Antibiotic Strategy in Nosocomial Pneumonia
Gamal Rabie Agmy, MD,FCCP Professor of Chest Diseases, Assiut university
ERS National Delegate of Egypt
ANTIMICROBIAL DRUGS
MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
Mechanism of action include: Inhibition of cell wall
synthesis
Inhibition of protein synthesis
Inhibition of nucleic acid synthesis
Inhibition of metabolic pathways
Interference with cell membrane integrity
MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS Inhibition of Cell wall synthesis
Bacteria cell wall unique in construction
Contains peptidoglycan
Antimicrobials that interfere with the synthesis of cell wall do not interfere with eukaryotic cell
Due to the lack of cell wall in
animal cells and differences in cell wall in plant cells
These drugs have very high therapeutic index
Low toxicity with high effectiveness
Antimicrobials of this class include
β lactam drugs
Vancomycin
Bacitracin
Inhibition of protein synthesis Structure of prokaryotic ribosome acts as target for
many antimicrobials of this class
Differences in prokaryotic and eukaryotic ribosomes responsible for selective toxicity
Drugs of this class include
Aminoglycosides
Tetracyclins
Macrolids
Chloramphenicol
MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
Inhibition of nucleic acid synthesis These include
Fluoroquinolones
Rifamycins
MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS Inhibition of metabolic
pathways Relatively few
Most useful are folate inhibitors Mode of actions to
inhibit the production of folic acid
Antimicrobials in this class include Sulfonamides
Trimethoprim
MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS Interference with cell
membrane integrity Few damage cell
membrane
Polymixn B most common
Common ingredient in first-aid skin ointments
Binds membrane of Gram - cells
Alters permeability
Leads to leakage of cell and cell death
Also bind eukaryotic cells
but to lesser extent
Limits use to topical application
EFFECTS OF
COMBINATIONS OF DRUGS
Sometimes the chemotherapeutic effects of two drugs given simultaneously is greater than the effect of either given alone.
This is called synergism. For example, penicillin and streptomycin in the treatment of bacterial endocarditis. Damage to bacterial cell walls by penicillin makes it easier for streptomycin to enter.
EFFECTS OF
COMBINATIONS OF DRUGS
Other combinations of drugs can be antagonistic.
For example, the simultaneous use of penicillin and tetracycline is often less effective than when wither drugs is used alone. By stopping the growth of the bacteria, the bacteriostatic drug tetracycline interferes with the action of penicillin, which requires bacterial growth.
EFFECTS OF
COMBINATIONS OF DRUGS
Combinations of antimicrobial drugs should be used only for:
1. To prevent or minimize the emergence of resistant strains.
2. To take advantage of the synergistic effect.
3. To lessen the toxicity of individual drugs.
Pharmacology
Pharmacokinetics
Pharmacodynamics
Pharmacokinetics
• Time course of drug absorption,
distribution, metabolism, excretion
How the drug
comes and goes.
“LADME” is key
Pharmacokinetic Processes
Liberation
Absorption
Distribution
Metabolism
Excretion
Pharmacodynamics
• The biochemical and physiologic
mechanisms of drug action
What the drug
does when it gets there.
Concepts
Pharmacokinetics
– describe how drugs behave in the human host
Pharmacodynamics
– the relationship between drug concentration
and antimicrobial effect. “Time course of
antimicrobial activity”
Minimum Inhibitory Concentration (MIC) – The lowest concentration of an antibiotic that inhibits
bacterial growth after 16-20 hrs incubation.
Minimum Bacteriocidal Concentrations. – The lowest concentration of an antibiotic required to
kill 99.9% bacterial growth after 16-20 hrs exposure.
C-p – Peak antibiotic concentration
Area under the curve (AUC) – Amount of antibiotic delivered over a specific time.
Concepts
Antimicrobial-micro-organism
interaction
Antibiotic must reach the binding site of
the microbe to interfere with the life cycle.
Antibiotic must occupy “sufficient” number
of active sites.
Antibiotic must reside on the active site for
“sufficient” time. Antibiotics are not contact
poisons.
Static versus Cidal
Control
Cidal
Static CFU
Time
Questions
Can this antibiotic inhibit/kill these bacteria?
Can this antibiotic reach the site of bacterial replication?
What concentration of this antibiotic is needed to
inhibit/kill bacteria?
Will the antibiotic kill better or faster if we increase its
concentration?
Do we need to keep the antibiotic concentration always
high throughout the day?
Can this antibiotic inhibit/kill these bacteria?
In vitro susceptibility testing
Mixing bacteria with antibiotic at different
concentrations and observing for bacterial
growth.
32 ug/ml 16 ug/ml 8 ug/ml 4 ug/ml 2 ug/ml 1 ug/ml
Sub-culture to agar medium MIC = 8 ug/ml
MBC = 16 ug/ml
Minimal Inhibitory Concentration (MIC)
vs.
Minimal Bactericidal Concentration (MBC)
REVIEW
What concentration of this antibiotic is
needed to inhibit/kill bacteria?
In vitro offers some help
– Concentrations have to be above the MIC.
How much above the MIC?
How long above the MIC?
Time
Conc MIC
Patterns of Microbial Killing
Concentration dependent
– Higher concentration greater killing Aminoglycosides, Flouroquinolones, Ketolides, metronidazole, Ampho B.
Time-dependent killing
– Minimal concentration-dependent killing (4x MIC)
– More exposure more killing Beta lactams, glycopeptides, clindamycin, macrolides, tetracyclines, bactrim
Persistent Effects
Persistent suppression of bacterial growth following antimicrobial exposure.
– Moderate to prolonged against all GM positives (In vitro)
– Moderate to prolonged against GM negatives for protein and nucleic acid synthesis inhibitors.
– Minimal or non against GM negatives for beta lactams (except carabapenems against P. aeruginosa)
Post-antibiotic sub-MIC effect.
– Prolonged drug level at sub-MIC augment the
post-antibiotic effect.
Post-antibiotic leukocyte killing enhancement.
– Augmentation of intracellular killing by
leukocytes.
– The longest PAE with antibiotics exhibiting this
characteristic.
Persistent Effects
Patterns of Antimicrobial Activity
Concentration dependent with moderate to
prolonged persistent effects
– Goal of dosing
Maximize concentrations
– PK parameter determining efficacy
Peak level and AUC
– Examples
Aminoglycosides, Flouroquinolones, Ketolides,
metronidazole, Ampho B.
Time-dependent killing and minimal to
moderate persistent effects
– Goal of dosing
Maximize duration of exposure
– PK parameter determining efficacy
Time above the MIC
– Examples
Beta lactam, macrolides, clindamycin, flucytosine,
linezolid.
Patterns of Antimicrobial Activity
Patterns of Antimicrobial Activity
Time-dependent killing and prolonged
persistent effects
– Goal of dosing
Optimize amount of drug
– PK parameter determining efficacy
AUC
– Examples
Azithromycin, vancomycin, tetracyclines,
fluconazole.
PK/PD patterns
Concentra
tion
MIC
Time
AUC AUC
C-p C-p
Antibacterial spectrum— R ange of activ ity
of an antim icrobia l against bacteria . A
broad-spectrum antibacteria l drug can
inhib it a w ide varie ty of gram -positive and
gram -negative bacteria , w hereas a
narrow -spectrum drug is active only
against a lim ited varie ty of bacteria .
B acteriostatic activity— -The level o f
antim icro-b ia l activ ity that inh ib its the
grow th of an organism . This is determ ined
in v itro by testing a s tandard ized
concentration of organism s against a
series of antim icrobia l d ilu tions. The
low est concentration that inh ib its the
grow th of the organism is referred to as
the m inim um inh ib itory concentration
(M IC).
B actericidal activity— The level o f
antim icrobia l activ ity that k ills the test
organism . This is determ ined in v itro by
exposing a s tandard ized concentration of
organism s to a series of antim icrobia l
d ilu tions. The low est concentration that
k ills 99.9% of the population is referred to
as the m inim um bactericidal
concentration (M BC ).
Antib io tic com binations— C om binations of
antib io tics that m ay be used (1) to broaden
the antibacteria l spectrum for em piric
therapy or the treatm ent of po lym icrobia l
in fections, (2) to prevent the em ergence of
res is tant organism s during therapy, and (3)
to achieve a synerg is tic k illing effect.
Antib io tic synerg ism— C om binations of
tw o antib io tics that have enhanced
bacteric ida l activ ity w hen tested together
com pared w ith the activ ity of each
antib iotic .
Antib io tic antagonism—C om bination of
antib io tics in w hich the activ ity of one
antib iotic in terferes W ith the activ ity of the
other (e.g., the sum of the activ ity is less
than the activ ity of the ind iv idual drugs).
B eta-lactam ase— An enzym e that
hydro lyzes the beta-lactam ring in the
beta-lactam c lass of antib io tics, thus
inactivating the antib io tic . The enzym es
specific for penic illins and cephalosporins
aret he penic illinases and
cephalosporinases, respective ly.
Resistance
Physiological Mechanisms
1. Lack of entry – tet, fosfomycin
2. Greater exit
efflux pumps
tet (R factors)
3. Enzymatic inactivation
bla (penase) – hydrolysis
CAT – chloramphenicol acetyl transferase
Aminogylcosides & transferases REVIEW
Resistance
Physiological Mechanisms
4. Altered target
RIF – altered RNA polymerase (mutants)
NAL – altered DNA gyrase
STR – altered ribosomal proteins
ERY – methylation of 23S rRNA
5. Synthesis of resistant pathway
TMPr plasmid has gene for DHF reductase; insensitive to TMP
(cont’d)
REVIEW
Resistance to β-Lactams – Gram pos.
Mechanism of Action CELL WALL SYNTHESIS INHIBITORS
(cont’d)
REVIEW
Resistance to β-Lactams – Gram neg.
Mechanism of Action CELL WALL SYNTHESIS INHIBITORS
(cont’d)
REVIEW
The Ideal Drug* 1. Selective toxicity: against target pathogen but
not against host
LD50 (high) vs. MIC and/or MBC (low)
2. Bactericidal vs. bacteriostatic
3. Favorable pharmacokinetics: reach target site
in body with effective concentration
4. Spectrum of activity: broad vs. narrow
5. Lack of “side effects”
Therapeutic index: effective to toxic dose ratio
6. Little resistance development
39
Pneumonias – Classification
• Community Acquired CAP
• Health Care Associated HCAP
• Hospital Acquired HAP
• ICU Acquired ICUAP
• Ventilator Acquired VAP
Nosocomial Pneumonias
*HAP: diagnosis made > 48h after admission
*VAP: diagnosis made 48-72h after endotracheal
intubation
*HCAP: diagnosis made < 48h after admission
with any of the following risk factors:
(1) hospitalized in an acute care hospital for >
48h within 90d of the diagnosis;
(2) resided in a nursing home or long-term care
facility;
(3) received recent IV antibiotic therapy,
chemotherapy, or wound care within the 30d
preceding the current diagnosis; and
(4) attended a hospital or hemodialysis clinic
Definitions of NP
The American Thoracic Society suggests that the
diagnosis should be considered in any patient with new or
progressive radiological infiltrates and clinical features to
suggest infection:
•Fever (core temperature >38°C),
• Leukocytosis (>10000mm-3) or leukopenia (<4000mm-3),
•Purulent tracheal secretions,
•Increased oxygen requirements, reflecting new or
worsening hypoxaemia.
Diagnosis
Sensitivity
Specificity
Clinical estimate 50% 58%
CPIS score > 6* 60% 59%
BAL Gram stain 85% 74%
Telescoping catheter 60% 90%
CPIS + BAL Gram stain
85% 49%
CPIS + telescoping catheter
78% 36%
*Hypotension.
*Sepsis syndrome.
*End organ dysfunction.
*Rapid progression of infiltrates.
*Intubation
Severe HAP
Gram-negative bacilli, particularly enterobacteria, are
present in the oropharyngeal flora of patients with chronic
underlying illnesses, such as COPD, heart failure,
neoplasms, AIDS and chronic renal failure.
Infection by P. aeruginosa and other more resistant
Gram-negative bacilli such as Acinetobacter baumannii and ESBL-producing enterobacteria should
be considered in patients discharged from ICUs,
submitted to wide-spectrum antibiotic treatment and in
those with severe underlying disease or prolonged
hospitalisation in areas with a high prevalence of these
microorganisms.
Risk Factors
An increased risk for Legionella spp. should be
considered in immunosuppressed patients (previous
treatment with high-dose steroids or chemotherapy.
Gingivitis or periodontal disease, depressed
consciousness, swallowing disorders and orotracheal
manipulation are usually recorded when anaerobes are
the causative agents of the pneumonia
Coma, head injury, diabetes, renal failure or recent
influenza infection are at risk from infection by S. aureus.
Risk Factors
HAP due to fungi such as Aspergillusmay develop in
organ transplant, neutropenic or immunosuppressed
patients, especially those treated with corticoids.
Risk Factors
Risk for ventilator-associated pneumonia
due to multidrug-resistant pathogens
Hospitalisation Especially if intubated and in the ICU for ≥5 days (late-onset
infection) Prior antibiotic therapy
Particularly in the prior 2 weeks Recent hospitalisation in the preceding 90 days Other HCAP risk factors
From a nursing home Haemodialysis
Home-infusion therapy Poor functional status
Risk factors for specific pathogens Pseudomonas aeruginosa
Prolonged ICU stay Corticosteroids
Structural lung disease Methicillin-resistant Staphylococcus aureus
Coma Head trauma
Diabetes Renal failure
Prolonged ICU stay Recent antibiotic therapy
The optimal empiric monotherapy for nosocomial
pneumonia consists of ceftriaxone, ertapenem,
levofloxacin, or moxifloxacin. Monotherapy may be
acceptable in patients with early onset hospital-
acquired pneumonia.
Avoid monotherapy with ciprofloxacin,
ceftazidime, or imipenem, as they are likely to
induce resistance potential.
Empiric monotherapy versus
combination therapy
Late-onset hospital-acquired pneumonia,
ventilator-associated pneumonia, and health
care–associated pneumonia require
combination therapy using an antipseudomonal
cephalosporin, beta lactam, or carbapenem
plus an antipseudomonal fluoroquinolone or
aminoglycoside plus an agent such as linezolid
or vancomycin to cover MRSA
Empiric monotherapy versus
combination therapy
Optimal combination regimens for proven P aeruginosa nosocomial pneumonia include (1)
piperacillin/tazobactam plus amikacin or (2) meropenem
plus levofloxacin, aztreonam, or amikacin.[12]
Avoid using ciprofloxacin, ceftazidime, gentamicin, or
imipenem in combination regimens, as combination
therapy does not eliminate the resistance potential of
these antibiotics.
Empiric monotherapy versus
combination therapy
When selecting an aminoglycoside for a combination
therapy regimen, amikacin once daily is preferred to
gentamicin or tobramycin to avoid resistance problems.
When selecting a quinolone in a combination therapy
regimen, use levofloxacin, which has very good anti– P aeruginosa activity (equal or better than ciprofloxacin at
a dose of 750 mg).
Empiric monotherapy versus
combination therapy
Hospital-Acquired, Health Care-Associated, and Ventilator-
Associated Pneumonia Organism-Specific Therapy
Pseudomonas aeruginosa
*Piperacillin-tazobactam 4.5 g IV q6h plus amikacin 20 mg/kg/day
IV plus levofloxacin 750 mg IV q24h or
*Cefepime 2 g IV q8h plus amikacin 20 mg/kg/day IV plus levofloxacin
750 mg IV q24h or
*Imipenem 1 g q6-8h plus amikacin 20 mg/kg/day IV plus levofloxacin 750
mg IV q24h or
*Meropenem 2 g IV q8h plus amikacin 20 mg/kg/day IV plus levofloxacin
750 mg IV q24h or
*Aztreonam 2 g IV q8h plus amikacin 20 mg/kg/day IV plus levofloxacin
750 mg IV q24h
Duration of therapy: 10-14d
Hospital-Acquired, Health Care-Associated, and Ventilator-
Associated Pneumonia Organism-Specific Therapy
Klebsiella pneumoniae
Cefepime 2 g IV q8h or
Ceftazidime 2 g IV q8h or
Imipenem 500 mg IV q6h or
Meropenem 1 g IV q8h or
Piperacillin-tazobactam 4.5 g IV q6h
Extended-spectrum beta-lactamase (ESBL)strain
Imipenem 500 mg IV q6h or
Meropenem 1 g IV q8h
K pneumoniae carbapenemase (KPC) strain
Colistin 5 mg/kg/day divided q12h or
Tigecycline 100 mg IV, then 50 mg IV q12h
Duration of therapy: 8-14d
Hospital-Acquired, Health Care-Associated, and Ventilator-
Associated Pneumonia Organism-Specific Therapy
MRSA
Vancomycin 15 mg/kg IV q12h for 7-14 d or
Linezolid 600mg IV or PO q12h for 7-14 d
Targocid 400mg IV once daily for 7-14 d
Hospital-Acquired, Health Care-Associated, and Ventilator-
Associated Pneumonia Organism-Specific Therapy
MSSA
Oxacillin 1g IV q4-6h for 7-14 d or
Nafcillin 1-2 g IV q6h for 7-14 d
Hospital-Acquired, Health Care-Associated, and Ventilator-
Associated Pneumonia Organism-Specific Therapy
Legionella pneumophila
Levofloxacin 750 mg IV q24h, then 750 mg/day PO for 7-
14d or
Moxifloxacin 400 mg IV or PO q24h for 7-14d or
Azithromycin 500 mg IV q24h for 7-10d
Hospital-Acquired, Health Care-Associated, and Ventilator-
Associated Pneumonia Organism-Specific Therapy
Acinetobacter baumannii
Imipenem 1 g IV q6h or
Meropenem 1 g IV q8h or
Doripenem 500 mg IV q8h or
Ampicillin-sulbactam 3 g IV q6h or
Tigecycline 100 mg IV in a single dose, then 50 mg IV
q12h or
Colistin 5 mg/kg/day IV divided q12h
Duration of therapy: 14-21d
Hospital-Acquired, Health Care-Associated, and Ventilator-
Associated Pneumonia Organism-Specific Therapy
Stenotrophomonas maltophilia
Trimethoprim-sulfamethoxazole 15-20 mg/kg/day of TMP
IV or PO divided q8h or
Ticarcillin-clavulanate 3 g IV q4h or
Ciprofloxacin 750 mg PO or 400 mg IV q12h or
Moxifloxacin 400 mg PO or IV q24h
Duration of therapy: 8-14d
Category Circumstances Treatment
Severe HAP# Severity criteria Cefepime 2 g every 8 h + aminoglycoside (Amikacin
20 mg·kg−1·day−1) or quinolone (Levofloxacin 750 mg i.v.
HAP with risk factors for
Gram-negative bacilli Chronic underlying disease Antipseudomonal β-lactam± aminoglycoside or quinolone
Cefepime 1–2 g every 8–12 h i.v.
Carbapenems¶: imipenem 500 mg every 6 h or 1 g every
8 h i.v.; or meropenem 1 g every 8 h i.v.; or
ertapenem+ 1 g·day−1i.v.
P. aeruginosaand multi-
resistant Gram-negative
bacilli Wide-spectrum antibiotics, severe
underlying disease, ICU stay
Antipseudomonal β-lactam±aminoglycoside or quinolone
Cefepime 1–2 g every 8–12 h i.v.
β-lactamic/β-lactamase inhibitor: piperacillin-tazobactam
4.5 g every 6 hi.v.
Carbapenems¶: imipenem 500 mg every 6 h or 1 g every
8 h i.v.; or meropenem 1 g every 8 h i.v.
Legionella# Hospital potable water colonisation and/or
previous nosocomial Legionellosis Levofloxacin 500 mg every 12–24 h i.v.or 750§ mg every
24 h i.v. or azitromycin 500 mg·day−1 i.v.
Anaerobes
Gingivitis or periodontal disease,
depressed consciousness, swallowing
disorders and orotracheal manipulation
Carbapenems¶: imipenem 500 mg every 6 h or 1 g every
8 h i.v.; or meropenem 1 g every 8 h i.v.; or
ertapenem+ 1 g·day−1i.v.
β-lactam/β-lactamase inhibitor amoxicillin/clavulanate 2 g
every 8 hi.v.¶; piperacillin-tazobactam 4.5 g every 6 h i.v.
MRSA Risk factors for MRSA or high prevalence
of MRSA Vancomycin 15 mg·kg−1 every 12 h i.v.Linezolid 600 mg
every 12 h i.v.
Aspergillus Corticotherapy, neutropenia or
transplantation
Amphotericyn B desoxicolate 1 mg·kg−1·day−1 i.v. or
amphotericyn liposomal 3–5 mg·kg−1·day−1 i.v.Voriconazol
6 mg·kg−1 every 12 h i.v.(day 1) and 4 mg·kg−1 every 12 h i.v.(following days)
Early-onset HAP <5 days Without risk factors and non-severe β-lactam/β-lactamase inhibitor: amoxicillin/clavulanate 1–2 g
every 8 hi.v.
Third generation non-pseudomonal cephalosporin:
ceftriaxone 2 g·day−1i.v./i.m. or cefotaxime 2 g every 6–8 hi.v.
Fluoroquinolones: levofloxacin 500 mg every 12–24 h i.v. or
750§ mg·day−1 i.v.
Late-onset HAP ≥ 5 days Without risk factors and non-severe Antipseudomonal cephalosporin (including pneumococcus):
cefepime 2 g every 8 h i.v.
Fluoroquinolones: levofloxacin 500 mg every 12–24 h i.v. or
750§ mg·day−1 i.v.