Rho Chis Clinical Pearls of Virology, Exam 1

7/27/2019 Rho Chis Clinical Pearls of Virology, Exam 1

1/49


2/49

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!!

Tips for Success


3/49

G+ aerobes: staph, strep, enterococci G- aerobes: Enterobacter, Pseudomonas,

Haemophilus, Moraxella

Anaerobeso Mouth: peptoo Gut: bacteroides, C. dif.

Atypical: mycoplasma, chlamydia,legionella Gram Stain

o

Positive - purpleo Ne ative - ink

Bacteria


4/49

Class ClinicalPearls


5/49

MOA: bind to PCN binding proteins needed to form cellwall

ADR: n/v, diarrhea, allergic reaction

Curve Chart Time-dependent Don't admin w/ aminoglycosides in same IV line Classes

o Natural Penicillinso Penicillinase resistanto Aminopenicillinso Extended-Spectrumo B-lactamase inhibitors

Clinical Pearls for Penicillins


6/49

Penicillin G (IV/IM)o Aqueous crystalline: Acute severe infection b/c high

peako 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 Natural PCNs


7/49

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 Penicillinase-Resistant PCNs


8/49

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 Aminopenicillins


9/49

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 Extended-Spectrum PCNs


10/49

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 B-lactamaseinhibitors


11/49

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

Clinical Pearls for Monobactams


12/49

Staph, strep, G-, pseudo, anaerobes, ESBL 11-50% cross-reactivity with PCN IV ADR: mental status changes, seizures Imipenem-cilastatin: broadest spectrum, highest seizure

risko Cilastatin is not an antibiotic, it prevents hydrolysis

of imipenem to improve efficacy Meropenem: wider TI, low seizure incidence, meningitistreatment

Ertapenem: q daily (longest t 1/2), no pseudo Doripenem: no neurotoxicity

Clinical Pearls for Carbapenems


13/49

MOA: Inhibit cell wall synthesis by binding to proteins needed tomake structure

Generations have increasing G- activityo 1: SPEcK;


14/49


15/49

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

Clinical Pearls for Aminoglycosides


16/49

Dosingo loading: based on BODY WT (standard dose of

2mg/kg)o maintenance: depends on severity and renal function

levels and monitoringo trough: 30 min before 4th dose

@ steady stateo peak: 30 min after 30 min infusion

Trough goalso Gent/Tobramycin:


17/49

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


18/49

Lipoglycopeptides Improved vanco: does everything vanco does IV

Clinical Pearls for Televancin &Dalbavancin


19/49


20/49

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 Synercid


21/49

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 Daptomycin


22/49

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 Metronidazole


23/49

MOA: bind to 30S and inhibit binding of tRNA toacceptor 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 Tetracyclines


24/49


25/49


26/49

MOA: inhibit trNA translocation by binding 50S BACTERIOSTATIC Erythromycin, Azithromycin, Clarithromycin

G+, Respiratory tract + HIV + H. pylorio 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 Macrolides


27/49

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 Clindamycin


28/49

MOA: DNA gyrase/topo inhibitor Coverage:o Cipro- pure G-, resp, pseudomonaso Levo- G+/G-, resp, pseudomonaso 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

Clinical Pearls for Quinolones


29/49

Avoid use in 1st trimester anduse older agent w/ more data Weigh risks/benefits B- may be acceptableo Azithromycin (likely ok

breastfeeding)o Cephalosporins

(breastfeeding ok)o Clavulanic Acido Erythromycin (breastfeeding

ok)o Nitrofurantoin (3rd

contraindicated)o Penicillinso Sulbactam (breastfeeding ok)

Pregnancy

C- use with cautiono Bactrim (1st/3rdcontraindicated)

o Clarithromycino Fluoroquinolones (safer

alternatives, no breastfeeding) D- positive evidence of risk (nobreastfeeding)

o Aminoglycosideso Tetracyclines


30/49

Helpful Lists

Pseudomonal Coverage

Extended Spect PCNCeftazadime (G-3)

Cefepime (G-4) Aminoglycosides AztreonamCipro/LevoCarbapenam (Except Ertapenam)

MRSA Coverage

VancoTelevancin

LinezolidCeftaroline (G-5)DaptomycinTigecyclineSynercidMinocycline, Bactrim,

Clindamycin (CA-MRSA)

C. Diff Coverage

MetronidazoleVanco PO

Photosensitivity

TetracyclinesBactrimQuinolones


31/49

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.

Study questions


32/49

Med Chem!


33/49

Beta Lactams

Includes penicillins, cephalosporins andmonobactams

Basic structure is a cyclic amide in a 4membered ringBinds to cell wall proteins and prevents

bacteria from forming cell walls


34/49


35/49

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 ringBacterial resistance in the form of beta lactamase

We can overcome beta lactamases by adding bulky R groups inan alpha-carbon di-substituted system .

We can also use beta lactamase inhibitor (clavulanic acid,sulbactam, tazobactam) which also contain a beta lactam ring

Penicillins Cont.


36/49

A bioisostere of penicillin. The sulfur of thethiazolidine ring of penicillins is replacedwith a carbon

Not orally stable because they dont haveEWG

Imipenem: easily degraded by renalpeptidases, therefore requires cilastatinMeropenem, Doripenem and Ertapenem havemethyl groups to prevent degradation

Carbapenems


37/49

Contains a single beta lactam ring with Rgroups.

Lactamase resistant due to alpha carbondi substitution system

Only beta-lactam with no history of allergies

Monobactams (Aztreonam)


38/49

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 groupso One R group determines spectrum of activityo 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 welland predicts beta lactamase resistance

In general, cephalosporins are not orally stable because their leavinggroups are esters.o We can improve oral stability by making ester pro-drugso 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

Cephalosporins


39/49

MOA: Binds to 30S unit of bacterial ribosome toinhibit 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

resistanceCannot be used with beta -lactams because

AG will break open the beta-lactam ring

and inactivate it

Aminoglycosides (AG)


40/49

Structure: Macrocyclic lactones MOA: Binds to 50S ribosomal subunit, inhibiting peptide

formation

Unstable to acid due to the C9 ketone right next to theC6 alcohol ketalization and inactivationMost contain a cladinose sugar at C3

May cause gastric cramping, which can be solved by a

water insoluble formation or enteric coating

Macrolides


41/49


42/49

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

Vanco and Synercid


43/49

Structure: Saturated Naphthacene nucleus MOA: Binds to 30S ribosome to inhibit peptide formation

Contains 3 ionizable groupsVinyl 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 C12Avoid dairy and antacids

Can undergo dehydration at C6If 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

Tetracyclines


44/49

Structure: Contains a nitrophenyl, chloracetic acid and2 alcohols

Has 2 forms: palmitate and hemisuccinate

MOA: Inhibits protein synthesis by preventing thebinding of t-RNA to the A site. May inhibitmitochondrial protein synthesis in humans

Chloremphenicol


45/49

Structure: Large cyclic lipopeptide MOA: Causes depolarization in bacterial

cells to interfere with protein andnucleic acid synthesis

Daptomycin


46/49

Structure: NitroimidazoleMechanism of action unknownMay be reduced by an intracellular electron transport

proteinThis creates a concentration gradient which promotesintracellular transport

Free radicals are formed which are toxic to bacteria

Flagyl


47/49

Structure: Polar glycosides containing athiomethyl amino octodie moiety

MOA: Protein synthesis inhibit bypreventing translation of t-RNA

Lincosamides


48/49

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

antibiotic exposure resulted in resistance

Types of resistanceo The bacteria can alter the target the antibiotic was acting ono Decreased influx/increased effluxo Degradation of the antibiotico Alternative pathways

Example: If antibiotics target a protein in cell wall creation, the bacteriawill use an alternative method of creating the cell wall while bypassingthat protein

How do bacteria acquire resistance?o Random mutationo Plasmidso Transposonso Integrons

Antibacterial Resistance


49/49

Documents

Rho Chis Clinical Pearls of Virology, Exam 1