Antibiotic Review (80% of the knowledge, 80% of the time) Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant.

Antibiotic Review(80% of the knowledge, 80% of the time)

Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmDPharmacist, Bruyere Academic FHT

Assistant Professor, Dept Family Medicine, UottawaTwitter: @RolandHalil

Feb, 2015

Objectives

• Review clinically relevant pathogens in human disease in an ambulatory care setting

• Review antibiotic classes and spectra of activity– Focus on bread and butter examples of each

• Review treatment recommendations for common infections in primary care

Process

1. Map the Bugs– “Know your enemy”

2. Map the Drugs– “Save your ammo”

3. Map the Battlefield

Part 1 - Map the (Clinically Important) Bugs“Know your enemy”

Aerobic

β-Lactamase Negative

β-Lactamase Positive

Bacilli (rods)

Cocci (spheres)

Gram Negative

Gram Positive

Anaerobic

Aerobes Anaerobes

Gram Positive Gram Negative Gram Positive Gram Negative

Cocci Bacilli Cocci Bacilli Cocci Bacilli Cocci Bacilli

b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Map the Bugs

AnaerobesAbove & below the diaphragm

Oral•Simple organisms•Easily handled by penicillins (beta-lactams)– Eg. Actinomyces

Bifidobacterium Fusobacterium Lactobacillus Peptococcus Peptostreptococcus Propionibacterium

etc

Gut•Approx the same, except:

•Human pathogens:• Bacteroides fragilis

(B.frag)• Clostridium difficile

(C.diff)

–More virulent bugs requiring ‘bigger guns’…

Aerobes

Gram Positive Gram Negative

Cocci Bacilli Cocci Bacilli

b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-]

1 2 3 4 5 6 7 8

Map the Bugs

Anaerobes

Above & Belowdiaphragm

B.Frag C.Diff

9.

Aerobes



b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-]

1 2 3 4 5 6 7 8

Map the Bugs

Anaerobes

Belowdiaphragm

B.FragC.Diff

9.

Gram[+] Bacilli

• Not usually pathogenic– Major Exception: Listeria monocytogenes• Listeriosis – enteritis, sepsis, meningitis +/- encephalitis

Aerobes



(Listeria)

β-L[+] β-L[-] b-L[+] b-L[-] β-L[+] β-L[-]

1 2 3 4 5 6

Map the Bugs

Anaerobes

Belowdiaphragm

B.FragC.Diff

7.

Gm[-] Cocci

• Not usually pathogenic– Major Exceptions: • Neisseria gonorrhea• Neisseria meningitidis and• Moraxella catarrhalis

– (formerly thought to be a type of Neisseria)

Aerobes


Cocci Bacilli Cocci Bacilli (Listeria) (Neisseria &

Moraxella)

β-L[+] β-L[-] β-L[+] β-L[-]

1 2 3 4

Map the Bugs

Anaerobes

Belowdiaphragm

B.FragC.Diff

5.

β-Lactamase Enzymes• First penicillinase described in 1940’s even

before penicillin was clinically available. • Most bugs produce some type of β-lactamase

enzyme that destroys β-lactam antibiotics (pen’s, ceph’s, carbapenems)

– Gm[+] cocci & β-lactamase [-]: Group A & B streps

give Penicillin

Aerobes


Cocci Bacilli Cocci Bacilli (Listeria) (Neisseria &

Moraxella)

β-L[+] β-L[-] β-L[+] β-L[-]

1 (G.A.S.) 2 3

Map the Bugs

Anaerobes

Belowdiaphragm

B.FragC.Diff

4.

Aerobes


Cocci Bacilli

β-L[+] both β-L[+]&[-]

1 2

Map the Bugs

Anaerobes

Belowdiaphragm

B.FragC.Diff

3.

Aerobes

Gram [+] Gram [-]

Cocci Bacilli

1 2

Map the Clinically Important Bugs

Anaerobes

(esp. Gut organisms)

Eg. C-Diff& B-frag

4.

Atypicals

1.Legionella pneumonia2.Chlamydia pneumonia3.Mycoplasma pneumonia

3.

1 - Gram [+] Cocci

Staphylococcus

•S. aureus– Methicillin resistant (MRSA)

– Methicillin sensitive (MSSA)

•S. epidermidis– Methicillin resistant (MRSE)

– Methicillin sensitive (MSSE)

– Skin commensal – Rarely pathogenic

Streptococcus•Group A (pyogenes) (β-Lact[-])

•Group B (agalactiae) (β-Lact[-])• Neonates, v. elderly, obstetrics

•S. pneumoniaetc. etc.

Enterococcus•(Formerly thought to be ‘Strep D’)

•E. faecalis•E. faecium

• A “mean” hospital organism

2 - Gram [-] Bacilli

“Easy” to Kill•Proteus mirabilis•Escherichia coli•Klebsiella pneumonia•Salmonella•Shigella•Haemophilus influenza– (Moraxella catarrhalis)

(actually a Gm[-] coccus)

PEcKSS-HiM

“Hard” to Kill•Serratia•Pseudomonas•Acinetobacter•Citrobacter•Enterobacter

SPACE bugs

2.5 - Gram [-] Bacilli“Easy” to Kill

•Proteus mirabilis•Escherichia coli•Klebsiella pneumonia•Salmonella•Shigella

PEcKSS bugs

“Hard” to Kill•Serratia•Pseudomonas•Acinetobacter•Citrobacter•Enterobacter

SPACE bugs

?“Moderate” To Kill• Haemophilus influenza–(Moraxella catarrhalis) (actually a Gm[-] coccus)

HiM bugs

Gram Negative vs Gram Positive Gm[-]: red on stain. (ie. Don’t retain stain) Gm[+]: blue-purple on stain;

Gm[-]: must pass through pores Gm[+]: molecules < 100kDa pass easily.

Gm[-]: b-lactamases concentrated in periplasmic space Gm[+]: b-lactamases diffuse outside cell;

Map the BugsSummary

• Gram positive aerobes:– Cocci

• Staph– Aureus

» MRSA (~8-10%)» MSSA

– Epiderimidis» MRSE (~65%)» MSSE

• Strep– Group A strep (pyogenes) – Group B strep (agalactiae) – Strep Viridans – Strep pneumo etc.

• Enterococcus– Faecalis– Faecium

– Bacilli• Listeria

• Gram negative aerobes:– Bacilli

• Easy to Kill– PEcKSS (Proteus, Ecoli,

Klebsiella, Salmonella, Shigella)– HiM (H.flu and Moraxella

(actually a Gm[-]coccus))

• Hard to Kill– SPACE bugs (Serratia,

Pseudomonas, Acinetobacter, Citrobacter, Enterobacter)

– Cocci• Neisseria

– gonorrhaea– meningitidis

• Moraxella catarhallis

Anaerobes:•Oral•Gut – Bfrag & Cdiff

Atypicals:•Mycoplasma pneumo•Chlamydia pneumo•Legionella pneumo

Map the Bugs - SummaryConjunctivitis: viral

Sinusitis: viral

Oral abscess: oral anaerobes

Pharyngitis: viral(Group A Strep)

Bronchitis: viral

Skin abscess: anaerobes, staph, strepN.B. Boils = Staph

H.pylori:Cdiff / Bfrag:

Otitis media: S.pneumo, Hi,M

AECOPD: S.pneumo, Hi,M

C.A.P: S.pneumo, atypicals –CAP+comorb./risk factors, or NHAP: also HiM bugs

Cellulitis: MSSA, GAS, GBS

UTI (Cystitis): PEcK

Pyelonephritis: PEcK

Traveller’s Diarrhea: (80% bacterial): EcSS, (camphlyobacter)

Part 2 - Map the Drugs(Save your Ammo)

Map the Drugs

• Arms race!– Remember: “Bigger guns

breed higher walls”

• Older drugs tend to be simpler drugs– More narrow spectrum– Broad spectrum drugs

breed resistance– Superbugs develop

• MRSA, VRE, ESBL, etc

• Older drugs have more safety data– Tend to be less toxic– Learn their history– Learn their

pharmacology

Part 2 - Map the Drugs“Save your Ammo”

Penicillins

Tetracyclines

Clindamycin

Vancomycin

Aminoglycosides

Fluoroquinolones

Macrolides

Cephalosporins

Metronidazole

Carbapenems

Antibiotics – Mechanisms of Action

From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12

Beta-Lactams - Penicillins

Penicillin

Amoxicillin / Ampicillin Cloxacillin / Methicillin(po) (iv) (clinic) (lab)

Amox + Clavulanic acid

Anti-Strep Anti-Staph

Beta-Lactams - Cephalosporins• 1st Generation– Cephalexin (Keflex™)(or Cefadroxil) (po)– Cefazolin (Ancef™) (iv)

• 2nd Generation– Cefuroxime (po & iv)

• 3rd Generation– Ceftriaxone, Cefotaxime, Ceftazidime (iv)– Cefixime (Suprax™) (po)

• 4th Generation– Cefepime (iv) In

crea

sing

Gra

m[-]

cov

erag

e

Beta-Lactams – Other (FYI)(IV only, inpatient use only)

• Piperacillin (plus tazobactam)– big gun, tazo = suicide substrate, like clavulanic acid

• Carbapenems– Meropenem – Imipenem– Ertapenem

• Monobactams– Aztreonam

Broad spectrum, big gun antibiotics that cover Gm[+], both easy and hard to kill Gm[-] bugs, even some anaerobes.



Fluoroquinolones• 2nd generation

– Ofloxacin– Ciprofloxacin– Norfloxacin

• 3rd generation– Levofloxacin

• 4th generation– Moxifloxacin

• Covers: Gm[-]’s– PEcKSS-HiM & SPACE bugs– 3rd and 4th gen. FQs cover

strep pneumo. well too

• Ofloxacin • Ciprofloxacin – Anti-pseudomonal – the

only PO option! – Norfloxacin

• Same spectrum as Cipro (even anti-Pseudomonal) – but only for cystitis UTI.

• Concentrates in the G.U. system only

• N.B. Not good enough for pyelonephritis or systemic infection

Fluoroquinolones• The “Respiratory FQs”– Concentrate in alveolar

macrophages – Greater than serum concn

1. Levofloxacin– the more active L-

enantiomer of Ofloxacin– Renal clearance

2. Moxifloxacin– Hepatic clearance

• Enhanced coverage of:1. Strep pneumo2. Oral Anaerobes3. Atypicals– N.B. only Moxi cover

B.frag– Neither covers C.diff

• (Both will cover Clostrium non-difficile strains)

• Both have 100% oral bioavailability– Therefore PO = IV dose



Macrolides• Coverage of:– Atypicals, Strep pneumo, &

Hi.M. (Hflu & Mcat)• So, good for respiratory

infections!

– N.B. But doesn’t cover PEcKSS or SPACE bugs

• Erythromycin– Efficacy: Poorer coverage of

H.flu, MSSA– Toxicity:

• Prokinetic = diarrhea!• Worse for QTc prolongation

– Convenience: QID dosing

• Clarithromycin– Better Hflu &MSSA coverage– Less QTc prolongation vs E– Shorter half-life vs Azithro

• BID dosing x 7-10days

• New daily ‘XL’ formulation

• Azithromycin– An azalide, (not a macrolide)

• Same spectrum of activity• Less QTc prolongation vs E & C!

– Long t1/2 – QD dosing x 5d• BUT can breed resistant

S.pneumo (since below [MIC] for long periods of time)



Aminoglycosides

1. Gentamicin2. Tobramycin– Reserved for Pseudomonas

aeruginosa

3. Amikacin

• All excellent Gram[-] coverage: – PEcKSS-HiM and SPACE

bugs

• Efficacy: excellent Gm[-]• Toxicity:– Nephrotoxicity– Ototoxicity– Less now with daily dosing

• Cost:– Cheap, old meds

• Convenience– Now Once daily IV/IM

PharmacodynamicsRelationship between Abx Concentration & Effect

Concentration Dependent Killing

• Higher the peak, better the kill

• i.e. Ratio of peak drug concentration and M.I.C. determines rate of kill.

• Eg. FQs, AGs

Time Dependent Killing• Time over MIC matters• i.e. Independent of peak

concentration. Determined by length of time over MIC

• Eg. B-lactams (Pen, Ceph etc)

Log [Conc]

Time (h)

Peak

MIC

Log [Conc]

Time (h)

MIC

PharmacodynamicsRelationship between Abx Concentration & Effect

Concentration Dependent Killing

• Higher the peak, better the kill

• i.e. Ratio of peak drug concentration and M.I.C. determines rate of kill.

• Eg. FQs, AGs

• With renal impairment:– Maintain the peak,

lengthen the interval– This ensures good rate of

killing while allowing enough time to eliminate the drug and avoid toxicities

– For eg: • If CrCL = 90mL/min -

Levofloxacin 750mg q24h po • If CrCL = 30mL/min –

Levofloxacin 750mg q48h po

Log [Conc]

Time (h)

Peak

MIC

Log [Conc]

Time (h)

Peak

MIC

PharmacodymamicsBactericidal vs Bacteriostatic

• Bactericidal Abx– B-lactams (Pen, Ceph)– Aminoglycosides (AGs)– Fluoroquinolones (FQs)– Rifampin– Metronidazole– Vancomycin

• Bacteriostatic Abx– Tetracyclines– Macrolides– Clindamycin– Chloramphenicol

Rarely a clinically important characteristic, unless the patient is immunocompromised or the risk of death with

delayed/incorrect therapy is high.

Combination Therapy

• Why?– Broaden spectrum • (eg. Mixed infection)

– Synergistic activity for hard to kill bugs • (eg. Enterococcus or pseudomonas)

– Prevent resistance• (eg. TB)

– Reduce dose and side effects

Map the DrugsPharmacology Summary

• Many antibiotic classes– Beta-lactams generally safest agents.• Even at high doses

– Some have overlapping mechanisms of action– Avoid combining similar mechanisms of action • Competing effects may reduce effectiveness of one agent• Eg. Penicillins + vancomycin – cell wall synthesis inhibitors• Eg. Tetracyclines + aminoglycosides –protein synthesis

inhibitors via 30-S subunit of the ribosome

Map the Drugs – Summary


For: TB, MRSA

For: skin, dental

infx (staph, strep, &

anaerobes)

Part 3 – Map the Battlefield

Map the BattlefieldRational Prescribing

Individual1.Efficacy

– Could be reduced, BUT:– Empiric tx still effective if

it is well chosen • (Lower risk infections,

properly dosed, clinically stable, true indication etc.)

2.Toxicity– Reduced with narrow

spectrum tx

3.Cost– Reduced with older tx

4.Convenience– Usually less convenient

Population1.Efficacy

– Maintained long term with lower resistance rates

2.Toxicity– Reduced since lifespan of

older drugs is maintained

3.Cost– Reduced insurance costs,

economic losses, hospital costs dealing with superbugs

4.Convenience

VS.

Map the Battlefield

Map the Bugs - SummaryConjunctivitis: viral

Sinusitis: viral

Oral abscess: oral anaerobes

Pharyngitis: viral(Group A Strep)

Bronchitis: viral

Skin abscess: anaerobes, staph, strep (GAS, GBS)N.B. boils = staph

H.pylori:Cdiff / Bfrag:

Otitis media: S.pneumo, Hi,M

AECOPD: S.pneumo, Hi,M

C.A.P: S.pneumo, atypicals –CAP+comorb./risk factors, or NHAP: also HiM bugs

Cellulitis: MSSA, GAS, GBS

UTI (Cystitis): PEcK

Pyelonephritis: PEcK

Traveller’s Diarrhea: (80% bacterial): EcSS, (campylobacter)

Map the BattlefieldConjunctivitis: viral – no tx

Sinusitis: viral – no tx

Oral anaerobes: abscess drainage +/- tx (Amox 2g – pre dental sx?)

Pharyngitis: viral – no tx (Group A Strep – Pen VK)

Bronchitis: viral – no tx

Skin abscess: drainage +/- tx

H.pylori: triple po tx PPI + (Clarithro +/- Amox +/- Metro)

Cdiff / Bfrag: Metro / po Vanco

Otitis media: S.pneumo, Hi,M (Amox +/- Clav, Cef2, Septra)

AECOPD: S.pneumo, Hi,M (Amox +/- Clav, Cef2, Septra)

C.A.P: S.pneumo, atypicals – (Amox, Macrolides (Clarithro/Azithro))CAP+comorb./risk factors, or NHAP: also HiM bugs (Combine AmoxClav or Cef2 + Macrolide (or use FQ))

Cellulitis: MSSA, GAS, GBS - (Clox, Cef1, & Clinda (more resistant)

UTI (Cystitis): PEcK – (Septra, Macrobid, Amox+/-Clav, Norflox)

Pyelonephritis: PEcK – (Septra, Amox-Clav, FQ (not Norflox)

Traveller’s Diarrhea: (80% bacterial): EcSS, (campylobacter) - Septra, FQ, (Azithro)

Map the Battlefield

Penicillin(Group A Strep, oral anaerobes, Neisseria)

Amoxicillin / Ampicillin Cloxacillin(Strep & Enterococcus plus (Staph aureus, Staph epi)Easy-to-Kill Gm[-](ie. PEcKSS))

Amox/Clav (Vancomycin)(for Strep & Entero & PEcKSS-HiM) (for MRSA / MRSE)(H.flu & Moraxella can be ~35% amox resistant) (~8-10% / ~ 65% resistant)

Beta-Lactams - Cephalosporins

• 1st Generation– Cephalexin (Keflex™) or Cefadroxil (po)– Cefazolin (Ancef™) (iv)

• 2nd Generation– Cefuroxime (po & iv)

• 3rd Generation– Ceftriaxone, Cefotaxime, Ceftazidime (iv)– Cefixime (Suprax™) (po)

• 4th Generation– Cefipime (iv)

Incr

easi

ng G

ram

[-] c

over

age

MSSA and Strep & PEcKSS (same as Amox)

N.B. never Enterococcus!

To boost: for PEcKSS-HiM(same as Amox/Clav)

SPACE bugs: The Big Guns

SPACE bugs

• The Big Guns:– 3rd and 4th generation Cephalosporins– Carbapenems (Meropenem)– Piperacillin/Tazobactam– Aminoglycosides (Gentamicin, Tobramicin)– Fluoroquinolones (Levofloxacin, Moxi, Cipro)

Reserved for Pseudomonas

• Ciprofloxacin (FQ)– The only PO agent! – (Use Norfloxacin for UTI if a FQ is needed)

• Ceftazidime (Cef3)• Cefipime (Cef4)• Tobramycin (AG)• Piperacillin/Tazobactam• Meropenem

Need for Bigger guns

• There is a higher risk of Gram negative SPACE bugs with:

– More risk factors / comorbidities– COPD, HIV, Diabetes, CKD etc

– More institutionalized settings• Community Retirement Home Nursing Home

Hospital ward ICU ventilated pt in ICU.

Map the Battlefield• PEN – for b-lact[-] Gm[+] cocci (GAS, GBS), oral anaerobes, Neisseria (meningitidis)• ?What to do for Strep pneumo /Enterococcus?

– Amox po / Amp iv (also good for PEcKSS)– How to boost? Amox/Clav (for HiM-PEcKSS)

• ?What to do for Staph?– Clox (MSSA, MSSE); Else Vanco (MRSA, MRSE)

• What about Cef1? (cephalexin / cefadroxil po or cefazolin iv)– Maps to Amox/Amp for PEcKSS and strep

• N.B. NOT Enterococcus (Cef’s never cover enterococcus!)

– How to boost? Cef2 (cefuroxime) for HiM-PEcKSS

• What about SPACE bugs?– FQs, AGs, Cef3, Cef4, Pip/Tazo, Meropenem)– Reserved for Ps aureginosa:(cipro, tobra, ceftazidime, cefipime, pip/tazo, meropenem)

• What about gut anaerobes? (Metro/PO Vanco)• What about atypicals? (Macrolides, Tetracyclines (doxy))• Where does Septra fit? (analogous with Amox/Clav and Cef2)

Summary

• This is far from an exhaustive review• Some parts have been highly simplified for use

in clinical practice• Some memorization is needed with regular

review of the material to retain this knowledge

• Doing so will allow you to choose empiric antibiotics with greater comfort in difficult situations and unfamiliar settings.

Case 1

• Mr. PT• 68 y.o. smoker with AE-COPD

– Vitals stable; ambulatory; fever, productive cough, phlegm is green – PMHx: HTN, COPD– Allergies: penicillin– Meds: Tiotropium 18mcg qd, Ramipril 10mg qd

– Expected pathogens?– Rx options? – Management of allergy status?

• Rx: ________ ?

Allergy status1. Severe diarrhea, pain2. Rash at age of 5 y.o.3. Rash 2 weeks post Rx

– involved hives (raised, intensely itchy spots that come and go over hours), with wheezing & swelling of the skin & throat

4. Major rash 3 yrs ago– flat, blotchy, spread over days but did not

change by the hour

5. Anaphylaxis

1. .2. .3. .

1. .

2. .

BL+ Aerobic GPCAerobic GNB

95% of Staph. species are BL +ve

Penicillin:BL-ve aerobic GPC

oral anaerobesN.meningitidis

Isoxazoyl PCNs:eg. Cloxacillin, Nafcillin

Gut anaerobes(B. fragilis)

Ampicillin/Amoxicillin:HiPEELSS

Easy to Kill GNB

Lacking Activity Vs.

TMP/SMX

Atypical Organisms

MSSA/MSSE

Macrolides:ErythromycinClarithromycinAzithromycin

TMP/SMXTetracyclines

Respiratory FluoroquinolonesGatifloxacinLevofloxacinMoxifloxacin

MRSA(7%)/ MRSE (>65%)

VancomycinRifampin

Fusidic AcidLinezolidSynercid

Amoxicillin/Clavulanic acidAmpicillin/Sulbactam

Second Generation Cephs

1st Generation Cephs:(Cefazolin iv / Cephalexin po)

PEcKSS

H. influenzaeB. fragilis

CefotetanCefoxitin

Metronidazole

Clindamycin

3rd Generation Cephs.

CeftriaxoneCefotaxime

Ceftazidime

4th Generation Cephs:Cefepime

Piperacillin:(P.aeruginosa, Enterobacter)

Never Use Alone!

Piperacillin/TazobactamTicarcillin/Clavulanic Acid

Carbapenems:Imipenem

Meropenem

AMGs:GentamicinTobramycin

Amikacin

CefuroximeCefuroxime axetil

Cefaclor

No Cephalosporin covers:MRSA / MRSE

enterococcus sp.Listeria monocytogenes

Difficult to Kill GNB

FQs:ciprofloxacinofloxacinnorfloxacin

Adapted from: Winslade N. On Continuing Practice 1990-1, volumes 17-18.Prepared By:Sandra A.N. Tailor, Pharm.D.Clinical Coordinator - Infectious DiseasesSunnybrook Health Science CentreDepartment of Pharmacy11/11/02

Antibiotic Review (80% of the knowledge, 80% of the time) Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant.

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