Principle of antibiotics use

Principle of

antibiotics use

Sophida Boonsathorn, M.D. M.Sc. Division of Infectious Diseases, Department of Pediatrics,

Outlines

•

Mechanisms of action of antimicrobial agents

•

Basic susceptibility test

•

Pharmacokinetics & Pharmacodynamics

•

General principles of antimicrobial selection

•

Syndromic infectious diseases

Host, pathogen, and drug

interactions

HOST

DRUG

BUG

Mechanisms of action of

antimicrobial agents

Inhibit cell wall synthesis

Structure of bacteria

Cell wall

Cytoplasmic

membrane

PABA: Para-aminobenzoic acid DHF: dihydrofolic

Inhibit cell wall synthesis

Mechanisms of action

Cell wall

Cytoplasmic

membrane

Structure of bacteria

Lipopolysaccharides Porin Protein

NAG NAM NAG NAM NAG NAM

Cell wall biosynthesis

peptide chains Peptidoglycan layer transglycosylase Cell membrane Cytoplasm D-Ala D-Ala L-Lys L-Glu L-Ala transpeptidase NAG: N-acetylglucosamine NAM: N-acetylmuramic acid

1. Cell wall active agents

•

Transpeptidase inhibitors:

•

Transglycosylase inhibitors

•

Fosfomycin

•

Bacitracin

•

Cycloserine

Beta-lactams

• Bactericidal by inhibiting bacterial cell wall synthesis,

leading to loss of cell wall integrity and cell lysis

β-lactams

Penicillins Monobactams Cephalosporins Carbapenems

Penicillinase-sensitive penicillins (natural penicillins) Penicillinase-stable penicillins Extended-spectrum penicillins (+ BLIs) Aztreonam 1st generation 2nd _generation 3rd_generation 4th _generation 5th _generation Cephalosporin + BLIs • Ertapenem • Imipenem • Meropenem • Doripenem Carbapenem + BLIs

Penicillins

Gram + - Streptococcus pyogenes

- viridans group streptococci - Group C, G, other streptococci - S. pneumoniae

- Enterococcus faecalis

- L. monocytogenes

Gram – - N. meningitidis

- (non-penicillinase producing)N. gonorrheae - Pasteurella multocida

Spirochetes - Treponema pallidum

- Leptospira spp. Anaerobes - Actinomyces spp.

- Clostridium spp. (not difficile) - Peptostreptococcus spp.

Penicillins

Penicillins Spectrum

Aminopeniciilins

- Ampicillin - Amoxicillin

Gram + As above for penicillins PLUS

Listeria monocytogenes

Gram – As above for penicillins PLUS - H. influenzae, E. coli,

(Salmonella spp., Shigella spp.) Anaerobes As above for penicillins

Penicillinase-stable penicillins - Methicillin, Oxacillin, Nafcillin - Cloxacillin, Dicloxacillin

Gram + - Staphylococcus aureus (MSSA) - S. pyogenes

β-lactamase inhibitor combinations

(

β-lactam/β-lactamase inhibitors: BL/BI)

BL/BI Spectrum

Amoxicillin/clavulanate Add activity to amoxicillin

- MSSA

- H. influenzae (BL-strains)

- Bacteroides spp., Prevotella spp. (BL-strains)

Ampicillin/sulbactam Add activity to ampicillin - MSSA - E. coli (BL-strains) - Klebseilla spp. - Proteus spp. - Morganella morganii - Bacteroides spp., Prevotella spp. (BL-strains)

Piperacilllin/tazobactam As above PLUS - P. aeruginosa

- S. marcescens

- Citrobacter spp. - Enterobacter spp.

Cephalosporins

Class Drugs Spectrum

1st _{Cephalexin (o)} Cefazolin (v) Gram + Gram – Anaerobes - group A, B, C, G streptococci - MSSA - E. coli - Proteus spp. - NO activity 2nd _{Cefuroxime (o)} Cefaclor (o) Cefoxitin (v) Gram + Gram – Anaerobes (only cefoxitin)

As above for 1st _generation

As above for 1st _{generation PLUS} - H. influenzae

- M. catarrhalis

- Bacteroides and Prevotella (non-BL) - Fusobacterium spp.

Cephalosporins

Class Drugs Spectrum

3rd _{Cefixime (o)} Cefdinir (o) Cefditoren (o) Cefotaxime (v) Ceftriaxone (v) Gram +

Gram – - As above for 2

nd _generation Most of aerobic GNB - Enterobacteriaceae - H. influenzae - M. catarrhalis - Morganella morgagnii - Neisseria spp. - Proteus spp. NOTE:

Cefixime Fair gram + coverage: GI and GU infection Cefdinir

Cephalosporins

Class Drugs Spectrum

3rd _{Ceftazidime (v) Gram +} Gram

-- Less activity against gram +

- As above PLUS P. aeruginosa

3rd BL/BI Cefoperazone/ sulbactam Gram + Gram

-- Less activity against gram + - As above PLUS

- P. aeruginosa

- A. baumanii

- ESBL+ E. coli / Klebsiella spp. 4th _{Cefipime (v) Gram +}

Gram

-- As above for 3rd _{generation PLUS}

- P. aeruginosa - AmpC+ Enterobacteriaceae 5th _{Ceftaroline (v)} Ceftobiprole (v) Gram + Gram

-- MRSA, VISA, VRSA, MRSE - S. pneumoniae (+ DRSP)

- GNB but no activity against NF-GNB (P. aeruginosa, A. baumanii, S. maltophilia)

Carbapenems

- S. aureus (MSSA) - E. faecalis

- Most Enterobacteriaceae including ESBL+ strains

- NO activity against P. aeruginosa

- Bacteroides and Prevotella (including BL-strains)

- Fusobacterium spp.

- Peptostreptococcus spp Imipenem/cilastatin As above PLUS P. aeruginosa

Meropenem As above PLUS P. aeruginosa

Monobactams

• Aztreonam: not available in Thailand

Carbapenems

•

All carbapenems has no activity against

• MRSA

• Enterococcus faecium • Burkholderia cepacia

Newer BL/BI

Extended-spectrum BL/BI Spectrum - Ceftolozane/tazobactam

(Zerbaxa®)

Gram - - Treatment of intra-abdominal infection, UTI

- Enhanced activity against

P. aeruginosa

- ESBL-producing organisms - Ceftazidime/avibactam

(Avycaz®)

Gram - - Treatment of intra-abdominal infection, UTI, pneumonia - P. aeruginosa,

Enterobacteroaceae BUT

- No activity against A. baumannii

or metallo-beta-lactamase producing organisms - Meropenem/vaborbactam (Vabomere®) Gram - - KPC-producing Enterobacteriaceae

- No activity against metallo-beta-lactamases and OXA-type

Newer antibiotics

Agents Enterobacteriaceae P. aeruginosa A. baumannii

ESBL AmpC KPC OXA-48 NDM Efflux AmpC Ceftolozane/ tazobactam + +/- - +/- - + + + Ceftazidime/ avibactam + + + + - + + + Meropenem/ vaborbactam + + + - - + + + Imipenem/ relebactam + + + - - + + + Eravacycline + + + + + + + + Plazomicin + + + + + + + + Cefiderocol + + + + + + + +

Drugs Strept

ococci Enterococci* MSSA MRSA (E.coli, Klebsiella, GNB Proteus)

GNB

(non-fermenter)** Anaer_obes Other

Penicillins Penicillin + - - - - - +/-Cloxacillin + - + - - - -Ampicillin Amoxicilln + + +/- - +/- - -Pip/tazo + + +/- - + + + 1st_{cep Cefazolin/} cephalexin + -+ - +/- -

-2nd_{cep Cefuroxime + - + (+H.influ) -}

-Cefoxitin +/- - + - + 3rd_{cep Cefotaxime/} Ceftriaxone +/- - + - -Ceftazidime - - - - + + - no G+ 4rd_{cep Cefepime + - + - + +} -5rd_{cep Ceftaroline + + + + + -} -Carbapenem Ertapenem + +/- + - + - + Imipenem/ Meropenem + +/- + - + + + Monobactam Aztreonem - - - - + + - no G+ * Enterococcus faecalis

1. Cell wall active agents (con’t)

•

Transpeptidase inhibitors:

•

Transglycosylase inhibitors

•

Fosfomycin

•

Bacitracin

•

Cycloserine

Glycopeptides

Fosfomycin

• Japanese product, no US FDA information

• Oral fosfomycin: uncomplicated UTI

• IV fosfomycin: use in combination with other active drugs for

Structure of bacteria

Cell wall

Cytoplasmic

membrane

2. Cell membrane active agents

Class Mechanism Spectrum Special considerations Lipopeptides - Daptomycin Depolarization of membrane → producing channel → cell contents leak → cell death

- MRSA - VISA - VRE

- Can be used for SSTI, BSI, endocarditis* - Inactivated by surfactant: not effective for treatment of pneumonia Polymyxins - Colistin (polymyxin E) Bind to LPS of cell membrane → membrane disruption → leak → cell death MDR gram -including A. baumanii - Renal toxicity - Neuromuscular toxicity - Unclear optimal dose

*SSTI: skin and soft tissue infections BSI: blood stream infections

Structure of bacteria

Cell wall

Cytoplasmic

membrane

3. Ribosome active agents

30S subunit

50S subunit

30S: Aminoglycosides

Drugs Spectrum

Streptomycin Gram - • Brucella spp. • Francisella spp. • M. tuberculosis Gentamicin Amikacin Netilmicin Tobramycin Gram + Gram -• S. aureus, CONS (+/-) • Enterobacteriaceae • P. aeruginosa

Paramomycin Parasites • Entamoeba histolytica • Dientamoeba fragilis • Cryptosporidium spp.

30S: Tetracyclines

- Mycoplasma pneumoniae, Chlamydophila pneumoniae

- Ureaplasma urealyticum

30S: Tetracyclines

- E. faecalis, E. faecium

- S. aureus (MRSA, VISA) - CONs - A. baumanii - S. trophomonas - Other Enterobacteriaceae - C. trachomatis, M. pneumoniae, C. pneumoniae, U. urealyticum

- Rapid growing mycobacterium: M. abscessus, M. chelonae, M. fortuitum

50S: Macrolides

- S. aureus, S. pneumoniae, S. pyogenes

- B. pertussis

- Legionella pneumophila

- N. gonorrheae

- C. trachomatis, M. pneumoniae, C. pneumoniae, U. urealyticum

- Increase activity against gram –

- H. influenzae, M. catarhalis, H. pylori

Azalides:

Azithromycin - As above but increase activity against GI _{pathogens (Salmonella spp., Shigella spp.,}

Campylobacter spp.) - Rickettsial disease

50S: Lincosamides

Drugs Spectrum Special

considerations Clindamycin Lincomycin Gram + Anaerobes - Group A, B streptococci - Viridans group streptococci - S. pneumoniae - S. aureus - C. diphtheriae - B. fragilis - Fusobacterium spp. - Actinomyces spp. - C. perfringens - Peptostreptococcus spp. - Bacteriostatic - Treatment of choice for TSS, CA-MRSA* - Common AE: antibiotic-associated pseudomembranous colitis

*TSS: toxic shock syndrome

50S: Oxazolidinones

Drugs Spectrum Special considerations Linezolid Gram + Others - Group A, B streptococci - Viridans group streptococci - CoNS - E. faecalis, E. faecium

- MRSA, VISA, VRSA, PRSP, VRE - Nocardia spp. - M. tuberculosis - Rapid growing mycobacterium - Bacteriostatic*

- High oral bioavailability - High level in epithelial

lining fluid (ELF)

- Treatment of pneumonia, SSTI, and bacteremia

- AE: neutropenia,

thrombocytopenia (most often with treatment

durations of > 2 weeks), lactic acidosis

50S: Streptogramins

Drugs Spectrum

Streptogramins:

Quinupristin/dalfopristin

Gram + - Group A, B streptococci - S. aureus

- CoNS

- E. faecium

- MRSA, VISA, VRSA, PRSP, VRE

• Combination of Streptogramin A and B

• Bind to the P binding site of the 50S ribosome subunit

• Streptogramin A binding causes a conformational of 50S subunit • Streptogramin B prevents protein chains elongation

Structure of bacteria

Cell wall

Cytoplasmic

membrane

4. Nucleic acid active agents

• Inhibit DNA replication: quinolones

• Inhibit RNA synthesis: rifamycins

• Inhibit DNA and RNA synthesis: folate pathway antagonist

Inhibit DNA-dependent DNA

polymerase: Quinolones

Drugs Spectrum

Nalidixic acid Gram - (not include P. aeruginosa) Norfloxacin

Ofloxacin

As above PLUS

- Enterobacteriaceae

- Shigella spp., Salmonella spp. Ciprofloxacin As above PLUSP. aeruginosa

Levofloxacin As above PLUS - S. pneumoniae

- M. pneumoniae, C. pneumoniae, L. pneumophila

Moxifloxacin Gatifloxacin

As above PLUS - S. pneumoniae

- Anaerobes (not C. difficile)

Inhibit DNA-dependent RNA

polymerase: Rifamycins

Folate pathway antagonist:

Trimethoprim/sulfamethoxazole

Precursors of DNA, RNA DNA, RNA

Inhibit dihydropteroate synthase Inhibit dihydrofolate reductase

Anaerobic DNA inhibitors:

Metronidazole

Drugs Strept

ococci Enterococci* MSSA MRSA (E.coli, Klebsiella, GNB Proteus)

GNB

(non-fermenter)** Anaer_obes Other

Penicillins Penicillin + - - - - - +/-Cloxacillin + - + - - - -Ampicillin Amoxicilln + + +/- - +/- - -Pip/tazo + + +/- - + + + 1st_{cep Cefazolin/} cephalexin + -+ - +/- -

-2nd_{cep Cefuroxime + - + (+H.influ) -}

-Cefoxitin +/- - + - + 3rd_{cep Cefotaxime/} Ceftriaxone +/- - + - -Ceftazidime - - - - + + - no G+ 4rd_{cep Cefepime + - + - + +} -5rd_{cep Ceftaroline + + + + + -} -Carbapenem Ertapenem + +/- + - + - + Imipenem/ Meropenem + +/- + - + + + Monobactam Aztreonem - - - - + + - no G+ FQ Ciprofloxacin - - - - + +

-Resp. FQ Levofloxacin + - + - + + - Stenotropho

monas

Antimicrobial

Susceptibility testing

• MIC, MIC₅₀, MIC₉₀

• Different guidelines and recommendations

• CLSI: Clinical Laboratory Standards Institute

• EUCAST: European Committee on Antimicrobial

Susceptibility Testing

Methods for AST

•

Phenotypic AST

• Dilution methods

• Broth dilution/microdilution tests

• Automated instruments

• Diffusion methods

• Disk diffusion test

• Antimicrobial gradient method

Blank 0.5 1 2 4 8 16 32 64 128 256 Antibiotic

Conc. (µg/ml)

MIC = 4

µg/ml

Broth dilution tests

Minimum inhibitory concentration (MIC): the lowest antibiotic concentration which prevents visible growth of bacteria

Antimicrobial gradient method

• E-test

• Impregnated strips with a dried

antibiotic concentration gradient

• MIC = the intersection of the lower

part of the ellipse shaped growth inhibition area with the test strip

Approach for the provision of

optimal antibiotic therapy

Antimicrobial agents

Pharmacokinetics

and

Relationship between PK and PD

Pharmacokinetics

“The time course of drug movement in the body”

A: Absorption

D: Distribution

M: Metabolism

E: Elimination

“A” Absorption

•

Factors influencing absorption:

• Drug characteristics:

• Molecular weight, ionization, solubility, formulation

• Patients factors:

• Route of administration, gastric pH, contents of GI tract

•

Bioavailability (F):

the fraction of administered dose of

unchanged drug that reaches the systemic circulation

F =

𝑨𝑨𝑨𝑨𝑨𝑨 𝒐𝒐𝒐𝒐𝒐𝒐𝒐𝒐

“D” Distribution

•

Membrane permeability

•

Plasma protein binding

•

Lipophilicity of drug:

hydrophilic

or lipophilic

•

Volume of distribution (Vd):

𝒔𝒔𝒕𝒕𝒐𝒐𝒂𝒂𝒂𝒂 𝒄𝒄𝒐𝒐𝒂𝒂𝒄𝒄𝒕𝒕𝒂𝒂𝒂𝒂𝒐𝒐𝒐𝒐𝒂𝒂𝒊𝒊𝒐𝒐𝒂𝒂

“M” Metabolism

•

Liver: major site for drug metabolism

•

Types of reactions

•

Phase I (CYP450 system)

•

Phase II

Metabolism

Phase I reactions Phase II reactions

• Cytochrome P450 system

• Located within the

endoplasmic reticulum of hepatocytes

• Oxidation or reduction

• Enzyme induction

• Drug interactions

• Polar group is conjugated to

the drug

• Results in increased polarity

of the drug

• Types of reactions

• Glycine conjugation

• Glucuronide conjugation

“E” Elimination

•

Removal of drug from the body

•

Renal: the most important route

•

Non-renal clearance: bile, lungs, milk

Pharmacodynamics

“The study of how a drug affects an organism”

•

Emphasis on dose-response relationships

•

Time-dependent killing

•

Concentration-dependent killing

•

Post-antibiotic effect (PAE)

Pharmacokinetic/Pharmacodynamic

predictors of efficacy

MIC

Area under the curve: “amount of drug” Time > MIC PK/PD parameters • T > MIC • Peak > MIC • 24-h AUC/MIC

MIC: how much antibiotics is required to inhibit growth in a test tube

Time-dependent killing

•

The time it takes for a pathogen to be killed by

exposure to an antimicrobial

•

Parameter:

Time > MIC

•

The require time above the MIC:

at least 40-50% of

the dosing interval

and

C

> 3-4 times of MIC

Strategies to optimize T > MIC

Correlation of serum PK with MIC of an organism

Drug B: a concentration of 2 mg/L for 30% of dosing interval Drug A: a concentration of 2 mg/L for 50% of dosing interval

Maximize the duration of drug exposure

• More frequent intervals • Larger doses

• Longer IV infusions or

Concentration-dependent killing

•

Goal: to maximize concentration and attain the

highest possible antimicrobial concentration at the

site of infection

•

Parameter:

24-h AUC/MIC

or

C

/MIC

•

Aminoglycosides, fluoroquinolones, azalides

Concentration-dependent killing

•

Aminoglycosides

- C

/MIC > 10

•

Fluoroquinolones

- AUC/MIC > 100-125 for gram negative bacilli and

seriously ill

Post antibiotics effect (PAE)

•

The ability to suppress bacterial re-growth after the

concentration has fallen below the MIC

•

Parameter:

AUC/MIC

Important PK/PD indices

Antimicrobial agents

PK/PD index

Target value for clinical efficacy

PK/PD properties

Aminoglycosides Cmax/MIC > 8-10 Concentration

dependent β-lactams - Penicillins - Cephalosporins - Carbapenems fT/MIC - T>MIC > 50-60% - T>MIC > 50-60% - T>MIC > 40-50% Time dependent Glycopeptides - Vancomycin

AUC24/MIC 400 Time and

concentration dependent

Fluoroquinolones AUC24/MIC - gram negative:

100-125

- gram positive: 25-35

General principles of

antimicrobial selection

Approach for the provision of

optimal antibiotic therapy

Antimicrobial agents

Selection and initiating an

antibiotic regimen

•

Obtaining an

accurate

infectious disease

diagnosis

(site of infection, host, microbiological diagnosis, investigations)

Timing of initiation of

antimicrobial therapy

•

In

critically ill

patients: empiric therapy should be

initiate immediately after/concurrently with collection

of diagnostic specimens

•

In

more stable

patients: antimicrobial therapy should be

Selection and initiating an

antibiotic regimen

•

Obtaining an accurate infectious disease diagnosis

(site of infection, host, microbiological diagnosis, investigations)

•

Timing of initiation of antimicrobial therapy

Empiric VS Definitive therapy

•

Empirical therapy:

•

Initial therapy that is guided by clinical presentation

•

Intend to cover multiple possible pathogens commonly

associated with the specific clinical syndrome

•

Definite therapy:

•

Every attempt should be made to narrow the antibiotic

spectrum once etiologic pathogens are identified and/or

antimicrobial susceptibility results are available

Selection and initiating an

antibiotic regimen

•

Obtaining an accurate infectious disease diagnosis

(site of infection, host, microbiological diagnosis, investigations)

•

Timing of initiation of antimicrobial therapy

•

Empiric VS Definitive antimicrobial therapy

•

Interpretation of

susceptibility testing

results

Pharmacodynamic of

antimicrobial agents

Primary target Class Pharmacodynamics

Cell wall β-lactams, Glycopeptides Bactericidal

Cell membrane Lipopeptides (Daptomycin) Polymyxins

Bactericidal

Ribosome Macrolides, Tetracyclines Bacteriostatic

Oxazolidinones Bacteriostatic (except

against S. pneumoniae)

Aminoglycosides,

Clindamycin, Rifamycins, Fluoroquinolones

Bactericidal

Streptogramins Bactericidal (except

against E. faecium)

Selection and initiating an

antibiotic regimen (cont’)

Combination therapy

• When agents exhibit synergistic activity against a microorganism

• When critically ill patients require empiric therapy before

microbiological etiology and/or antimicrobial susceptibility can be determined

• To extend the antimicrobial spectrum beyond that achieved by

use of a single agent for treatment of poly-microbial infections

Selection and initiating an

antibiotic regimen (cont’)

•

Use of antimicrobial combinations

•

Host factors

to be considered in selection of

antimicrobial agents

• Renal and hepatic function

• Age

• Genetic variation

• Pregnancy and lactation

• History of allergy or intolerance

Selection and initiating an

antibiotic regimen (cont’)

•

Oral

VS

Intravenous

therapy

•

Pharmacodynamic

characteristics

Efficacy at the site of infection

•

Depends on the capacity to achieve a concentration >

MIC* at the site of infection

• 1st , 2nd generation cephalosporins and macrolides do not

cross blood-brain barrier: not recommended for CNS infections

• Aminoglycosides: less active in low pH and high-protein

environment of abscesses

* MIC (minimum inhibitory concentration): the lowest antibiotic concentration which prevents visible growth of bacteria

Infection site and dosing regimen

Infection site

PK alteration Potential change to dosing regimen

Blood Expanded volume of

distribution (Vd), enhanced clearance (CL)

Loading dose, increase frequency

Lung Impaired permeability Increase dose of

hydrophilic agents

(beta-lactams, vancomycin, aminoglycosides)

Soft tissue Contingent on body composition

Increase dose in obesity

Bone Impaired permeability Increase dose, duration of

therapy

Selection and initiating an

antibiotic regimen (cont’)

•

Oral VS Intravenous therapy

•

Pharmacodynamic characteristics

•

Efficacy at the site of infection

Use of therapeutic drug

monitoring (TDM)

•

Useful for agents with narrow therapeutic index

•

Toxicity at high drug levels (e.g. aminoglycosides) or

therapeutic failure at low drug levels (e.g. vancomycin)

Drug level monitoring

Agents Multiple-daily Once-daily Optimal sampling time Steady state Gentamycin Peak: 5-10 mg/L Trough: < 2 mg/L Peak: 20 mg/L Trough: undetectable Peak: 30-60 min after stop infusion Trough: 30 min before next dose 10-15 h Amikacin Peak: 20-30 mg/L Trough: < 10 mg/L Peak: 60 mg/L Trough: undetectable Same as above 10-15 h Vancomycin AUC/MIC 400-600 mg.h/L Peak: 1 h after stop infusion Trough: 30 min before next dose 18-39 h (after 3rd_-4th dose)

Vancomycin

• The mainstay of treatment for MRSA infections

• Problems with vancomycin usage

• For S. aureus (MIC < 1 mg/L): serum vancomycin through

serum concentrations of 15-20 mg/L is recommended

• Need drug level monitoring

• Need high concentration of vancomycin for severe infection

Vancomycin

•

Monitoring not required: when IV treatment < 4 days

•

Through level

• IV treatment > 4 days

• Receiving concomitant nephrotoxic drugs

• Rapid changing or unpredictable renal function

• ESRD and likely to receive more than one dose

• Morbid obesity

•

Peak and through level

Selection and initiating an

antibiotic regimen (cont’)

•

Pharmacodynamic characteristics

•

Efficacy at the site of infection

•

Use of therapeutic drug monitoring (TDM)

•

Selection of antimicrobial agents for

outpatient

parenteral

antimicrobial therapy

Considerations for continuing

antibiotic therapy

•

Duration

of antimicrobial therapy

•

Assessment of

response to treatment

Special situations

•

Foreign body-associated infections

•

Prophylactic or suppressive therapy

• Pre-surgical antimicrobial prophylaxis

• Antimicrobial prophylaxis in immunocompromised patients

• Antimicrobial prophylaxis to prevent transmission of communicable

pathogens to susceptible contacts

• Antimicrobial prophylaxis before dental and other invasive

procedures in patients susceptible to bacterial endocarditis

Prophylaxis therapy

•

High risk of infection

•

Administer at the time of risk

•

Likely causative organisms and their susceptibilities

•

To reduce incidence of postop. surgical site infections

•

Antibiotics should cover most likely organisms and

should be present in the tissues when incision is made

•

Adequate serum concentrations should be maintained

during the operation

•

Common surgical pathogens:

• Clean procedures: skin flora, including S. aureus, CoNs

• Clean-contaminated procedures: skin flora, GNB, enterococci

•

Timing:

•

Selection and dosing:

• clean-contaminated

• contaminated procedures

• Certain clean procedures where there are severe

consequences of infection (e.g. prosthetic implants)

•

Redosing

• If the duration of the procedure exceeds two half-lives of the

antimicrobial or there is excessive blood loss (i.e., >1500 mL)

•

Duration of prophylaxis:

Surgical antimicrobial prophylaxis

Recommendations for surgical

antimicrobial prophylaxis

Type of procedure Recommended agents and dosing Cardiovascular surgery Cefazolin 2 g IV

Gastrointestinal surgery - Esophageal, duodenal - Biliary tract - Colorectal Cefazolin 2 g IV Cefazolin 2 g IV Cefoxitin 2 g IV or Cefazolin 2 g IV + metronidazole 500 mg IV OBGYN surgery Cefazolin 2 g IV

Head & neck surgery Cefazolin 2 g IV Orthopedic surgery Cefazolin 2 g IV Urologic surgery - Clean - Clean-contaminated Cefazolin 2 g IV Cefoxitin 2 g IV or Cefazolin 2 g IV + metronidazole 500 mg IV Adapted from Bratzler DW, et al. Am J Health Syst Pharm. 2013.

Consider vancomycin if: colonized with MRSA, high rate of post-operative MRSA infection

Common misuses of antibiotics

•

Prolonged empiric

antimicrobial treatment without clear

evidence of infection

•

Treatment of a positive culture in the

absence of disease

•

Failure to narrow

antimicrobial therapy when a causative

organism is identified

•

Prolonged prophylactic

therapy

Approach for the provision of

optimal antibiotic therapy

Syndromic infectious diseases

•

Central nervous system

•

Ocular infection

•

Upper respiratory tract infection

•

Lower respiratory tract infection

•

Cardiovascular system

•

Gastrointestinal infection

•

Intra-abdominal

•

Urinary tract infection

Community-acquired

pneumonia (CAP)

• Addresses the clinical entity of pneumonia that is acquired outside

of the hospital setting

• Focuses on patients in the United States, adults, who do not have an

immunocompromising condition

Pathogens

•

Streptococcus pneumoniae

•

Haemophilus influenzae

•

Moraxella catarrhalis

•

Mycoplasma pneumoniae

•

Chlamydia pneumoniae

•

Staphylococcus aureus

•

Legionella

species

Outpatient setting: Antibiotics

for empiric treatment of CAP

Inpatient setting: Antibiotics for empiric

treatment of CAP without risk factors for

MRSA and

P. aeruginosa

Hospital-acquired pneumonia

(HAP) and

Diagnosis for VAP

•

Patients with suspected HAP (non-VAP) should be

treated according to results of microbiologic studies

performed on respiratory samples obtained

non-invasively (rather than being treated empirically)

•

In patients with ventilator-associated tracheobronchitis

(VAT), suggest not providing antibiotic therapy

Diagnosis for VAP

“Microbiological method”

Invasive Sampling

BAL, Blinded BAL

Non-invasive Sampling

Endotracheal aspiration

Quantitative culture Semiquantitative culture

VS

VS

Diagnostic threshold for VAP

Endotracheal aspirates (ETA) <105 _CFU/mL

Bronchoalveolar lavage (BAL) <104 _CFU/mL

Protected specimen brush (PSB) <103 _CFU/mL

 Antibiotics should be withheld if culture results are below diagnostic

threshold for VAP

•

ATB regimens: guided by local antibiotic-resistance data

•

For VAP, coverage for

S. aureus

(MSSA),

P. aeruginosa

,

and other gram-negative bacilli (GNB)

•

Coverage for MRSA if

• In the units where > 10% - 20% of S. aureus are MRSA

• Risks of ATB resistance

•

2 anti-pseudomonal ATB

if

• Risks of ATB resistance

• In the units where > 10% of GNB are resistant to agent being

considered for monotherapy

Treatment of VAP and HAP

Risk factors for MDR pathogens

•

Risk factors for MDR VAP

• Prior intravenous antibiotic use within 90 days

• Septic shock at time of VAP

• ARDS preceding VAP

• >5 days of hospitalization prior to the occurrence of VAP

• Acute renal replacement therapy prior to VAP onset

•

Risk factors for MDR HAP

• Prior intravenous antibiotic use within 90 days

•

Risk factors for MRSA, MDR

P. aeruginosa

VAP/HAP

• Prior intravenous antibiotic use within 90 days

Kalil AC, et al. Clin Infect Dis. 2016.

- Having risk factors for ATB resistance - > 10-20% of

S. aureusare MRSA - Prevalence of MRSA is unknown

- Having risk factors for ATB resistance - > 10-20% of

S. aureusare MRSA - Prevalence of MRSA is unknown - Need ventilator

support due to HAP and septic shock

Empiric ATB options for HAP

Pathogen-specific therapy

•

P. aeruginosa

who are not in septic shock or at high

risk for death, and ATB susceptibility testing are known

• Recommend monotherapy

• Definitive ATB: based upon susceptibility testing results

•

ESBL-producing GNB

• Recommend based upon susceptibility testing results and

patient-specific factors (allergies, co-morbidities)

•

GNB that are susceptible to only aminoglycosides or

polymyxins

• Suggest both systemic and inhaled ATB

Pathogen-specific therapy

•

Acinetobacter

species

• Carbapenem or ampicillin/sulbactam if susceptible

• If S only to colistin: IV colistin and adjunctive inhaled colistin

•

Carbapenem-resistant pathogen

• If S only to colistin: IV colistin and adjunctive inhaled colistin

•

MRSA

• Vancomycin or linezolid

Duration of ATB for HAP and VAP

•

Optimal duration: 7 days

• Shorter or longer duration may be indicated, depending

upon the rate of improvement of clinical, radiologic, and laboratory parameters

•

Recommend to

de-escalate ATB

• Broad-spectrum to narrower ATB

•

Use PCT + clinical to guide discontinuation of ATB

Intra-abdominal infection (IAI)

Solomkin JS, et al. Clin Infect Dis. 2010.

Maxuki JE et al. Surg Infect (Larchmt). 2017.

2017

Intra-abdominal infection(IAI)

•

Initial diagnostic evaluation

• Routine history, physical examination, laboratory studies to

identify patients with suspected IAI

•

Rapid fluid resuscitation

•

Source control and empiric antibiotics

• ATB should be initiated once an infection is suspected

• ATB should be given ASAP for patients with septic shock

•

Microbiologic evaluation

• Obtain cultures in high-risk patients with CA-IAI and HA-IAI

to identify potential resistant pathogens

Intra-abdominal infection(IAI)

Risk assessment: low VS high

•

Host factors

• Signs of sepsis/septic shock • Extreme age

• Comorbidities

•

Community-acquired (CA-IAI) VS hospital-associated

(HA-IAI)

•

Extent of abdominal infection

• Adequacy of initial source control

• Ability to achieve adequate source control • Microbiological characteristics

• Presence or persistent of resistant pathogens

Hospital-acquired IAI (HA-IAI)

•

Criteria for HA-IAI

• Infection developing > 48 h after initial source control

• Hospitalized > 48 h in current admission or within previous 90 days • Use of broad-spectrum ATB for > 5 days during preceding 90 days • Residing in a skilled nursing/long-term facility during the previous

30 days

• Home IV infusion therapy, wound care, or dialysis within preceding

30 days

Intra-abdominal infection(IAI)

•

Intravenous antimicrobial agents

•

Recommended ATB regimens

• ATB for empirical treatment should active against

gram-negative aerobic Enterobacteriaceae, gram-positive cocci and obligate anaerobic bacilli

•

Do not use routinely for empiric therapy

• Aminoglycosides • Ampicillin/sulbactam • Amoxicillin/clavulanic acid • Cefoxitin • Cefazolin + metronidazole • Tigecyclin • Clindamycin (unless

metronidazole can’t be used)

Use fluoroquinolones with caution!!

Regimens for initial empiric

treatment of

CA-IAI

CA-IAI in pediatric patients CA-IAI in adult patients

Low risk High risk Low risk High risk Cefotaxime / ceftriaxone + metronidazole (preferred) Pip/taz Meropenem Imipenem Ceftazidime / cefepime + metronidazole Aztreonem + metronidazole + vancomycin Ertapenem Moxifloxacin Cefoperazone/ sulbactam (option) Pip/taz Imipenem Meropenem Doripenem Cefuroxime + metronidazole Ciprofloxacin / levofloxacin + metronidazole Ceftriaxone / Cefotaxime / + metronidazole Ciprofloxacin + metronidazole Cefuroxime + metronidazole Cefepime + metronidazole Ceftazidime + metronidazole (option) Aztreonem + metronidazole + vancomycin

FQ is suggested only patients with significant reactions to beta-lactams, levofloxacin may be substituted for ciprofloxacin

Adapted from Maxuki JE et al. Surg Infect (Larchmt). 2017. Solomkin JS, et al. Clin Infect Dis. 2010.

Hospital-acquired

intra-abdominal infection

(HA-IAI)

•

Anti-MRSA

• Patients with risk factors for MRSA (advanced age, co-morbid

medical conditions, previous hospitalization/surgery, recent exposure to ATB, known to be colonized with MRSA)

• Vancomycin or teicoplanin

• Linezolid or daptomycin: alternatives

•

Anti-enterococci

• Patients with post-op. infection, colonized with VRE, signs of

severe sepsis/shock, recent exposure to broad-spectrum ATB

• Vancomycin or teicoplanin

• Linezolid or daptomycin: colonized with or high risk for VRE

Hospital-acquired

intra-abdominal infection

(HA-IAI)

•

ATB for resistant gram-negative organisms

• Patients who have received broad-spectrum ATB, prolonged

hospitalizations, undergone multiple invasive interventions, colonized or infected with resistant gram-negative organisms

Regimens for initial empiric

treatment of HA-IAI

Duration of ATB therapy

Duration Conditions

< 24 hours • Traumatic bowel perforations operated on within 12 h

• Gastro-duodenal perforations operated on within 24 h

• Acute or gangrenous appendicitis in absence of perforation • Acute or gangrenous cholecystitis in absence of perforation • Ischemic, non-perforated bowel

< 4 days • Patients who had adequate source control

5-7 days • When a definitive source control is not performed

• Re-assess within 5-7 days for source control intervention

7 days • Patients with secondary bacteremia because of IAI

• Who have undergone adequate source control and are no

longer bacteremia

7-10 days • Pediatric patients age < 1 month (45 wk post-concept. age) NO DATA • Patients receiving immunosuppressive medications

Oral ATB

•

May be considered oral agents with good bioavailability

with adequate GI function

• Only to complete a shore course of treatment

• BUT NOT to prolong ATB

•

Options:

Common misuses of antibiotics

•

Prolonged empiric

antimicrobial treatment without clear

evidence of infection

•

Treatment of a positive culture in the

absence of disease

•

Failure to narrow

antimicrobial therapy when a causative

organism is identified

•

Prolonged prophylactic

therapy

Take home messages

•

Appropriate use of antimicrobial agents involves

• Accurate diagnosis

• Possible causative organisms and their susceptibilities

• Determining the need for and timing of antimicrobial therapy

• Understanding antimicrobial activities

• Using the narrowest spectrum and cost-effective agents for

the shortest duration

•

Non-antimicrobial interventions are equally important