypicals, H. influenzae, M. catarrhalis, H. pylori,
Spectrum
Mycobacterium avium
of
Moderate: S. pneumoniae, S. pyogenes
activity
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
S. pneumoniae
(non-sterile)
Ceftriaxone
Azithromycin
Levofloxacin
30/34
88%
45/74
(61%)
73/73
(100%)
Azithromycin and risk of CV death
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?
Ray WA, et al. N Engl J Med. 2012; 366:1881-90.
Oxazolidinones
Example
Linezolid
Mechanis Inhibits protein synthesis by binding to 23s ribosomal RNA of the
m of
50Sribosomal subunit. Prevents the formation of functional 70s
action
initiation complex necessary for bacterial translation process
Good: MSSA, MRSA, streptococci (MDR S. pneumoniae), enterococci
Spectrum
(VRE), Nocardia
of
Moderate: some atypicals
activity
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 
GFR
Scr without in
◦ Crystalluria and AIN

Cross reactivity to other sulfonamide containing drugs?
◦ Furosemide, celecoxib, glipizide
2011 CCHS antibiogram
E. coli
Cefazolin
Ceftriaxone
TMP/SMX
Levofloxacin
88%
95%
74%
78%
Lincosamides
Example
Clindamycin
Mechanism Inhibits protein synthesis by reversibly binding to the 50s
of action
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.
B.
C.
D.
E.
Tigecycline
Linezolid
Ceftaroline
Daptomycin
All of the above
Question

Which of the following could be
considered for an ESBL cystitis?
A.
B.
C.
D.
E.
Imipenem
Fosfomycin
Cefepime
Ceftriaxone
A and B
Question

Which of the following covers VRE?
A.
B.
C.
D.
E.
Daptomycin
Linezolid
Tigecycline
Vancomycin
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.
