Principles of Antibiotics Use & Spectrum of Some

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Rabee Adwan. MD Infectious Diseases Consultant (Pediatric and Adult)

Head Of ID Unit and IPAC Committee- AL-Makassed Hospital-AlQuds Head of IPAC Committee Istishri Arab Hospital-Ramallah

RABEE_ODWAN@YAHOO.COM

DISCLAIMERS

There is No “fun” way to remember all Organisms and Antimicrobials :)

The goal of this talk is to provide you with some basics and principles.

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Some Principles

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Start Smart ! Always think on it as aTriad:-

• HOST: How sick is this person? Immunocompromised? Allergies? Ability to adhere to medications? comorbidities? pregnancy? Age?

• BUG: What organisms could be causing the problem? Does this patient have risk factors for resistant organisms?

• DRUG: Will it penetrate to the organ involved? Do you need a bactericidal drug (eg. for endocarditis/CNS infections)? Side effects? Renal or hepatic clearance?

HOST

BUG DRUG

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Is it a Bacterial infection?

ANTIBIOTIC CHOICE

Reassess after 48-72 hours (or when culture results available)

Don't guess about which antibiotic(s) to use - look it up or ask for help

Don't delay giving antibiotics if the patient needs them (e.g., sepsis, meningitis)

Don't forget to obtain appropriate cultures prior to starting antibiotics

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USE BUNDLE:- THE 6 DS:-

The Right Drug

The Right Dose

The best Route of Delivery

Attention To Deescalation

The appropriate Duration of Rx6

The Right Diagnosis

COMMON MISUSES OF ANTIBIOTICS

1. Prolonged Empiric Antimicrobial Treatment Without Clear Evidence of Infection.

2. Treatment of a Positive Clinical Culture in the Absence of Disease.

3. Failure to Narrow Antimicrobial Therapy When a Causative Organism Is Identified.

4. Prolonged Prophylactic Therapy.

5. Excessive Use of Certain Antimicrobial Agents.

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1.Use antibiotics only when needed; teach the patient how to manage symptoms of non-bacterial infections;

2.Select the adequate ATB; precise targeting is better than shotgun therapy;

3.Consider pharmacokinetics and pharmacodynamics when selecting an ATB; use the shortest ATB course that has proven clinical efficacy;

4. Encourage patients’ compliance;

5.Use antibiotic combinations only in specific situations;

6.Avoid low quality and sub-standard drugs; prevent prescription changes at the drugstore;

7.Discourage self-prescription;

8.Follow only evidence-based guidelines; beware those sponsored by drug companies;

9.Rely (rationally) upon the clinical microbiology lab; and

10.Prescribe ATB empirically – but intelligently; know local susceptibility trends, and also surveillance limitations.

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KILLING ABILITY

Bactericidal:- agents kill the Bacteria

Bacteriostatic:-agents inhibit the growth of Bacteria

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ANTIMICROBIAL PK/PDConcentration Dependant:- Rate and extent of Killing is dependent on the ratio that can be achieved between the peak drug concentration and the MIC of the infecting organism.

Time Dependant:- Rate and extent of killing is dependant on the Duration of time that the drug is above the MIC of infecting organism.

BACTERIAL CLASSIFICATION: GRAM STAIN

Gram +ve (blue/purple)Thick peptidoglycan cell wall retains primary stain

Gram -ve (pink/red)Thin peptidoglycan cell wall does not retain primary stain

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BACTERIA STRUCTURAL DIFFERENCES

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DNA

mRNARibosomes

Metabolism

B-Lactames

CephalosporinsPenecillinsMonobactamsCarbapenems

Glycopeptides

Colistin Daptomycin

30 S

50 S

Aminoglycosides Tetracyclines (Tigecycline)

Macrolides Clindamycin Chloramphenicol Synercid

Quinolones Metronidazole

Transcription

Rifamycins

Sulfonamides Trimethoprim

*Linezolid acts on the initiation complex

Coverage Spectrum Of ATB

MOA of Action

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Beta-lactams

• Members:- • Penicillins• Cephalosporins• Carbapenems• Monobactam

• MOA:- • Cell wall synthesis inhibitors

• Antimicrobial Properties: • Bactericidal • Time dependant Killing

Penicillin G/V

• •Narrow spectrum agent; mostly aerobic gram positive cocci

• Useful against: • ß- hemolytic streptococci (Group A, B, C & G) • Treponema pallidum (Syphillis) – Gram negative spirochete • N. menigitidis *note: resistance 1-3% • oral anaerobes (peptococcus, peptostreptococcus)

• enteroccocus (E. facaelis, NOT E. faecium)

• NOT useful against: • most gram negative organisms • beta-lactamase producing organisms (S. aureus - ~90%)

Amoxicillin/Ampicillin

• narrow spectrum agent; mostly Gram positive aerobes, some Gram negative aerobes

• covers everything that penicillin does (streptococcus, enterococcus, oral anaerobes)

• Gram negative coverage (HiPEEL) - Non-beta-lactamase producing • – H. influenzae (~25% resistance) • – Proteus mirabilis • – E. coli (~30% resistance)

• Gram positive coverage • – better coverage of enterococcus (E.faecalis vs. penicillin) • – Listeria monocytogenes (HiPEEL)

• Useful against: ß- hemolytic streptococci (Group A, B, C & G), E. faecalis (<1% resistance), Listeria

Amoxicillin-Clavulanic Acid

• Amoxicillin + ß-lactamase inhibitor • –broad-spectrum agent • –extends spectrum of amoxicillin to cover

more gram negatives (E.coli, H. influenzae, Salmonella, Shigella) + gut anaerobes (B. fragilis)

• Not useful against: Pseudomonas

• “Like an oral pip/tazo (minus Pseudomonal coverage)”

Piperacillin-Tazobactam

• Piperacillin + ß-lactamase inhibitor • Most broad-spectrum penicillin; aerobic Gram positives

(including MSSA, E. faecalis), difficult aerobic Gram negatives (including Enterobacter, Klebsiella, Serratia, Pseudomonas, Acinetobacter), anaerobes (including B. fragilis)

• Useful against: Pseudomonas, harder to kill Gram negatives (traditional ß-lactamase producers), most aerobic Gram positives (including MSSA)

• NOT useful against: MRSA, E. faecium

Cloxacillin

• Very narrow spectrum; gram positive aerobes • drug of choice for MSSA • maintains coverage for Streptococci (less so

than penicillin/amoxicillin) • some oral anaerobic coverage (less so than

penicillin/amoxicillin)

• Not useful against: enterococci, N. meningitis

• Niche: methicillin-sensitive S. aureus

1st Generation Cephalosporins (cefazolin, cephalexin, cefadroxil)

• Narrow spectrum: • aerobic gram positives (MSSA, ß-hemolytic

Streptococcus) • Some aerobic gram negatives (PEcK: Proteus,

E.coli, Klebsiella) • oral anaerobes

• Useful for: MSSA, ß-hemolytic Streptococcus • Not useful for: Enterococci, gut anaerobes

2nd Generation Cephalosporins (cefuroxime, cefaclor, cefoxitin)

• “Middle of the road” coverage* • Covers everything that 1st generations cover*:

• Gram positives: MSSA, Streptoccocus (↓activity vs. 1st generation)

• Gram negatives: PEcK + H. influenzae & Moraxella • oral anaerobes, NOT gut anaerobes*

• *exception: cefoxitin – poor Gram positive coverage; covers B. fragilis (but resistance ~20%)

• Place in Therapy: oral stepdown for CAP

3rd Generation Cephalosporins (ceftriaxone, cefotaxime)

• Broad-spectrum • Gram positive coverage: MSSA (reasonable

coverage), Streptococcus (excellent coverage)

• Gram negatives: difficult to kill Gram negatives (Serratia, Enterobacter, Citrobacter), N.menigitidis, N.gonnorhea

• oral anaerobes

• NOT useful for: enterococcus, Pseudomonas, gut anaerboes

3rd Generation Cephalosporins (ceftazidime)

• Less broad-spectrum vs. ceftriaxone/cefotaxime • Gram positive coverage: poor • Gram negatives: difficult to kill Gram negatives

(Serratia, Enterobacter, Citrobacter), Pseudomonas

• NOT useful for: enterococcus, gut anaerobes

• Useful for: treatment of documented Pseudomonal infections, empiric Gram negative coverage where Pseudomonal coverage is desired

3rd Generation Cephalosporins (cefixime)

• Gram positive coverage: poor • Gram negatives: good; N. gonnorhea

• NOT useful for: enterococcus, gut anaerobes, Pseudomonas

• Useful for: treatment of N. gonnorhea (niche)

3rd Generation Cephalosporins (Cefdinir)

• Gram negative coverage: poor • Gram Positive: good; NO staph aureus

Coverage

4th Generation Cephalosporins (cefepime)

• broad-spectrum • Like ceftriaxone, but:

• – Gram positives: better activity vs. MSSA • – Gram negatives: Pseudomonas

• NOT useful for: enterococcus, gut anaerobes

• Useful for: treatment of documented Pseudomonal infections, empiric Gram negative coverage where Pseudomonal coverage is desired

CARBAPENEMS

• Ertapenem • Meropenem • Imipenem-cilastin • Doripenem

CARBAPENEMS

•“Tanks” of the ß-lactams • Extremely broad-spectrum:

• most aerobic Gram positives • most aerobic Gram negatives- including

ESBLs!!! • most anaerobes

• Drugs of choice for ESBLs

• Reserve for serious infections with resistant organisms! :) NOT CRE

CARBAPENEMS (Ertapenem)

• Least broad-spectrum carbapenem

• Useful for: aerobic gram negatives (including ESBLs), aerobic gram positives (MSSA, Streptococcus), anaerobes

• • Not useful for: enterococcus, Acinetobacter,

Pseudomonas (“Pseudomonal sparing”), MRSA • Doesn't Cross BBB

CARBAPENEMS (Meropenem, Imipenem, Doripenem)

• Most broad-spectrum of all the carbapenems

• like ertapenem, but also cover: • Pseudomonas aeruginosa • Enterococcus • Acinetobacter

• Generally all 3 agents considered clinically equivalent, but based on MIC data:

• E.faecalis (I > M = D) • Pseudomonas (D > M > I) • Acinetobacter ( I > M = D)

• Bottom line: basically cover everything, except for MRSA, VRE

Vancomycin • Bactericidal • Time-dependent killing • Inhibits cell wall formation

• Narrow spectrum - ONLY Gram positives: • Aerobes: Staphylococci (MRSA, MSSA, CNST), Enterococci

(E. faecalis & E. faecium) • Anaerobes: C. difficile, Propionibacterium spp.

• Useful for: gram positive infections (MRSA, E. faecium)

• Not useful for: any gram negative, VRE

Fluoroquinolones

• Members • Ciprofloxacin • Levofloxacin • Moxifloxacin • Gemifloxacin

• Antimicrobial Properties • bactericidal • concentration-dependent killing

• Mechanism of Action: • – inhibit DNA gyrase/Topoisomerase – inhibit DNA

replication

Gram Negative

Gram Positive

Fluoroquinolones (Ciprofloxacin)

• Relatively narrow spectrum • mostly aerobic gram negatives (including

Pseudomonas) • unreliable gram positive coverage • unreliable anaerobic coverage (gut & oral)

• Useful for: aerobic gram negatives (Pseudomonas if susceptible)

• Not useful for: gram positive or anaerobic infections

Fluoroquinolones (levofloxacin, moxifloxacin, Gemifloxacin)

• Respiratory fluoroquinolones (cover S. pneumoniae) • Broad-spectrum

• aerobic gram positives (excellent S. pneumoniae coverage, reasonable MSSA coverage)

• aerobic gram negatives • atypicals (Chlamydia, Mycoplasma, Legionella)

• Differences between agents: • Gram negatives: L > M (moxifloxacin has inferior Gram neg. coverage) • Pseudomonas: levofloxocin (note increasing resistance ~30%), NOT

moxifloxacin or Gemi • gut anaerobes: moxifloxacin (note: increasing resistance ~30%) NOT

levofloxacin or Gemi

• Useful for: aerobic gram positives/Gram negatives, atypicals (classic indication: CAP)

• Not useful for: MRSA, enterococcus

Metronidazole (Flagyl)

• Bactericidal with Concentration-dependent activity • Free radical formation ( DNA damage)

• Narrow spectrum: anaerobes only • Highly active against: gut anaerobes (B. fragilis,

Clostridium spp) • Variably active against: Peptostreptococcus (oral

anaerobe) • Inactive against: E. corrodens (human bite pathogen),

Actinomyces (oral anaerobe), Propionibacterium spp. • Other: Trichomonas spp., Giardia spp.

• Useful for: intra-abdominal anaerobic infections, C. difficile infections

Cotrimoxazole (Trimethoprim/Sulfamethoxazole)

• Bactericidal with Time-dependent activity Inhibits folate synthesis

• Broad-spectrum • variable activity against MRSA/ MSSA) & streptococci!

(check C&S before using) • most aerobic gram negatives, ESBLS, NOT Pseudomonas • others: Pneumocystis, Burkholderia cepacia (GNB),

Stenotrophomonas maltophilia (GNB), Nocardia (GPB)

• Niches: MRSA (check C&S), ESBLs, Pneumocystis, Burkholderia cepacia, Stenotrophomonas maltophilia, Nocardia

• If have a highly resistant organism, consider It!

Aminoglycosides

• Members • Tobramycin • Gentamicin • Amikacin

• Antimicrobial Properties • bactericidal • concentration-dependent killing

• Mechanism of Action: • inhibit protein synthesis

Aminoglycosides

• Narrow spectrum; aerobic gram negatives only (including ESBLs)

• Can be used for synergy with a ß-lactam against Gram positives (streptococci, enterococci)

• Differences between agents: • Klebsiella, Serratia: G > T > A • Pseudomonas: T > G >A • Amikacin has lowest resistance; but 4X higher MICs

• Useful for: aerobic gram negatives, ESBLs, Pseudomonas (Tobramycin)

• Not useful for: gram positives (except synergy with ß-lactams)

Clindamycin • Bacteriostatic • Time-dependent activity • Inhibit protein synthesis

• Narrow spectrum: Gram positives & anaerobes • Gram positive aerobes: Staphylococcus (MSSA, CA-MRSA

– note increasing resistance ~30%), Streptococcus (note increasing resistance)

• anaerobes: gut anaerobes (B. fragilis, Clostridium spp), oral anaerobes

• Useful for: MSSA/MRSA(check C&S), oral anaerobes • Not useful for: any aerobic gram negative, enterococcus • Caution: gut anaerobes, Staphylococcus

Macrolides

• Members • Erythromycin • Azithromycin • Clarithromycin

• Antimicrobial Properties • bacteriostatic • Time-dependent killing

• Mechanism of Action: • inhibit 50S ribosomal unit – inhibit protein

synthesis

Macrolides

• Relatively broad-spectrum • Gram positives: Streptococci (note increasing

resistance with S. pneumoniae ~20%) • some Gram negatives (A & C only): H.

influenzae, M. cattarhalis • atypicals • NO anaerobic coverage

• Niche: RTIs, Legionella • Not useful for: MRSA, enterococcus

Tetracyclines

• Members • Tetracycline • Doxycycline • Minocycline

• Antimicrobial Properties • bacteriostatic • time-dependent killing

• Mechanism of Action: • inhibit protein synthesis

Tetracyclines

• broad-spectrum • Aerobic Gram positives: Streptococci, Staphylococci

(including MRSA!), Listeria • Aerobic Gram negatives: easy to kill (E.coli, Klebsiella),

N. menigtidis, Brucella spp. • Atypicals • Others: P. acnes, Vibrio, Treponema pallidum, H.

pyelori, Plaspmodium spp. (malaria), Bartonella, spp., Rickettsiae

• Niches: MRSA, atypicals, Rickettsiae, Bartonella

• If have a highly resistant organism, consider a tetracycline!

Linezolid (Zyvox)

• Bacteriostatic • Time-dependent activity • Inhibition of protein synthesis

• Spectrum: narrow - aerobic Gram positives • Staphylococci (MSSA, MRSA, CNST) • Streptococci (penicillin-resistant) • Enterococci (E. faecalis, E. faecium, VRE)

• Useful for: resistant aerobic Gram positives • Not useful for: any gram negative, any anaerobe

Daptomycin• Bactericidal • Concentration-dependent • Disruption of the bacterial cell membrane

• Narrow spectrum – aerobic Gram positives • Staphylococci (MSSA, MRSA, CNST) • Streptococci (penicillin-resistant) • Enterococci (E. faecalis, E. faecium, VRE)

• Useful for: resistant aerobic Gram positives

• Not useful for: any gram negative, any anaerobe, Chest infection!

Tigecycline (Tygacil)

• Bactericidal Time- dependent activity Inhibit – inhibit protein synthesis

• “Special” member of the Tetracycline family

• VERY broad-spectrum: • aerobic Gram positives: MSSA/MRSA, Streptococci,

Enterococci (-faecalis, -faecium, VRE)

• most gram negatives, ESBLS, CREs (NOT 3Ps: Pseudomonas, Providencia, Proteus & Morganella)

• –anaerobes: mostly oral (poor activity vs. B. fragilis)

• Useful for: most aerobic Gram positives & negatives, including resistants (MRSA, VRE, ESBLs)

• Not useful for: Pseudomonas, Proteus, Morganella, Providencia, gut anaerobes

Polymixin E (Colistin)

• Bactericidal • Concentration-dependent • Disruption of the bacterial outer membrane

• Narrow spectrum: aerobic Gram negatives • Reliable activity against: ESBLs, CREs, Pseudomonas, Acinetobacter

• Less reliable against: Serratia spp, Proteus, spp, Providencia spp. B. Cepatia

• Useful for: highly resistant aerobic gram negative infections where there are no other options

• Not useful for: Gram positives

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Miscellaneous

Fosfomycin

• Act on Cell wall synthesis • Available as PO option

• Niche: indicated for the treatment of cystitis only (NOT pyelonephritis, abscess) caused by:

• E.coli (including ESBLs) • E. faecalis

Nitrofurantoin

• Relatively broad-spectrum: • aerobic gram negatives: E.coli, Klebsiella, ESBLs

• (NOT: Proteus, Serratia, Pseudomonas)

• aerobic Gram positives: Enterococci (-faecalis, -faecium, VRE)

• Niche drug: urinary tract (cystitis ONLY) – useful for ESBL cystitis

• Caution: insufficient serum levels to treat pyelonephritis (+/- bacteremia)

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Use for Cystitis &prophylaxis

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Take home Messages

• Antibiotics use is the single most important factor leading to antibiotic resistance.

• Up to 50% of all antibiotics prescribed are not needed.

• What to do? Promote appropriate antibiotics use (ASP).

Start Smart and then go with 6 Ds Bundle!