Antibiotic Review (80% of the knowledge, 80% of the time) Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, Uottawa Twitter: @RolandHalil Feb, 2015 print off mechanism of action wheel, flow chart beforehand Avoid overtreating wound swab cultures and [+]ur C&S (catheterized or NH pts or recurrent UTIs being retested despite being asxs) fosfomycin for recurrent UTI or other options used up or nosocomial UTIs

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 Map the Bugs Map the Drugs Map the Battlefield “Know your enemy” Map the Drugs “Save your ammo” Map the Battlefield

Part 1 - Map the (Clinically Important) Bugs “Know your enemy” Gram Negative Aerobic β-Lactamase Negative Cocci (spheres) Gram Positive Bacilli (rods) Anaerobic β-Lactamase Positive

Map the Bugs Aerobes Anaerobes 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 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

Anaerobes Above & 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’…

Map the Bugs Aerobes Anaerobes Above & Below diaphragm 9 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 Anaerobes Above & Below diaphragm B.Frag C.Diff 9 .

Map the Bugs Aerobes Anaerobes Below diaphragm 9 1 2 3 4 5 6 7 8 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 Anaerobes Below diaphragm B.Frag C.Diff 9 .

Gram[+] Bacilli Not usually pathogenic Major Exception: Listeria monocytogenes Listeriosis – enteritis, sepsis, meningitis +/- encephalitis

Map the Bugs Aerobes (Listeria) Anaerobes Below diaphragm 7 Gram Positive Gram Negative Cocci Bacilli Cocci Bacilli (Listeria) β-L[+] β-L[-] b-L[+] b-L[-] β-L[+] β-L[-] 1 2 3 4 5 6 Anaerobes Below diaphragm B.Frag C.Diff 7 .

Gm[-] Cocci Not usually pathogenic Major Exceptions: Neisseria gonorrhea Neisseria meningitidis and Moraxella catarrhalis (formerly thought to be a type of Neisseria)

Map the Bugs Aerobes Anaerobes Below diaphragm 5 1 2 3 4 Gram Positive Gram Negative Cocci Bacilli Cocci Bacilli (Listeria) (Neisseria & Moraxella) β-L[+] β-L[-] β-L[+] β-L[-] 1 2 3 4 Anaerobes Below diaphragm B.Frag C.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 http://www.cdc.gov/abcs/reports-findings/survreports/gbs10-suscept.html Beta hemolytic strep are all b-lactmase neg – all 100% pen sensitive – Group B, (obs) and now more prominent pathogens group C, group G, - oral and skin cellulitis pathogens

Map the Bugs Aerobes Anaerobes Below diaphragm 4 1 (G.A.S.) 2 3 Gram Positive Gram Negative Cocci Bacilli Cocci Bacilli (Listeria) (Neisseria & Moraxella) β-L[+] β-L[-] β-L[+] β-L[-] 1 (G.A.S.) 2 3 Anaerobes Below diaphragm B.Frag C.Diff 4 .

Gram Positive Gram Negative Map the Bugs Aerobes Gram Positive Gram Negative Cocci Bacilli β-L[+] both β-L[+]&[-] 1 2 Anaerobes Below diaphragm B.Frag C.Diff 3 .

Map the Clinically Important Bugs Aerobes Gram [+] Gram [-] Cocci Bacilli 1 2 Atypicals Legionella pneumonia Chlamydia pneumonia Mycoplasma pneumonia 3 . Anaerobes (esp. Gut organisms) Eg. C-Diff & B-frag 4 .

1 - Gram [+] Cocci Staphylococcus S. aureus S. epidermidis 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. pneumonia etc. 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 Bugs Summary Atypicals: Anaerobes: Gram positive aerobes: Mycoplasma pneumo Chlamydia pneumo Legionella pneumo Map the Bugs Summary Anaerobes: Oral Gut – Bfrag & Cdiff 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 Strep viridan – 10-20% resistant to clinda – fine with cefs

Map the Bugs - Summary Otitis media: S.pneumo, Hi,M Conjunctivitis: viral Sinusitis: viral AECOPD: S.pneumo, Hi,M Oral abscess: oral anaerobes C.A.P: S.pneumo, atypicals –CAP+comorb./risk factors, or NHAP: also HiM bugs Pharyngitis: viral (Group A Strep) Bronchitis: viral Skin abscess: anaerobes, staph, strep N.B. Boils = Staph Cellulitis: MSSA, GAS, GBS Pyelonephritis: PEcK H.pylori: Cdiff / Bfrag: UTI (Cystitis): PEcK Traveller’s Diarrhea: (80% bacterial): EcSS, (camphlyobacter)

Part 2 - Map the Drugs (Save your Ammo)

Map the Drugs Arms race! Older drugs tend to be simpler drugs 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” Fluoroquinolones Penicillins Tetracyclines Aminoglycosides Macrolides Vancomycin Carbapenems Cephalosporins Clindamycin Metronidazole

Antibiotics – Mechanisms of Action From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12

Beta-Lactams - Penicillins Amoxicillin / Ampicillin Cloxacillin / Methicillin (po) (iv) (clinic) (lab) Amox + Clavulanic acid Anti-Staph Anti-Strep

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) Increasing Gram[-] coverage Cefadroxil (po) 500mg BID or 1g BID – good alternative to KEFLEX 250mg QID or 500mg QID - Same spectrum of activity, better serum and tissue levels, only QD-BID, cheap and covered by ODB too. - Ceftaz, cefixime weak on MSSA – others are ok in general

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.

Antibiotics – Mechanisms of Action From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12

Fluoroquinolones 2nd generation 3rd generation 4th 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” Levofloxacin Moxifloxacin Concentrate in alveolar macrophages Greater than serum concn Levofloxacin the more active L-enantiomer of Ofloxacin Renal clearance Moxifloxacin Hepatic clearance Enhanced coverage of: Strep pneumo Oral Anaerobes 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

Antibiotics – Mechanisms of Action From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12

Macrolides Coverage of: Clarithromycin Azithromycin Erythromycin 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)

Antibiotics – Mechanisms of Action From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12

Aminoglycosides Gentamicin Tobramycin Amikacin Reserved for Pseudomonas aeruginosa 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

Pharmacodynamics Relationship 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] Peak Log [Conc] MIC MIC Time (h) Time (h)

Pharmacodynamics Relationship 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 Peak Peak Log [Conc] Log [Conc] MIC MIC Time (h) Time (h)

Pharmacodymamics Bactericidal 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 Drugs Pharmacology 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

For: skin, dental infx (staph, strep, & anaerobes) Map the Drugs – Summary For: TB, MRSA For: skin, dental infx (staph, strep, & anaerobes) Clinda resistance higher in all groups of staph and strep all >10%, some >20-25% (MSSA 25% MRSA 50% resistance) plus some oral anaerobes From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12

Part 3 – Map the Battlefield

Map the Battlefield Rational Prescribing Individual Efficacy Could be reduced, BUT: Empiric tx still effective if it is well chosen (Lower risk infections, properly dosed, clinically stable, true indication etc.) Toxicity Reduced with narrow spectrum tx Cost Reduced with older tx Convenience Usually less convenient Population Efficacy Maintained long term with lower resistance rates Toxicity Reduced since lifespan of older drugs is maintained Cost Reduced insurance costs, economic losses, hospital costs dealing with superbugs Convenience VS.

Map the Battlefield

Map the Bugs - Summary Otitis media: S.pneumo, Hi,M Conjunctivitis: viral Sinusitis: viral AECOPD: S.pneumo, Hi,M Oral abscess: oral anaerobes C.A.P: S.pneumo, atypicals –CAP+comorb./risk factors, or NHAP: also HiM bugs Pharyngitis: viral (Group A Strep) Bronchitis: viral Skin abscess: anaerobes, staph, strep (GAS, GBS) N.B. boils = staph Cellulitis: MSSA, GAS, GBS Pyelonephritis: PEcK H.pylori: Cdiff / Bfrag: UTI (Cystitis): PEcK Traveller’s Diarrhea: (80% bacterial): EcSS, (campylobacter)

Map the Battlefield Otitis media: S.pneumo, Hi,M (Amox +/- Clav, Cef2, Septra) Conjunctivitis: viral – no tx Sinusitis: viral – no tx AECOPD: S.pneumo, Hi,M (Amox +/- Clav, Cef2, Septra) Oral anaerobes: abscess drainage +/- tx (Amox 2g – pre dental sx?) 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)) Pharyngitis: viral – no tx (Group A Strep – Pen VK) Bronchitis: viral – no tx Skin abscess: drainage +/- tx Cellulitis: MSSA, GAS, GBS - (Clox, Cef1, & Clinda (more resistant) H.pylori: triple po tx PPI + (Clarithro +/- Amox +/- Metro) Pyelonephritis: PEcK – (Septra, Amox-Clav, FQ (not Norflox) Cdiff / Bfrag: Metro / po Vanco UTI (Cystitis): PEcK – (Septra, Macrobid, Amox+/-Clav, Norflox) Traveller’s Diarrhea: (80% bacterial): EcSS, (campylobacter) - Septra, FQ, (Azithro)

(Group A Strep, oral anaerobes, Neisseria) 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 MSSA and Strep & PEcKSS (same as Amox) N.B. never Enterococcus! 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) To boost: for PEcKSS-HiM (same as Amox/Clav) Increasing Gram[-] coverage SPACE bugs: The Big Guns Cefadroxil (po) 500mg BID or 1g BID – good alternative to KEFLEX 250mg QID or 500mg QID - Same spectrum of activity, only BID, cheap and covered by ODB too. serratia, enterobacter and citrobacter – have inducible beta-lactamase genes – avoid Cephalosporins in general

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: ________ ? Explore allergy type – sensitivity vs allergy Type 3 delayed hypersensitivity reactions – up to 21 days after exposure Options: Amox +/- Clav, Cefuroxime, Septra to cover Strep pneumo, HiM bugs

Allergy status Severe diarrhea, pain Rash at age of 5 y.o. Rash 2 weeks post Rx involved hives (raised, intensely itchy spots that come and go over hours), with wheezing & swelling of the skin & throat Major rash 3 yrs ago flat, blotchy, spread over days but did not change by the hour Anaphylaxis . http://www.uptodate.com/contents/allergy-to-penicillin-and-related-antibiotics-beyond-the-basics GI upset = side effect, not allergy Rash - hypersensitivity not true allergy (IgE mediated) “Only about 20 percent of people will be allergic to penicillin 10 years after their initial allergic reaction if they are not exposed to it again during this time period” 10% report allergy to penicillin (~90% not true allergy) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3255391/ estimated frequency of anaphylaxis at 1-5 per 10 000 cases of penicillin therapy. the major determinant in the immunological reaction is the similarity between the side chain of first generation cephalosporins and penicillins, rather than the ß-lactam structure that they share. This means that the risk of an allergic reaction to cephalosporins in those with an established IgE-mediated allergy to penicillin may be low or non-existent, - avoid Cef1; ok with Cef2, Cef3, Cef4