Antimicrobial therapy

L. Rókusz MD, Ph.D.

MD State Health Centre

Department of Medicine
05.11. 2010.
 Objectives

• Introduction to basic antimicrobial principals

– Pharmacokinetics (PK)
– Pharmacodynamics (PD)
• Provide an overview of some the most common antimicrobial drug
classes
– ß-lactam AB
– AG
– FQ
– A few others
 Background

• Basic mechanism of action

– Time-dependent killing
– Concentration-dependent killing
• PK
– Peak & Through serum concentrations
– Half-life (T1/2)
– Source of metabolism
– Source of excretion (kidney, GI, etc)
• PD – relationship between PK & minimum inhibitory concentration
(MIC)
 PD principals

1. Area under the curve (AUC/MIC)

2. Time above MIC
3. Peak MIC
 PD goals

Parameter Goal AB Drug Classes

Time above MIC > 50-60% of the dosing • All ß-lactams

interval • Macrolides
• Linezolid
Peak conc. : MIC ratio ≥ 10:1 • AGs vs G- organisms
Area under the Curve • ≥ 30-50:1 • FQ vs G+ orgs
(AUC) : MIC ratio • ≥ 125:1 • FQ vs G- orgs.
 FD

• Conc. dependent killing agents

– FQ, AG, ML, metro, dapto
– Eliminate bacteria when their conc.-s are well above the MIC of the
organisms

• Time dependent killing agents

– P, CS, aztreonam, vanco, carbapenems, ML, linezolid, tige, doxy,
clinda
– Kill G- bacteria only when the conc. at the site of the bacteria is higher
than the MIC of the organisms
 Mechanisms of action

Mechanism of action Antibacterial Family

Inhibition of cell wall synthesis -ß-lactams
-Vancomycin
Inhibition of protein synthesis -AG
-Linezolid
-Tetracyclin
Inhibition of DNA synthesis -FQ
Inhibition of folic acid synthesis -TMP/SMX
Inhibition of RNA synthesis -Rifampicin
Disruption of cell membrane integrity -Daptomycin
-Polymyxin B, E (Colistin)
Others -Metronidazole
-Nitrafurantoin
Mechanisms of action

Amikacin
Gentamicin
Tobramycin

Tigecyclin Daptomycin
 Antibiotic therapy

• Identify causative agent

• Evaluate drug sensitivity
• Target site of infection
• Drug safety/side effect profile
• Patients factor
• Cost
 Factors in Selecting
Initial Appropriate Therapy
• Patient features: Choose empirical therapy that is based on site
and severity of infection and clinician assessment of the likelihood
for deterioration and mortality.
• Local susceptibility and epidemiology: Choose empirical therapy to
cover the likely infecting pathogen based on local susceptibility
patterns while considering prior antibiotic therapy.
• Initial antibiotic therapy dosing and duration: Choose initial
empirical therapy that will deliver enough antibiotic to the site of
infection and
be well tolerated (consider AB penetration)
• Combination vs. monotherapy: Initial AB choose should give broad
enough coverage, avoid emergence of resistance, and have the
potential for synergy if necessary (TB, IE, Sepsis, Anthrax …)
 General principles when considering
How to de-escalalate

• Identify the organism and know its susceptibilities; recognize any

limitation in the available microbiology support system (eg, length
of time to receiving antibiogram)
• Assess and potentially modify initial selection of ABs based on
organism susceptibility report
• Make the decision in the context of patient progress on the initial
regimen
• Individualize the duration of therapy based on patient factors and
clinical response
 Guideline-Based De-escalation

• Before guideline: 50 patients, standard treatment

• After guideline: 52 patients, treatment guideline
• Culture
• Empirical therapy
– Vanco + IMP + CIP
– 90% coverage based on local resistance data
• Therapy reassessed after 24-48 hours
– De-escalation recommended and usually occurred
• 7-day duration recommended
– Unless signs and symptomps persist

Ibrahim EH et al. Crit. Care Med 2001,29:1109-1115

 Penicillins

• Bactericidal cell-wall synthesis inhibitors

• G+ activity maintened across spectrum
• G- activity dependent on ability to cross porin channels
• ß-lactamase inhibitor combinations:
– MSSA coverage
– Enhanced anaerobic activity
• Therapeutic concentration in most tissues
• Poor CSF penetration
• Renal excretion
 Activity of Penicillins against selected bacilli

Usual Minimal Inhibitory Concentration (ug/ml)

Organism Pen G Pen. V Amp, Amoxi Oxacillin PIP
S. pneumoniae 0,01 0,02 0,02 0,04 0,02
S. pyogenes 0,005 0,01 0,02 0,04 0,02
S. agalactiae 0,005 0,01 0,02 0,06 0,15
Viridians streptococci 0,01 0,01 0,05 0,1 0,12
MSSA 0,025 0,02 0,05 0,3 0,8
MRSA > 25 > 25 > 25 0,4 25
N. meningitidis 0,05 0,25 0,05 6,0 0,05
 Activity of Penicillins against selected bacilli
and anaerobic organisms

Mean Minimal Inhibitory Concentration (ug/ml)

Organism Pen G Amp, Amoxi Oxacillin Ticarcillin PIP
Cl. perfringens 0,5 0,05 > 0,5 0,5 0,05
Corynebact. diphteriae 0,1 0,02 > 0,1 0,1 1,0
L. monocytogenes 0,5 0,5 > 4,0 4 0,5
H. influenzae 0,8 0,5 > 25 0,5 0,1
Fusobacterium nucleatum 0,5 0,1 > 100 0,5 0,5
B. fragilis 32 32 > 500 64 32
 Pen; G-
Spectrum of activity
Amino Carboxy Ureido
Side chain Side chain Side chain

Penicillin Ampicillin Ticarcillin Piperacillin

N. meningitidis

E. coli

Proteus sp.

H. influenzae

Klebsiella sp.
Pseudomonas sp.
 Penicillins

• Major adverse Events

– Anaphylaxis
– Rash and/or urticaria
– Seizures
– Nephritis
– Platelet dysfunction
• Anti-Staphylococcus aureus Penicillins
– Resistant to ß-lactamase
– NO G- acitivity

– Nafcillin (4x2 g/d, IE= 6x2 g/d iv.) – (No renal adjustment)
– Oxacillin „ „
 Extended-spectrum Penicilins

• Piperacillin/Tazobactam
– Sodium content (1.85 mEq/g)
– Dosing
• Serious infections (Pneumonia): 4x4,5 g/d
• Other infections: 4x3,375 g/d

• Ticarcillin/Clavulanic acid
– Sodium content (5,2 mEq/g)
– 2nd line agent for S. maltophilia
 Cephalosporins

• Bactericidal cell-wall synthesis inhibitors

• DO NOT treat Enterococcus spp.
• G+ activity generally decreases with each generation
• G- activity increases with generation
• W eak anaerobic activity with 2 generation
 Cephalosporin
Spectrum of activity

G- coverage

G+ coverage

1st 2nd 3rd 4th

 Cephalosporins

• 1st generation (ex: cefazolin)

– Excellent MSSA activity
– Some G- activity – E. coli, Klebsiella
– Major role in surgical systemic prophylaxis

• 2 generation (ex: cefotetan, cefoxitin, cefuroxim)

– Good G-, moderate G+ and anaerobic coverage
– Primarily used for abdominal surgery prophylaxis
 Cephalosporins

• 3rd generation (ex: ceftriaxon, ceftazidim)

– 1st ß-lactams with Pseudomonas coverage (ceftazidim)
– Ceftazidim selects out MDR organisms (MDR organisms (MDR G-,
VRE, C. difficile, MRSA)
– Ceftriaxon
• Excellent CSF penetration
• Excellent S. pneumoniae activity
• 4th generation (ex: cefepime)
– Excellent MSSA and P. aeruginosa sp. coverage
 Cephalosporins

• Major Adverse Events

– Rash
– Anaphylaxia
– Seizures

• Cross-Sensitivity with Pen-s

– 1-10%
– Concern if patient has history of anaphylaxia
 Carbapenems

• Bactericidal cell-wall synthesis inhibitors

• Broadest-spectrum antimicrobials available
• Stable against most ß-lactamases
• Some intrinsic Resistance
– Enterococcus faecium
– MRSA
– S. maltophilia
– Burkholderia spp.
– Penicillinase-resistant S. pneumoniae
 Carbapenems

• 4 drugs
– Imipenem/Cilastatin
– Meropenem
– Ertapenem (NOT use for P. aerugonisa)
– Doripenem
• Incomplete class cross-resistance
– Ex: P. aerugonisa
 Classification of allergic reactions to ß-
lactam ABs based on time of onset

Reaction type Onset after Clinical reactions

drug adm.
Immediate (hr)
0-1 Anaphylaxis
Hypotension
Laryngeal edema
Wheezing
Accelerated 1-72 Urticaria, angioedema
Laryngeal edema
Wheezing
Late > 72 Morbilliform rash Stevens-Johnson sy
Interstitial nephritis Exfoliative dermatitis
Hemolytic anemia
Neutropenia
Thrombocytopenia
Serum sickness
Drug fever
ß-lactam allergy
 Monobactam

• Aztreonam
• Bactericidal cell-wall synthesis inhibitors
• Pure G- coverage
– Including Pseudomonas
• No cross-sensitivity with penicillins/CS
• Major AE
– Rush
– GI upset
– Injection-site thrombophlebitis
 Fluoroquinolones

• DNA synthesis inhibitors

– DNA-gyrase inhibitor in G- bacteria
– Topoisomerase IV inhibitor in G+ bacteria
• Concentration dependent killers
– G- AUC/MIC Goal ≥ 125:1
– G+ AU/MIC Goal ≥ 10:1
 Fluoroquinolones

Cipro 400 mg iv. – AUC~ 25

Pseudomonas MIC ≤ 0,25

Urine AUC/MIC = 100:1
Sputum AUC/MIC = 10:1
(only ~ 10% penetration)

Anti-Pseudomonal agents
* CIP
* Levofloxacin (<)
* trovafloxacin (!)
 Fluoroquinolones

• G+ coverage
– Class has POOR S. aureus drugs
– Select out MRSA
– Newer agents excellent S. pneumoniae coverage

• Major AE:
– QT prolongation
• Moxifloxacin >>> levofloxacin >>> ciprofloxacin
– C. difficile colitis

• Drug interaction
– phenytoin;
– warfarin
 Aminoglycosides

• Inhibit bacterial protein synthesis at 30S & 50S ribosomal subunits

• Concentration-dependent killers
– Goal Peak:MIC = 10:1
– PAE
 Aminoglycosides

• Place in Therapy:
– Treatment of G- infections
– Gentamicin for G+ synergy in combination with a ß-lactam or
vancomycin

• Major AE
– Nephrotoxicity (high through)
– Otoxicity (prolonged duration of therapy)

• Drug IA
– Neuromuscular blockers
 Aminoglycosides

• Gentamicin/Tobramycin
– G- non-Burn 7 mg/kg iv q24 h
– G- Burn: 2,5-3 mg/kg iv. 8-12 h
– Gentamicin G+ Synergy: 1 mg/kg iv. q8 h

• Amikacin
– G- non-Burn: 15-20 mg iv. q24
– G- Burn: 7.5 mg/kg iv. Q8

• Dose calculator: www.surgicalcriticalcriticalcare.net

 Aminoglycosides

• Colistin (Polymyxin E)
– Reserved for MDR G- organisms
– Nebulized: 150 mg inhaled q12 h
– Iv. (VERY nephrotoxic): 2-3x2,5 mg/kg/d

• Polymyxin B
– Also reserved for MDR G- organisms
– Iv: 2x15.000 – 25.000 U/kg/d

• No way to monitor levels for iv. polymyxins

 Aminoglycosides

• Polymyxin B & Colistin

– Major AE

• Nephrotoxicity
• Neurotoxicity

– Drug IA

• Neuromuscular blockers
 Vancomycin

• Inhibits bacterial cell wall synthesis

• Time-dependent killer (time above MIC)
– Some concentration-dependent characteristic
• P, CS, aztreonam, vanco, carbapenems, ML, linezolid, tige, doxy, clinda
• Kill G- bacteria only when the conc. at the site of the bacteria is higher than the MIC of
the organisms
– Uses
• Iv: treatment of G+ infections
• Per os: treatment of C. difficile colitis
 Vancomycin

• Dosing
– Iv: 20 mg/kg iv 1x, than 15 mg/kg, iv – q8-12 h
– Per os: 4x125-250 mg/die

• Major AEs
– Red Man syndrome – slow down infusion
– Not neprotoxic – but accumulates
 Vancomycin dosing

The Mayo Medical Center vancomycin dosing nomogram*

Creatinin clearence ** (ml/min) Dosing interval

> 80 Every 12 h
65-80 Every 12 to 18 h
50-64 Every 24 h
35-49 Every 24-36 h §
21-34 Every 48 h §

* Use of 15 mg/kg; The dosing interval is based on renal function

**The estimated renal function is near the border of two dosing intervals Cr Cl: (140 – age)
x lean body weight (x 0,85 for females) / se creatinin
§ Patient with serious infection, whom the initial dosing interval is >24 h should have
serum level monitoring

Mayo Clinic 1999

 Linezolid

• Oxazolidinone – inhibits bacterial protein synthesis

– Bacteriostatic: Enterococcus sp., Staphylococcus sp.
– Bactericidal: Streptococcus sp.

• Large volume of distribution

• Dosing: 2x600 mg Iv/Per os
 Linezolid

• Major AE
– Thrombocytopenia/pancytopenia
– Blurred vision
– Serotonin Syndrome

• Drug IA
– Selective Serotonin Reuptake Inhibitors (SSRIs)
 Quinupristin/Dalfopristin (Synercid®)

• Inhibits bacterial protein synthesis

• Major organisms:
– VRE
– MSSA & MRSA
– S. pyogenes
• Dose
– 7,5 mg/kg iv q8-12 h (no renal adjustment)
• Major AE
– Hyperbilirubinaemia
– Infusion site reaction
– Infusion-related arthralgias/myalgias
• Drug IA
– No significant
 Daptomycin

• Cell membrane disruption leading to inhibition of DNA/RNA/protein

synthesis - Lipopeptide
• Spectrum of activity
– MRSA
– VRE
• Indications
– Bacteremia
– Endocarditis
– Skin/Soft tissue infection
• Does NOT treat pneumonia!
 Daptomycin

• Dose
– 4-6 mg/kg iv q24 h
– Adjust for renal dysfunction
• Major AE
– Anemia
– Constipation/Nausea/Vomiting
– Elevation of CPK, myalgia
– Injection-site reaction
 Sulfamethoxazole/Trimethoprim

• Interferes with bacterial folic acid synthesis (Bactrim®)

• Drug of choice
– S. maltophilia
– PCP
• Alternative: for MRSA
 Sulfamethoxazole/Trimethoprim

• Dosing
– Based on TMP component
– UTI: 800/160 (DS) 2x1 tbl.
– Severe infections
• MRSA/PCP/S. maltophilia
– 5 mg TMP/kg iv/po q6-8 h
– Adjust for renal dysfunction

• Major AE
– Stevens-Johnson sy.
– Rash
– Hyponatremia
– Hyperkalemia
– GI upset (large PO dose)
 Tetracycline

• Inhibit bacterial protein synthesis

• Bacteriostatic
• Spectrum of activity
– G+ including MRSA
– G- (including Borrelia sp.)
– Atypicals (Mycoplasma, Chlamydia, Rickettsia)
– Alternative for H. pylori
 Tetracycline

• 3 agents
– Tetracycline 250-500 mg po q6 h
– Doxycycline 100 mg po/IV q12 h
– Minocycline

• Major AE
– Photosensitivity
– Teeth/enemal discoloration in children (< 12 y)
– Hepatotoxycity
 Tigecycline

• Glycylcycline – structurally similar to tetracyclines

• Protein synthesis inhibitor
• Bacteriostatic
• Spectrum of activity
– G+, including MRSA, VRE
– G-, including MDR A. baumannii, E. coli, Klebsiella
– Anaerobes
• Does not cover
– Pseudomonas sp.
– Proteus sp.
 Tigecycline

• Indications
– Complicated skin and soft tissue infections
– Complicated intraabdominal infections
– CAP (FDA in march 2009 approved)

• Dose
– 100 mg iv x1, than 50 mg q12 h

• Major AE
– N/V
– Abdominal pain
– Super infections (P. aeruginosa, Proteus)
 Macrolides

• Inhibit RNA-dependant protein synthesis

• Spectrum of activity
– G+; including MSSA
– G- (H. influenzae)
– Atypicals (Legionella, Mycoplasma, Chlamydia sp.)

• Several Agents
– Erythromycin
– Clarithromycin
– Azithromycin
 Macrolides

• Erythromycin
– Used for Adverse Drug Event – GI motility
– Used for surgical prophylaxis with neomycin (in Hungary – not)
• Azithromycin
– CAP
– Bronchitis, sinusitis
• Clarithromycin
– CAP
– Bronchitis, sinusitis
– H. pylori eradication
• Major AE
– Abdominal pain/cramping (E >> C >> A)
– N/V/Diarrhea
– Headache
 Clindamycin

• Inhibits bacterial protein synthesis

• Spectrum of activity
– G+; MSSA, Sterptococcus sp., some MRSA
– Anaerobes
• Excellent alternative for Penicillin allergic patients
• Major AE
– Diarrhea (C. diff.)
 Metronidazole

• Interacts with DNA causing strand breakage and ultimately inhibits

protein synthesis
• Spectrum of activity
– C. difficile diarrhea
• Major AE
– N/V
– Diarrhea
• Dosing
– C. difficile: 500 mg po q6 h
 Antimicrobal Resistance

• Unsuppressed production of ß-lactamase

– AMP-c
– ESBL
• Alteration in bacterial cell membrane
– Vancomycin-resistant Enterococcus
• Pseudomonas sp.
– AG-altering enzymes
– Efflux-pump – pump out drug
– Alter porin channel – drug can’t get it
 Antibiotic prophylaxis

• Post-op wound infection is the second most common nosocomial

infection
• Cost of this complication >
• Prolongs hospital LOS by ~ 15 days
• Cover bacterial flora involved in the surgical field
• Administer within 1 hours before
• Maintain therapeutic blood level during lengthy procedures
• Continue prophylaxis for the 24 hour period surrounding surgery
 Take Home Points 1.

• Penicillins – R increase G- and maintain G+

• Addition of ßL inhibitor = anaerobic coverage
• CSs – avoid 3rd generation overuse
• Carbapenems – reserve for last resort (NB: sepsis: often empiric
therapy)
• Vancomycin – aim high trough conc.
• PD-based drug dosing
 Take Home Points 2.

 Antibiotic resistance often leads to worse patient outcomes

 Based on well-described epidemiology, control measures include:

: Hand hygiene

: Isolation precautions

: Prudent antimicrobial use

: Prevention of device-related (eg. vascular, catheter)

infections

: Environmental clearing