Rho Chi's Clinical Pearls of Viro

Laliberte, B., Chung, J., Hwang, A., Luo, X., Duong, J., Tito, A.

Tips for Success

Go to class! Listen to lecture Make study guides Read cases Quiz each other Go to review sessions Ask for help Follow bolded information; DIs; ADRs IDSA guidelines Review! Easy points: brand/generic/generation Remember case specific allergies!!

Bacteria

G+ aerobes: staph, strep, enterococci G- aerobes: Enterobacter, Pseudomonas, Haemophilus, Moraxella Anaerobes
o o

Mouth: pepto Gut: bacteroides, C. dif.

Atypical: mycoplasma, chlamydia, legionella Gram Stain

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o

Positive - purple Negative - pink

Class Clinical Pearls

Clinical Pearls for Penicillins

MOA: bind to PCN binding proteins needed to form cell wall ADR: n/v, diarrhea, allergic reaction Curve Chart Time-dependent Don't admin w/ aminoglycosides in same IV line Classes o Natural Penicillins o Penicillinase resistant o Aminopenicillins o Extended-Spectrum o B-lactamase inhibitors

Clinical Pearls for Natural PCNs

Penicillin G (IV/IM) o Aqueous crystalline: Acute severe infection b/c high peak o Benzathine PCN G: not for severe or acute infection Penicillin V (po) o ~6 hour action, small peak G+ strep, mouth anaerobes W/o food Watch Na/K b/c renal/heart Requires dose adjustment in renal disease Resistance: B-lactamase Allergic rxn

Clinical Pearls for PenicillinaseResistant PCNs

Nafcillin/Oxacillin IV Dicloxacillin/Cloxacillin PO aka 'anti-staph' PCN staph, strep, no anaerobes, no MRSA hepatic metabolism warfarin and nifedipine interaction with nafcillin

Clinical Pearls for Aminopenicillins

Ampicillin (IV/po): no food Amoxicillin (po): with food staph, strep, enterococci, limited G- (PCN + G-) o used primarily for respiratory tract infections dose adjustment renal disease allergy, diarrhea DIs w/ contraceptives, methotrexate, warfarin, venlafaxine

Clinical Pearls for ExtendedSpectrum PCNs

aka 'anti-pseudomonal' PCN Carboxypenicillin: Ticarcillin (disodium salt) Ureidopenicillin: Piperacillin Aminopenicillins + pseudo o Pseudo: Piperacillin > Ticarcillin synergy w/ aminoglycoside watch Na/K, renal, cardiac Use: more severe broad G- infection/ pseudomonas Do NOT co-administer with AG in same IV line AE: Thrombophlebitis

Clinical Pearls for B-lactamase inhibitors

Prevent B-lactamase degradation Augmentin (amoxicillin+clavulanic acid) Timentin (ticarcillin +clavulanic acid) Unasyn (ampicillin+sulbactam) Zosyn (piperacillin+tazobactam) Increased efficacy NOTE: B-lactamase inhibitors have NO abx activity

Clinical Pearls for Monobactams

Aztreonam IV G-, pseudomonas no nephrotoxicity no PCN cross-reactivity

Clinical Pearls for Carbapenems

Staph, strep, G-, pseudo, anaerobes, ESBL 11-50% cross-reactivity with PCN IV ADR: mental status changes, seizures Imipenem-cilastatin: broadest spectrum, highest seizure risk o Cilastatin is not an antibiotic, it prevents hydrolysis of imipenem to improve efficacy Meropenem: wider TI, low seizure incidence, meningitis treatment Ertapenem: q daily (longest t 1/2), no pseudo Doripenem: no neurotoxicity

Clinical Pearls for Cephalosporins

MOA: Inhibit cell wall synthesis by binding to proteins needed to make structure Generations have increasing G- activity o 1: SPEcK; <7.5% PCN cross-sensitivity o 2: HNM-SPEcK Cephamycins-Cefoxitin/Cefotetan (SPEcK + anaerobes) o 3: G- activity; Ceftaz-pseudo coverage; Ceftriaxone interacts with Ca2+ fluids (48 hr spacing) o 4: Cefepime: broad spectrum + pseudo o Ceftaroline: MRSA coverage Give with food ADR: n/v, diarrhea, LFTS (w/ ceftriaxone) Renal excretion except: cefazolin, ceftriaxone, cefixime IV v. po

Clinical Pearls for Cephalosporins

Cephalosporins
o 1st- Cefa/Cepha (G+) o 2nd- 9 letter Cefo + Cefaclor + Cefuroxime + Cefprozil o 3rd- Cefo/Cefd/Ceft + Cefixime+ Cefpodoxime o 4th- Cefepime (G+/-, pseudo) o 5th- Ceftaroline (broad, MRSA)

Clinical Pearls for Aminoglycosides

MOA: binds 30S, create membrane holes/fissures IV/IM Gentamicin, Tobramycin, Amikacin, Streptomycin G- including pseudo! Gent has staph/strep ADR: nephrotoxicity (reversible), ototoxicity (not), neuromuscular blockade (rare) Synergy w/ penicillinase-resistant, cefaz, vanco, ampic Renal adjustment Once daily Dosing --> concentration v. time-dependent Post antibiotic effect

Aminoglycosides continued

Dosing o loading: based on BODY WT (standard dose of 2mg/kg) o maintenance: depends on severity and renal function levels and monitoring o trough: 30 min before 4th dose @ steady state o peak: 30 min after 30 min infusion Trough goals o Gent/Tobramycin: <2mcg/ml o Amikacin: <10mcg/ml o high troughs indicate nephrotoxicity --> change interval

Clinical Pearls for Vancomycin

KNOW EVERYTHING ABOUT MOA: physically blocks cross-linking in G+ cell wall G+ coverage ONLY including MRSA and enterococci IV; C. diff. PO Renal adjustment if CrCl<45 ADR: Red man syndrome, ototoxicity, nephrotoxicity, neutropenia, hypersensitivity reaction Dosing nomogram Monitoring not necessary if normal renal function o Trough for efficacy: dialysis, obesity, renal dysfunction, nephrotoxic taken 30 min before 4th dose, if needed o Red man syndrome is infusion rate based

Clinical Pearls for Televancin & Dalbavancin

Lipoglycopeptides Improved vanco: does everything vanco does IV

Clinical Pearls for Linezolid

Zyvox MOA: inhibits formation of complex w/ tRNA for methionine codon w/ 50 S o BACTERIOSTATIC Broadest G+: MRSA, VRSA/VISA, VRE, strep, entero IV; 100% oral bioavailability Hepatic elimination= no renal dosing ADR: n/v, diarrhea, headache reversible thrombocytopenia, myelosuppression MAOI = SEROTONIN NO CYP interactions

Clinical Pearls for Synercid

Quinupristin/Dalfopristin MOA: Inhibition of early/late protein synthesis via synergy G+, including MRSA (3rd line) IV, incompatible w/ NS, use D5W or Sterile Water Hepatic metabolism ADR: site reaction, myalgias (STATINS) inhibits cyp 3A4 o STATINS, cyclosporin, Ca2+ channel blockers, antihistamines

Clinical Pearls for Daptomycin

Cubicin MOA: depolarization of bacterial cells = interferes w/ protein/RNA/DNA synthesis G+, including MRSA IV High protein binding = Interactions (warfarin, phenytoin, ibuprofen) Doesn't penetrate into lung/CSF (not for pneumonia) Renal elimination Myopathy = increased CPK levels

Clinical Pearls for Metronidazole

Flagyl MOA: nitro reduction into free radicals GUT ANAEROBES, C. diff., H. pylori IV/po Excellent oral bioavailability Hepatic elimination via cyp3A4 o DIs: coumadin, carbamazepine, cyclosporine Renal excretion (no adjustment mild/mod) ADRs: GI, dry mouth, metallic taste, neuropathy, seizures, DISULFIRAM reaction

Clinical Pearls for Tetracyclines

MOA: bind to 30S and inhibit binding of tRNA to acceptor site Tetra, Mino, Doxy (IV/po) Respiratory, strep, staph, atypicals Bacteriostatic Tetracycline renal, doxy hepatic ADRs: photosensitivity, tooth discoloration in children, nausea, GI, teratogenic, Fanconi Syndome DIs w/ cations, bile acid sequestrants, anticonvulsants

Clinical Pearls for Tigecycline

MOA: tetracycline o Bacteriostatic IV Broad spectrum: G+, G-, no pseudo, gut/mouth anaerobes, MRSA, C. Diff. ADR: primarily GI (nausea, diarrhea, vomiting), photosensitivity, tooth discoloration

Clinical Pearls for Bactrim

Sulfamethoxazole and trimethoprim MOA: inhibits DHF synthesis by mimicking PABA; bacterial DHFR inhibitor BACTERIOSTATIC Resp GI/UT CSF penetration Liver metabolism and renal excretion LOTS OF WATER ADR: GI, photosensitivity, allergy, crystalluria, suppress bone marrow, hyperkalemia DIs: warfarin, phenytoin, oral hypoglycemics

Clinical Pearls for Macrolides

MOA: inhibit trNA translocation by binding 50S BACTERIOSTATIC Erythromycin, Azithromycin, Clarithromycin G+, Respiratory tract + HIV + H. pylori o Azithromycin has some G- coverage FOOD ADRs: n/v, diarrhea, dizziness o Azith least, Eryth most ADR (check LFTS) o All equal QT prolongation risk (new study) o Cyp 3A4 inhibition (except Azith!) DIs: antacids, warfarin, benzos, cyclosporine, carbamazepine

Clinical Pearls for Clindamycin

Cleocin BACTERIOSTATIC G+ (no MRSA), mouth anaerobes IV, po Excellent oral bioavailability Use if can't use B-lactam May cause C. diff Hepatic elimination

Clinical Pearls for Quinolones

MOA: DNA gyrase/topo inhibitor Coverage: o Cipro- pure G-, resp, pseudomonas o Levo- G+/G-, resp, pseudomonas o Moxi-G+/G-, resp, NO pseudo, anaerobes Bioavailability: Levo/moxi 1:1; Cipro 80% Elimination: Levo/cipro renal; moxi hepatic FOOD DOESNT MATTER (except cations ex. calcium in milk) Cations 2/2, 2/6, 4/8 (hour spacing before/after) ADRs: C. diff., GI, taste perversion, HA, dizziness, seizures, photo, tendon, QT prolongation, allergies, hyper/hypoglycemia DIs: theophylline, coffee increases CNS effect, anticoag drugs, arrhythmia, NSAIDs, cyclosporine

Pregnancy

Avoid use in 1st trimester and use older agent w/ more data
Weigh risks/benefits B- may be acceptable

C- use with caution

o o o

Bactrim (1st/3rd contraindicated) Clarithromycin Fluoroquinolones (safer alternatives, no breastfeeding)

o o o o o o o

Azithromycin (likely ok breastfeeding) Cephalosporins (breastfeeding ok) Clavulanic Acid Erythromycin (breastfeeding ok) Nitrofurantoin (3rd contraindicated) Penicillins Sulbactam (breastfeeding ok)

D- positive evidence of risk (no breastfeeding)

o o

Aminoglycosides Tetracyclines

Helpful Lists
Pseudomonal Coverage
Extended Spect PCN Ceftazadime (G-3) Cefepime (G-4) Aminoglycosides Aztreonam Cipro/Levo Carbapenam (Except Ertapenam)

MRSA Coverage
Vanco Televancin Linezolid Ceftaroline (G-5) Daptomycin Tigecycline Synercid Minocycline, Bactrim, Clindamycin (CA-MRSA)

C. Diff Coverage
Metronidazole Vanco PO

Photosensitivity
Tetracyclines Bactrim Quinolones

Study questions

How can you differentiate the members of the PCN class? How can you differentiate the cephalosporins? How do you dose & monitor aminoglycoside & vanco therapy? Name all antibiotics with G+ activity; rank according to use. Name all antibiotics with G- activity. Which have pseudomonas activity? Which have MRSA activity? Which are bacteriostatic vs. bactericidal?

Which can cause photosensitivity?

Which need therapeutic drug monitoring? Which can cause seizures? Which are nephrotoxic? Ototoxic? Which are primarily hepatically eliminated? Which are "safe" in pregnancy? What are the brand/generics? Define MBC, MIC and PAE.

Med Chem!

Beta Lactams
Includes penicillins, cephalosporins and monobactams Basic structure is a cyclic amide in a 4 membered ring Binds to cell wall proteins and prevents bacteria from forming cell walls

Penicillins
Penicillins are beta lactam rings fused to a 5-membered thiazolidine ring (right side) with variable R groups attached (left side) Hydrophobic R groups work best in G+ bacteria, hydrophillic R groups can affect G- bacteria Poor bioavailability because they are susceptible to acid. Electron withdrawing groups (EWG) can increase oral stability. MOA: Penicillin resemblPenicillins are beta lactam rings fused to a 5membered thiazolidine ring (right side) with variable R groups attached (left side) Hydrophobic R groups work best in G+ bacteria, hydrophillic R groups can affect G- bacteria Poor bioavailability because they are susceptible to acid. Electron withdrawing groups (EWG) can increase oral stability. MOA: Penicillin resembles the 2 terminal D-alanines in bacterial cell wall proteins, so they bind PBP (penicillin binding protein) and render them inactive

Penicillins Cont.
Bacterial resistance in the form of beta lactamase We can overcome beta lactamases by adding bulky R groups in an alpha-carbon di-substituted system. We can also use beta lactamase inhibitor (clavulanic acid, sulbactam, tazobactam) which also contain a beta lactam ring Bacterial resistance in the form of beta lactamase We can overcome beta lactamases by adding bulky R groups in an alpha-carbon di-substituted system. We can also use beta lactamase inhibitor (clavulanic acid, sulbactam, tazobactam) which also contain a beta lactam ring

Carbapenems
A bioisostere of penicillin. The sulfur of the thiazolidine ring of penicillins is replaced with a carbon Not orally stable because they dont have EWG Imipenem: easily degraded by renal peptidases, therefore requires cilastatin
Meropenem, Doripenem and Ertapenem have methyl groups to prevent degradation

Monobactams (Aztreonam)

Contains a single beta lactam ring with R groups. Lactamase resistant due to alpha carbon di substitution system Only beta-lactam with no history of allergies

Cephalosporins

Contain 6 membered thiazine rings bound to a beta lactam ring

They are more hydrophillic less likely than penicillins to cause allergic reactions Contains 2 R groups o One R group determines spectrum of activity o The second R group determines potency and oral stability The better the leaving group, the more potent the drug Alpha-di-carbon substitution applies to cephalosporins as well and predicts beta lactamase resistance

In general, cephalosporins are not orally stable because their leaving groups are esters. o We can improve oral stability by making ester pro-drugs o Amino groups can contribute to oral stability
Be able to identify which cephalosporin is which generation and their general spectrum of activity based on the structure

Aminoglycosides (AG)
MOA: Binds to 30S unit of bacterial ribosome to inhibit translation of RNA

Potent G- agents due to hydrophilicity Cannot be used orally and have poor bioavailability because they are polar Streptomycin is no longer used due to resistance Cannot be used with beta-lactams because AG will break open the beta-lactam ring and inactivate it

Macrolides
Structure: Macrocyclic lactones MOA: Binds to 50S ribosomal subunit, inhibiting peptide formation Unstable to acid due to the C9 ketone right next to the C6 alcohol ketalization and inactivation Most contain a cladinose sugar at C3 May cause gastric cramping, which can be solved by a water insoluble formation or enteric coating

Systemic/ Topical Polypeptides

Structure: Generally cyclic peptides with an NHCO backbone The NHCO backbone is polar but side chains can be hydrophillic or hydrophobic MOA: Detergents that penetrate bacterial membranes but human membranes as well

Vanco and Synercid

These are sytemic polypeptides Vancomycin
MOA: Binds to peptidoglycan to prevent cross linking. However, it does not inactive PBP like penicillins. Their structure contains amino acids on aromatic rings VISA: vancomycin intermediate sensitive S. aureus. Resistance is due to thickened cell walls VRSA: vancomycin resistant S. aureus. Terminal D alanine has mutated into a D-lactate, preventing vancomycin from binding

Synercid
Protein synthesis inhibitor that inhibit initiation of translation Dalfopristin enhances binding of quinupristin

Tetracyclines
Structure: Saturated Naphthacene nucleus MOA: Binds to 30S ribosome to inhibit peptide formation
Contains 3 ionizable groups
Vinyl Alcohol pKa=3 Conjugated phenol pKa=7.5 Dimethylamino pKa 9.4

Problems with tetracycline structure that creates inactive drug

Dimethylamino at position 4 must be in alpha position. Tautomerization can occur and create beta formation Chelation can occur at C11 and C12
Avoid dairy and antacids

Can undergo dehydration at C6

If we have dehydration at C6 and an epimer at C4, we get epianhydrotetracycline, which is highly toxic to the kidney
This is not an issue in minocycline or doxycycline

Chloremphenicol
Structure: Contains a nitrophenyl, chloracetic acid and 2 alcohols Has 2 forms: palmitate and hemisuccinate MOA: Inhibits protein synthesis by preventing the binding of t-RNA to the A site. May inhibit mitochondrial protein synthesis in humans

Daptomycin
Structure: Large cyclic lipopeptide MOA: Causes depolarization in bacterial cells to interfere with protein and nucleic acid synthesis

Flagyl
Structure: Nitroimidazole Mechanism of action unknown May be reduced by an intracellular electron transport protein This creates a concentration gradient which promotes intracellular transport Free radicals are formed which are toxic to bacteria

Lincosamides
Structure: Polar glycosides containing a thiomethyl amino octodie moiety MOA: Protein synthesis inhibit by preventing translation of t-RNA

Antibacterial Resistance

Classification of resistance:
o o Intrinsic resistance Resistance due to inherent characteristics of bacteria Acquired resistance - Initially the bacteria was susceptible but further antibiotic exposure resulted in resistance

Types of resistance

o
o o o

The bacteria can alter the target the antibiotic was acting on
Decreased influx/increased efflux Degradation of the antibiotic Alternative pathways Example: If antibiotics target a protein in cell wall creation, the bacteria will use an alternative method of creating the cell wall while bypassing that protein

How do bacteria acquire resistance? o o Random mutation Plasmids

o
o

Transposons
Integrons

Study questions

Penicillins: Which penicillins have acid stability? Which penicillins have resistance to beta lactamase? Which penicillins work against G- bacteria? What is the MOA of a beta lactam inhibitor? Aminoglycosides: What are R factors? Which AG has which R factors? Macrolides: What are the 3 patterns of resistance? Which macrolides are water soluble and which are water insoluble? Which are acid stable and why? Which cause less gastric cramping? Tetracyclines: What are the patterns of resistance? What is the bioavailability and level of activity of each tetracycline? Chloramphenicol: What is gray baby syndrome? What are the resistance patterns of chloramphenicol? What are the resistance patterns of lincosamides?