Antibiotic strategy in nosocomial pneumonia

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


OF ANTIBACTERIAL DRUGS


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


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


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 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


Time above the MIC

– Examples

Beta lactam, macrolides, clindamycin, flucytosine,

linezolid.



Time-dependent killing and prolonged

persistent effects

– Goal of dosing

Optimize amount of drug


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

http://erm.ersjournals.com/content/erm/ermnp/1/SEC16/F24.large.jpg

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


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.


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).


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



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




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



MSSA

Oxacillin 1g IV q4-6h for 7-14 d or

Nafcillin 1-2 g IV q6h for 7-14 d



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



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




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


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.


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


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.

Antibiotic strategy in nosocomial pneumonia

Health & Medicine

Transcript of Antibiotic strategy in nosocomial pneumonia