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Antimicrobial Pharmacology

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Robert Pa:rton PA-C, M.P.A.S.

Robert Paxton graduated from the University ofNebraska-Lincoln with a Bachelor's degree in biology, which was followed by two years of infectious disease research and teaching microbiology. He received his Masters of Physician Assistant Studies from Marquette Universrty. He currently works for a private infectious disease practice at St. Joseph's Regional Medical Center in Milwaukee, Wf. Mr. Paxton is an adjunct clinical professor and clinical preceptor for Marquette University, where he teaches a series of lectures on infectious disease. He is a member of the American Academy of Physician Assistants (AAPA) and the Wisconsin Academy of physician Assistants (V/APA).

CME Resources Certification & Recertification Exam Review

Certification & Recertification Exam Review CME Resources Antimicrobial Topics Robert Paxton PA-C, MPAS
l)General Review of Basic Antimicrobial Pharmacology -Antibiotic Mechanisms -Mechanisms of Antibiotic Resistance -Bacteriocidal vs. Bacteriostatic Antibiotics -Time-Dependent vs. Concentration-Dependent Antibiotics -Hepatic vs. Renal Excretion of Antibiotics -Antibiotics Associated with Ototoxicity -Antibiotics Asso ciated with Nephlotoxicity -Antibiotics Associated with Disulfram-Like Reaction -Antibiotics Associated with Co lor Associations -Antibiotics Asso ciated with Potassium Dysre gulation -Antibiotics Associated with C. dfficile -Antibiotics Associated with EBV Rash -Risk Categories of Antibiotics During Pregnancy -Ciass of Immunopatirologic Reactions to Antibiotics -Ciinical Evaluation of Penicillin Allerg.v -Oral Antibiotic Pearls -Parenteral Antibiotic Pearls

2)Specific Antibiotic Pharmacology 'Penicillins -Cephalosporins -Monobactams -Carbapenems -Glycopeptides -Tetracyclines -Macrolides -Aminoglycosides -Fluoroquinoiones - Sulfonamides & Trimethoprim -Streptogramins -Lincosamides -Oxazolidinones -Miscellaneous Antibiotics 3)General Overview of Antivirals 4)Generai Overview of Antifungals

Antimi crobial Phamaeol o gy


-Antibiotic Mechanisms of Action
-Inhibit or disrupt cell wall growth - B-lactams (PCNs, cephalo sporins, carbapenems, monobactams) -glycopeptides (vancomyciri) -Inhibit protein synthesis - 50 S ribo somal subunjt (macrolides, clindamycin" chloramphenicol, quinupri stin- dalfop ri stin) -3 0 S ribosomal subunit (aminoglycosides, tetracyclines) -Inhibit DNA or RNA synthesis -DNA gyrase / topoisomerase IV (fluoroquinoiones) -DNA-dependent RNA polymerase (rifampin) -DNA alteration (metronidazole) -inhibit folic acid synthesis (TMP-S}VDQ

-Bacterial Mechanisms of Antibiotic Resistance


-

I intracellular [drug]

-generally by 1 effiux (tetracyclines) - 1 decreased outer membrane permeability (p-lactams) -drug inactivation by specific enzymes -BJactamases (B-lactams) / aminoglycosidases (aminoglycosides) -antjbiotic target modifi cation - J affinity for penicillin-binding proteins (p-lactams) -DNA gyrase modification (fluoroquinolones) -rRNA methyiation (macrolides)

-Bacteriocidal vs. Bacteriostatic


-Bacteriocidal 'B-lactams, glycopeptides, aminoglycosides, fluoroquinolones, metronidazoie -Bacteriostatic -t etracyclines, macrolid es, clindamycin, sulfonamides

Note: this is highly generalized -> some agents are -cidal against some organisms and -static against others Note: -cidal agents are preferable if the host is compromised (i.e. neutropenic) or the host defenses do not operate well (ex. bacterial endocarditis or meningitis)

if

'Time-Dependent vs. Concentration-Dependent Bacteriocidal Effects

-Concentration-DependentEffects -t bacteriocidal effect correlateswith 1 ldrug]

l-atr.\e J

;ffirquffl O;tr\\

-Example: aminoglycosides, fluoroquinolones

Note: ABX that are concentration-dependent should be given as large, infrequent doses to achieve the desirable high levels, but I potential toxicities
-Time-Dependent Effects -bacterial killing has little relationship to concentration -effective as long as the antibiotic level at the site of infection is above the minimal inhibitory concentration concentrations Q\fl C)

-Example:
-B-lactams (PCNs, cephalosporins, -monobactams (monobactams) -glycopeptides (vancomycin)

&

carbapenems)

Note: ABX that are time-dependent should be dosed so that the Ievels achieved are as low as possibleo to reduce toxicities, but rernain as long as possible above the MIC -this may be done with moderate doses at short intervals or more appropriately with a continuous slow infusion

-Postantibiotic Effect
-this is where a short exposure of ABX prevents the organism from growing after the ABX has been removed -thought to be from residual drug binding of target proteins, delayed recovery of metabolism, or prolonged bacterial morphological alterations -examples include aminoglycosides and fluoroquinolones

-Situations for Antibiotic Cornbinations -empiric treatment of the febrile neutropenic patient -treatment of polymicrobial infections to cover organisms with dissimilar antimicrobial
sensitivities (i. e. intra- abdominal infections) -synergism to enhance bacterial killing in serious or difficult-to-treat infections (i.e. penicillin plus gentamicin for enterococcus) -treatment of TB in order to prevent the development of resistance will on therapy

-Hepatic vs. Renal Antibiotic Excretion -Renal Excretion -B-lactams (not nafcillin, cefoperEtzone, ceftriaxone), monobactams (aztreonam),
and glycopeptides (vancomycin)

-aminoglycosides -fluoroquinolones (usually split excretion) -trimethoprirn -tetracyclines (usually split excretion) -HePatic Excretionne

-nafcillin

& ceftriaxone

-rifampin -metronidazole
qglaogrvc-otGi -vancomycin
-minocycline
'

-clinda:nycin&rnacrolides

"\

ifl

gfnin

zc

r-l - > Kt,'rpl '\'er ,,


-6rr

\ / .\o rr-i ,jr,,,,i\ ,Iu"c / fic>''\ Fr"'\i'd

-Antibio$cs=Assoergled with Ototoxicity - >

'

I rf "'r fid\,\ + Ur,-rur,, ,\

-this is really more rrestibuiar dysfunction (dizziness, ata-xi_-a,_lyv) -found in2ASATo of people, especially older women

-Antimicrobials Associated with Nephrotoxicity -amphotericin B (>39% of patients will experience nephrotoxicity) -aminogiycosides i
-causes proximal tubuiar necrosis

-various B-lactams (ex. nafcillin) -acute interstitial nephritis -tetracycline (only in outdated preparations and its degradation products) -can cause Fanconi syndrome (reversible proximal renal tubular dysfunction with renal glucosuria and hyperphosphaturia) -vancomycin -historically from impurities in the IV form -currently, problems arise only when administered with other nephrotoxic agents

-Antibiotics Associated with a Disulfiram-Like Reaction with Concomitant Aicohol -a disuifiramlike reaction is characterized by tachycardia, flushing, FIAs, abdominal
cramps, ?_4d__NIYA

-metronidazole -B-lactams with a methylthiotetrazole (MTT) side chain


-cefamandole, cefotetan, cefoperazone -B-lactams with a methylthiotetrazole-like side chain -cefazolin

-Antibiotics Associated with Color Associations -red man syndrome Fiu:;lr ,n_ clqc..j I rue-t1

,i Rac_ -rapid inflr sion of vancomycih.'releases histamine -slow infusion down and give diphenhydramine -red lobster syndrome -rifbmpi\causes a red-orange discoloration of urine, tears, and sweat -discolixed fdefh-tetracyclines may cause darkening of developing teeth -contraindicated in kids < 8 yrs. loss ofred i green perception -high-do se ethambuto\ may cause optic neuritis
with
Potas sium

-Antibio: tigq

+glocialgd -tryperkalemiii

Dysregulation ,-5 t16*'. i\*se

,D/
ofNa*

-trimethopri_m-(usually as TMP-SIr,DQ blocks distal tubular reabsorption and secretion of K+

-nypg_\femij

-various PCNs, especially nafcillin and piperacillin, may act as non-reabsorbed anions in the kidney

-Antibiotics Associated with Clostridiunt difficilediarrhea

C - ,\.(t- hcr^i-

u-l

rn

t u'tar\

( -clindamycin \__--l-#

-aminopenicillin products -amoxicillirq amoxicillin / clavulanate, ampicillin, ampicillin / sulbactam c-epha I oworins (especially cephalexin) iIAl hcn'r

)- f:1r,. ll.e .c";r+-

v(41er /

Note: almost any A-BX can cause C. dfficile colitis

-Antibiotics .dssociated with Rash when Concurrently used in Infectious Moncnucleosis -classic association _=@/as EBV -can occur with any aminopenicillin product
-characteized by a maculopapular, nonurticarial (non-penicillin allergic rash) rash in 65-1.00% of patients with infectious mononucleosis (usually EBV, but may be CMV) -the cause is the virus causing a antibody to be released that cross-reacts with aminopeniciliins -occurs in other situations as well

-CLL -CMV
-coadministration of allopurinol

-Risk Categories of Antibiotics during pregnancy


-p-lactams -penicillins, cephalosporins, monobactams (B) -carbapenerns (meroperlem, ertapenem) (B); (imipenem) (C) -macrolides (erythromycin, azithromycin ) @), (clarithromycin) (c) -clindamycin (B) -metronidazole (B) -fluoroquinolones (C) Jinezolid (C) -TMP-SI\,D( (C) -vancomycin (C) -aminoglycosides (D) -tetracyclines (D) /

> BnS

-Classification of Hypersensitivi[ $gr_q!io.ng to B-lactams (Scheme of Gell & Coombs) -Type I Reaction ti-\' ' '. ' -anaphylactic (immediate hypersensitirrity) \ +tr* 3*,ils ra, n \ yy{rt"
,.

','.;

\, I

',-_-IgEnrediated
llaracf3ilzed

. by hypotensiorl

urticariao algio6derna, bronchospglm

'rr'

-cytolytic or cytotoxic -IgG rilediated '. -characterized by hemolytic anemia, cy'topenias, nephritis -Type ITT Reacticn
-immun-e qqnlglg4_ disease

b.-)v

r'tt''{f;',.,,

5"'{f'rv1

-mediated by soluble immune complexes (Ab-Ag) and IgM -characterized by c.o5rta9t, de,-gnatitis & serum sickness -Type fV Reaction -idiopathic disease -mediated by ? -characterized by maculopapular eruptions, eosinophilia, Stevens-J syndrome, exfoliative dermatitis

"J

Bnn

TiN

t^

ctt'+{; lLl'l

-Clinical Evaluation of Penicillin ..Allergyoo


. :.1-5%-ingidence in the generai popuiation -less than 1% will anaphylaxis; 300 deaths/yr in US -applies to all penicillins, cephalosporins, and carbapenems -Jr'',6x,n,'ry.s, -common PCN skin test won't predict anaphylaxis

<.Q fl "/
r-

l)Was it a maculopapuiar rash? -if o'rash'o don't rechallenge with pCNs \ rh\'\ fni't"'' ' ; S -may use cephalosporins, rnonobactams, and carbapenems (nray have a 5-10% cross-reactivity)

,' Lrt

'

i''

o \))"'

2)Did urticaria, angioedema, bronchospasm, or anaphylaxis occur? -if they have a true PCN allergy (i.e. any anaphylaxis like reactions) don't challenge them with ANY penicillin, eephalosporin or carbapenem -can use monobactams (aztreonam)

-cephalexin is iess actirze -minocycline > TMP-sIfl( are also fairly effective {bacteriostatic)

-A.nti-I\E SA Oral ARX -linezolid -minocycline > TMP-ShO{ are also fairly effective (check sensitivity pattern)
-

AlttAnaersU:c- orallBx -metronidazole and amoxicillin / clariulanate (Augmentin) are gold standard -clindamycin is silver standard

-AntrIGE_ Arai ABX -iinezolid

7n
-ParenteralAntibjotic Pearls

@IVABX / tazobactam -piperacillin


-aztreonam -ceftazidime -cefepime -ciprofl oxacin & levofl oxacin -tobramycin -carbapenems (meropenem > imipenem)

ABX
-cefazolin is less active -vancomycin

Note: there are many anti-staphylococcal ABX' but these are generally regarded as the top choices (listed in order)

-Anti-MRSA tV ABX
-vancomycin -dalfopristin / quinopristin -linezolid -Anti-VRE IV ABX -linezolid

@"ABX -Ggld Stand.ara


-p-lactam I p-lactamase inhibitor combination ex. QsPlcillin / sulbactam or piperacillin / tazobactam
-carbapenems ex. imipenenr, meropenern, ertapenem

-metronidazole -Silver Standard -clindamycin -Bronze Standard -cephamycins (cefotetan or cefoxitin)

-Penicillins -Mechanism of Action -arrests cell wall synthesis by binding to penicillin-binding proteins (PBFs) -bacteria need to be actively dividing for pJactams to work
-Mechanisrns of Bacterial Resistanee -3 mechanism account for resistance to B-lactams l)destruction of ABX by p-lactamases 2)failure of the ABX to penetrate to PBP targets 3)low-affinity binding of ABX to pBp -Pharmacology
-usually renally excreted

-probenecid blocks secretion -> 1 plasma levels -time-dependent kiliing -natural PCI'{s and anti-staphylococcal PCNs have good generations you lose 6-r activity and gain G- activity

Gr activiry

as

you ascend

-Major Adverse Effects


-NIV,D
-hypersensitivity reactions (rash -> immediate anaphylaxis)

-drug fever -thrombocytopenia, hemolytic anemia, neutropenia -neurotoxicity (irritability, hallucinations, seizures, confu sion, etc. ) -associated with high doses or when not renally adjusted -occurs with other PCNs" but this association may be on the boards -Peniciltrin Classes & Microbial Coverage -Class : Natural Fenicillins i rt rn 3 .\ -penicillin V CPO) -> Fen VK Veetids, generics nnrnA \ -penicillin G (IV) -> generics -peniciliin G procaine (tryf) -> Wycillin O.-rc 5V -penicillin C procaine / beiizathine (tr\.{) -> Bicillin-CR Lri-\ pC -peniciliin G benzathine (IM) -> Biciltin-LA

-Microbial Coverage
-5.

p),og"nts (GAS), Treponenta palli&tn

l].(p"-rh.y-f c. Sy Oi"t'llU; lYote: an immediate, but transient {5-30 rnin. aften injection with procaine products) reaction u,ith bizarre behavior / neurologic reactions can occur -> Efoignes S5'p6r.o*"

-Class = $_Al11$lqphgssoeealPeui cillins (stable a gainst staphyloco ccal fiJactamases) -nafsillin (W) -> Unipen, Nafcil, generics -dicloxacillin (PO) -> Dynapen, generics -oxacillin (PO / tV) -> Prostaphlin -cloxacillin (PO) -> Cloxapen

-Microbial Coverage
-5.

pltogenes (GAS), S. aureus

-Class

Aminopenicillins

-ampicillin GV) -> Principen, -amoxicillin (PO) Amoxil, Trimox, generics

generics \

1=cirrr4-

-Microbial Coverage
-5.

pyogenes (GAS), S. pneumoniae, S. agalactiae (GBS), Enterococci, B oryelis burgdorferi, P asteurella multacida, Protezrs, Listeria ftlonocytogene s *some H. influenzae,

ff d(irS !,rrc,.

{.

_7oli
'

-Class = Augmented Aminop.ni"iniirl -amoxicillin / clar,ulanate fPO) -> Augmentin -ampicillin I sulbactam CV) -> Unasyn

-Micnobia! Coverage -5. p),og"nes (GAS), S. pneumoniae, S. agalactiae (GBS) , Enterococci, M. catarrhalis (even amoxicillin resistant strains), H. influenzae (erien amoxicillin resistant strains), Proteus, P asteure lls nrultocida -Covers most anaerobes -some E. coli, Klebsiella
= Carboxypenicillins -ticarcillin (IV) -> Ticar -carbenicillin (PO) -> Geocillin
-Class

: Ureidopenicillins
-piperacillin GV) -> Piperacil -mezlociliin (IV) -> Mezlin

10

-Class = Au gmented Extended-Spectrum Penicillins -piperacillin / tazobactam (IV) -> Zosyn -ticarcillin / clawlanate (IV) -> Timentin

-Microbial Coverage
p),ogtrus (GAS), S- pneumoniae, S. agalactiae (GBS), Enteracocci, M. catan'halis, H. influenzae, Proteus, E. coli,
-5.

KI eb si e I I a, Enter ob a ct er, S err ati a, P s e u don t tnta s -Covers most anaerobes

-Cephalosporins -Mechanism of Action -arrests cell wall synthesis by binding to peniciliin-binding proteins (PBPs) -bacteria need to be actively dividing for BJactams to work
-Mechanisms of Bacterial Resistance -3 mechanism account for resistance to B-lactams l)destruction of ABX by B-lactamases 2)failure of the ABX to penetrate to PBP targets 3)low-affinity binding of ABX to PBP

-Pharmacology -usually renally excreted -probenecid blocks secretion -> may t plasrna levels -time-dependent killing -the 1" &.2"d generation cephalosporins have good Gf activity; as you ascend generations you lose Gf coverage and gain G- activity Note: no cephalosporin covers Enterococci or Listeria

-Major Adverse Effects


-hypersensitivity reactions (rash -> imurediate anaphylaxis)

-N/V/D
-drug fever -thrombocytopenia, hemolytic anemia, neutropenia -disulfi ram-like reaction with concomitant alcohol -p-lactams with a methylthiotetrazoie (MTT) side chain -cefamandole, cefotetan, cefoperazone -B-lactams with a methylthiotetrazole-like side chain -cefazolin -serum-sickness like reaction possible with cefaclor -biliary sludging (pseudocholelithiasis) possible with ceftriaxone

11

-Cephalosporin Classes & Microbial Coverage -Class : L"t Generation Cephalosporins -cefazolin (IN,f / IV) -> Ancef Kefzo@ -cephalexin (PO) -> Keflex, Keftab, generics -cefadroxil (PO) -> Duricef, Llltracef -cephradine (PO I frvI lIV) -> Velosel generics

-Microbial Coverage
-5. azrreus, S. pltogenes (GAS) -some E. coli,- Klibsiella, Proteus { irr+'fi':}

-Class

: 2nd Generation Cephalosporins*& Cephamycins


-ceturoxime (PO / IM / IV) --fttgPO), Zinacef (IM / iV), generics -cefaclor (PO) -> I -cefprozil (PO) -> l-,*,-.,1 t,;,:/khe ,e i0nd,b;r,t" u'\'4r -loracarbef (pO) -> -cefamandole (R4 / IV) -> Mandoi -cefonicid (IV) -> N{onocid

Ceclor Cefzil L) Lorabid

-Microbial Coverage
-5. pyogenes (GAS), S. przeumoniae, S. aureus, M. cataryhctlis (even amoxicillin resistant strains), H. i.nfiuenzae (even amoxicillin resistant strains), Proteu s, Pasteurella multocida -some E. coli, Klebsiella

Cephamycins

(l S. awreus coverage, I ,,wimpy', GNB and anaerobe

co\rerage) -cefoxitin Gv{ / n}-> Mefoxin -cefotetan (IM / IV) -> Cefotan -cefmetazole (IV) -> Zefazone

o';!p1

ke{i

ex e C*h.,

T2

-Class = 3'd Generation Cephalosporins -cefpodoxime (PO) -> Vantin -cefixime (PO) -> SuPrax -cefclitoren (PO) -> SPectracef -ceftibuten (PO) -> Cedax -cefdinir (PO) -> Omnicef -ceftriaxone (IM / IV) -> RocePhin -cefotaxime (IM / W) *> Claforan -cefoperazone (M / IV) -> Cefobid -ceftizoxime (n{ /IV) -> Cefizox

-Microbial Coverage
-most "wimpy" GNBs (Proteus, E' cali, Klebsiella, M. catarrhalis, H. influenzae) -some GPC (.t pneumoniae, S. pltogenes (GAS))

-Class:3'd /

Generation Cephalosporins -ceftazidime (IM / IV) -) Fortaz, Tazidime, Tazicef -cefepime (IV) -> MaxiPime
4th

-Microbial Coverage

-covers the above organismsp/gs "resistant" GNBs (Enterobacter, P seudontonas, Setratia)

-Monobactams L,.u\

rr\

'*Q\'

Ct"-n

et>-

'r\D|'\

t'thu ti,.,.*:h yl'v

{ pe"'t'l'lin \

-Meehanism of Action -arrests celi wali synthesis by binding to peniciliin-binding proteins (PBPs) -bacteria need to be actively dividing for B-lactams to wor-k
-Mechanisms of Bacterial Resistance -3 mechanism account for resistance to pJactams 1)destruction of ABX by p-lactamases 2)failure of the ABX to penetrate to PBP targets 3)low-affinity binding of ABX to PBP -Pharmaeology -renal excretion -time-dependent kiiling -can be given to patients with anaphylactic reactions to penicillins / cephalosporins -be careful if history of anaphylaxis to ceftazidime

13

-Major Adverse Effects -N/V/D


-rash has been reported

-Example & Microbial Coverage -aztreonam (IM / IV) -> Azactam

-Microbial Coverage
-Used predominately 1s treat "resistant" GNB @nteroltacter, P seudam onas, Serratia) -has only G- coverage

-Carbapenems -Mechanism of Action -arests cell wall synthesis by binding to penicillin-binding proteins (PBPs) -bacteria need to be actively dividing for p-lactams to work -l\4echanisms of Bacterial Resistance -absence or loss of an outer membrane protein -> I penetration to PBP targets -seen predominately with P seudonxonas aeru gi n o sa

-Pharmacology
-renal excretion -time-dependent killing

-Major Adverse Effects -NTVD


-B

-lactam hyp

ers

ensitivity reactions (rash -> anaphylaxis )

-Exarnples & l\ficrobial Coverage -imipenem / cilastatin OiI / IV) -> primaxin -cilastatin is used to inhibit dihydopeptidase, an en4tme in the brush border of the kidney that degrades imipenem -meropenem (IV) -> Merrem -ertapenem (IM / IV) -> Invanz (na Psettdamonal or Enterococcal covera,qe)

-Microbial Coverage
-efiremely broad-spectrum ABX (G+, G-, anaerobes) -good for ESBL producing organisms -doesn't cover MRSA' \,lRE, C. dfficile -use is often restricted -> generally used to treat serious irosocomial infections when a resisiant G- organism is iikeiy

t4 -Glycopeptides -Mechanisrn of Action -inhibits synthesis and assembly of the 2"d stage of cell wall construction -may also impair RNA synthesis -Mechanism of Resistance -alterations in binding to cellwall targets
-Pharrnacology -renal excretion -no oral absorption (PO formulation) -time-dependent killing -measure ftrough] -I\{aj or Adverse Effects -ototoxicity and nephrotoxicity (rare) rnsy sssut, but more common with coadministration of other ototoxic i nephrotoxic drugs (i.e, aminoglycosides) -Red Man Slmdrome also possible -Exarnple & Microbial Coverage -vancomycin (PO / IV) -> Vancocin Note: don't use oral vancomycin to treat systemic infections (only refractory C. difficile)

-Microbial Coverage -covers MSS,\

I\4R.SA"

MRCNS, Streptococcal spp., Enterococcal

spp.,

and Clostt"idial spp. (C. perfi.ingens and C.

dfficile)

-Tetracyclines -Mechanism of Action

iYr l$ u,t",o rrrn frt\ +)t*"L Pni:'Jlrn: \6q"-i .h L-'T- Co.?Y

-inhibit bacterial protein synthesis by binding to the 30S ribosomal unit -Mechanisrn of Resistanee -main mechanism is via traxsport pump

ABX accumulation because of 1 efflux by

an active

-Pharrnacology -usually hepatic excretion -bacteriostatic -longtrL life (qd-bid dosing) -bind divalent and trivalent cations (ca, Fe, Mg, Zn) -> -don't take with antacids, dairy products, etc.

absorption

i5

-Major Adverse Effects


-bind calcium and can be deposited in teeth / bone (contraindicated in pre-qnant women I children < 8 )ns.) -nausea (to reduce risk take with food)

-photosensitivity

-vestibular s)rynptoms (vertigo, ataxia, NIV) with minocycline

.-:iU* brey

-Exarnples & Microbial Coverage -do4vcircline (PO / ry) -> Vibramycin, Dor5x, Monodox, generics -tetracycline (PO / IV) -> Sumycin, Achromycin, generics -minocycline (PO) -> Minocin

-Microbial Coverage

i^rf ,r.)b ' ,l'-f -Macrolides -Mechanism of .dction -inhibit bacteria-l protein synthesis by binding to the 50S bacterial ribosoma-l subunit

enzaffiA Le gi orzella, chro@ Pasteure#anrurtocida % fb,sfurl\,1 pfteuw\dt*4 -most S. aureus (including MR.SA) Lyn,a C>\rhs r r Ortpt' t-r,iorkh*rse" A-t: r:
oniae, M. catarrhali s, H. infl M),coplantsa, Ri cketrsia, Ehrli
-

S. pn eum

-Mechanism of Resistance -50S ribosomal modification -> I macrolide binding - I ABX accumulation because of T efflux by an aotive transport pump
-Pharmacology -undergo hepatic metaboiism -erythromycin and clarithromycin inhibit Cyp-450 enzlrnes interactions -bacteriostatic -very high ftissue], but low [serum]

-> d*g

-Major Adverse Effects


-erl4hromycin products activate motilin receptors -) uncoordinated peristalsis -> anorexia / vomiting / diarrhea -motilin is a gastric hormone that activates duodenal / jejunal receptors to initiate peristalsis -clarithromycin may have metaliic taste

i6
-Specific Drugs -clarithromycin (PO) -> Biaxin -azithromycin (PO / n) -> Zithromax -dirithromycin (PO) -> Dynabac -various erythromycin formulations (PO / IV)

Sa**

t1t,,r5 CaoY

co'9f-

-Microbial Coverage
-5.

pneumoniae,

C hlamydi a, Legi

pyogenes (GAS), M. catarrhalis, H. influenzae:---onella, M),coplam sa


S.

-Aminogtycosides

( f*S'*

sifui.zi85,

*-rrtf J

-Mechanism of Action -inhibit bacterial protein synthesis by binding to the 30S bacterial ribosomal subunit
-Mechanisms of Bacterial Resistance -3 mechanism account for resistance to AG 1)50S ribosomal modification -> I AG binding 2) J ABX accumulation because of 1 efflux by an active transport pump 3)synthesis of modifying enzymgs -> AG is changed and no longer binds its target

-Fharmacology -renal excretion


-bacteriocidal -concentration-dependent kiliing -measure [peak] 60 min, after irifusion on the 3'd dose; rneasure ftrough] 30 min. before next dose

-Rationale Behind Once-Daily Aminoglycoside (AG) Dosing -AG are concentration-dependent


-higher levels show faster bacteriocidal effect

-AG have an extended postantibiotic effect (often iasting 2-3 times longer than the half-life of the drug) -even after levels have dropped, bacteria are stilled killed -toxicities of AG maybe time dependent -uptake into renal tubular cells and into the inner ear is saturable and gTeater with constant, iow serum leveis
-neomycin and kanamycin are not systemically absorbed skin itFections and as bowel preps prior to surgery

->

used topically to treat

17

-Major Adverse Effects


-ototoxicity characterized by cochlear damage (hearing loss, tinnitus) or vestibular damage (vertigo, ataxia)
-nephrotoxicity (ATN) -neuromuscular blockade in myasthenia gravis patients -Examples & Microbial Coverage -gentamicin (Itl; Garamycin, generics -toUranyun (inhalation / IV) -> Tobi / Nebcin, generics -amikacin (IV) -> Amikin, generics -netilmicin (IV) -> Netromycin -streptomycin (IV) -) generics -kanamycin (IV) -> Kantrex -neomycin (topical, PO, IV) -> Mycifradin, generic

-t

-Microbial Coverage
-Most GNBs {Proteus, E. coli, Klebsiella, Enterohacter, PsettdonxoTl(rs, Serratia) -Used with PCN or ampicillin for "SYNERGY" ur

ffiG-l

Note: tobramycin is the other main aminoglycoside in clinical usel its main advantage is that it is much better against Pseudomonas than gentamicin

-Fluoroquinolones -lMechanisrn of Action -bind to and inhibit DNA gyrase -> DNA replication inhibited -Mechanism of Resistance -alterations in the bacterial DNA gyrase -Fharmacology -renal > hepatic excretion (depends on drug) -undergo hepatic metaboiism, but are excreted unchanged in the urine -bind divalent and trivalent cations (Ca, Fe, Mg, Zn) -> t absorption -don't take with antacids, dairy products, etc. -bacteriocidal -concentration-dependent & time-dependent killing -long % life

18

-Major Adverse Effects


{enthesitis (contraindicated in preganant women and kids < i8 yrs.) insomnia, seizures, aruiiety, and irritability)
tosensrtr

-alterations in

K
common (especially gatifl oxacin)

-Fluoroquinolone Classes & Microbial Coverage -class : l't Generation (urinary) Quinolones -> No Real crinicar use -enoxacin (PO) -> Pentrex -norfloxacin (PO) *> Noroxin
-Class

: Znd Generation Fluoroquinolones


-ciprofloxacin (PO I IV) -> Cipro -ofloxacin (PO) -> Floxin -lomefloxacin (PO) -> Maxaquin

UTT

-Microbial Coverao"
-Covers most G- organisms (E. coli, Klebsiella, Enterobacter, P,seudomonas aeruginasa, Pr oteus, Serrati a, N. gon art"hae ae,

Pastelrella multocida, M. catanhalis, H, influenzae) -use for E. cmthracis


-Class

3'd Generation Fluoroquinolones (..Respiratory -levofloxacin (PO / IV) -> Levaquin -qatifloxacin (PO / W) -> Tequin -moxifloxa.cin (PO / [V) -> Avelox -sparfloxacin (PO) -> Zagam -gemifloxacin (PO) -> Factive

Fe")

c\\

'60
, r,(

-h{icrobial Coverage

"''

.t-)itr)

-rc'

-Covers most G- organisms (E. coli, Klebsiella, Enterobacter, P seu domonas aerugitto sa, Protezt s, S errctia, N. gotton.ltoe ae, Pasteurella multocida, M. catsn.halis, H. influenzae) -Excellent coverage of respiratory pathogens, including atypicais (5. pneumoniae, S. pyogenes (GAS), Legionella. M),coplasma, Chlanrydia)

19

-Sulfonamides & Trimethoprim -Mechanisrn of Action -sulfa products interfere with bacterial folic acid synthesis by inhibiting dihydrofolic acid synthesis (structural analogue of para-aminobenzoic acid (PABA)) -trimethoprim inhibits dihydrofolic acid reduction to tetrahydrofolate Note: this results in sequential enryrne inhibition -Mechanism of Resistan ce
-altered enzyme targets for both sulfa and trimethoprim - I sulfa accumulation - I production of PABA

-Pharmacology (based on TMP-SMX) -renal excretion


-bacteriostatic
-1ong %

life

-Major Adverse Effects -N/V


-hypersensitivity reaction (rash - including SJS) -reversible myelosuppression (mostly HIV patients on j dose) -hemolytic anemia in patients with G6pD d.eficiency

-Example & Microbial Coverage (fypically used as a combination product) -trimethopiim + sulfamethoxazoie (PO / ry) -> Bactrirn, Septra, generics

-Microbial Coverage
-5. pneumoniae,

H. infl,uenzae, M. catcnrhalis, PnemnocJtstic jir'.oveci,

P ast e ut' e I l.a mu k o ci da, Ste no tr" op It afti onas nm I t op hi I a

-Most E. coli, Klebsiella, Proteus, MRSA

Note: there are many other sulfa products fypicalty used topieally for burns Note: trimethoprim (Trimpex) can be used alone if sulfa allergy exists

*,*o, c* trys

20

-Streptograrnins -Mechanism of Action -inhibit bacterial protein slmthesis by binding to the 50S bacteriai ribosomal subunit -Mechanism of Resistance -ribosomal target site modifi cation -Pharmacology & Spectrum of Coverage -bacteriocidal when both compounds are used together

-MajorAdverse Effects -IV site phiebitis (eliminated with C\{L)


-myalgias

-Example & Microbia! Cover*ge -dalfopristin l quinupristin GV)

->

Synercid

-Microbial Coverage
-Staphylococcal spp. (including MRSA), Stt'eptococcl spp., and vancomycin-resistant E. fae ciunt

-Lin cosamtd* -Mechanisrn of Action -inhibit bacterial protein synthesis by binding to the 50S bacterial ibosomal subunit -Mechanism of Resistance -ribosomal target site modification -Pharrnacology & Spectrum of Coverage liver metabolisin and excretion
-bacteriostatic,

G,. erloa:)

-Major Adverse Effects


-diarrhea (including C.

dfficile colitis)

-Exarnples & Microbial Coverage -clindamycin (PO i IV) -> Cieocin

-Microbial Coverage
-5. aureus, S. pneumoniae, S. pyogevles (GAS), Bacteroides spp., and other oral / colon anaerobes

21

-Oxazolidinones -Mechanism of Action -bacterial protein synthesis inhibitor

-Mechanism of Resistance -unknown -Pharrnacology & Spectrum of Covenage -bacteriostatic

-Major Adverse Effects -N/V/D


-reversible thrombocytopenia (monitor platelets) -reversibie inhibitor of monoamine oxidase (watch dietary tyramine)

-Examples & Microbial Coverage -linezolid (PO / IV) -> Zyvbx

-Nlicrobial Coverage -used for MRSA anfl We infections only


-Miseellaneous Antibiotics -Metronidazole (PO / n4 -t Ftagytr -Meehanism of Action -metronidazole, by itself is inactive, but an enzyme found in anaerobes (and possibly protozoa) conrzerts it to toxic fi-ee radicals, which interacts with DNA to cause helical DNA structure and strand breakage resulting in inhibition of protein synthesis and cell death

-Mechanism of Resistance -unknown (very littlf resistance) -Pharmacology

&

Spectru

of Coverage

-covers

lon some proto zo a {Tt" i c /rom onas,

En

9:qi?,

-Nlajor Aslverse Effects

Lg.lAElme' *disulfiramlike

reaction r','ith alcohol -? fetotoxic in l"t trimester

22

-Nitrofurantoin (PO) -= Macrodantin, Macrobid -Mechanism of Action

3,*pl.

eyl+hs

-inhibits several bacterial enzT/me systems inciuding acetyl COA interfering with metabolism and possibly cell wali synthesis

-Mechanism of Resistance -unknown


-Pharrnacology & Spectrum of Coverage -excreted quickiy into the urine -most urinary pathogens (G- organisms and Enterococcus)

-Major Adverse Effects


Jong-term use may possibiy lead to pulmonary fibrosis

-Chloramphenicol
-binds 50S ribosomai subunit -> bacteriostatic -active against H. inflztenzae, S. pentrmoniae, N. nreningitidis, and some anaerobes -reaches therapeutic CNS levels (potentially used as last resorl in CNS infections) -rarely used because of toxicities -bone malrow suppression and possibly falal aplastic anemia

-Fosfomycin -inhibits bacterial cell wall synthesis -typicaliy used for uncompiicated UTIs due to Enterococci or E. coli

-Polymyxin B
-interact with plasma membrane phospholipids -> loss of intracellular components -active only against G- organisms -often used as part of a cornbination topical ABX product

-Methanamine
-rapidly excreted into the urine (no systemic effects) that in an acidic urinary environment is broken down to formaldehyde and ammonia -fonnaidehyde is bacteriocidal to most bacteria -may be used to treat uncompiicated / chronic UTIs

-Daptomycin (IM / fV) -> Cubicin

.1
i

23 \

-Antivirals

-Acydlivir (PO / nr) -> Zavirax


-used to treat HSV and VZV infections -main SE include GI intolerance and HA

-high-dose rV may cause ARF (from crystalline nephropathy)

* t'\rmantadine Efp)=:Sqrm etret used fo@iluer@prophylaxis S,f symptom onset) ft

or treatment (if sta*ed within 48 hrs.

of

-main SE include GI intolerance and CNS effects (nervousness, anxiety, insomnia, lethargy, etc.)

-Cidofovir (topicat I fD -t \zistide -used for cMV retinitis and is active

a-eainst smalrpox in ttitt.o -main SE include nephrotoxicity, neutropeni4 and metaboljc acidosis

-Farnciclovir (PO) -> Famvir -used to treat HSV and VZV infections -once absorbed its converted to penciclovir -main SE include GI intolerance and IIA

-Ganciclovir {fV} -> Cytovene \ -used for CMv infections -main SE is myelosuppression

\/

CnV

-trnterferon AIfa Froducts (Se / il\C) -exarnples include -interferon-u, products (Infergen, Alferon N, Roferon-{ Intron A) -pegylated interferon-s products (PEG-Intron, pegasysf ["rrr5 ,l t.l,R -used to treat HBV and HCV -pegylated products are dosed less frequently ap4 are more effective than standard interferon alfa products -main SE is an " influenza-like syndrome,'

)L

-Oseltamivir (PO) -> Taruiflu

-used rot@ffiE-lorophylaxis or treatment (if started within 36 hrs. of syrxptom -main SE is N/V

onse|-*

-Penciclovir (topical) -> Denavir -used for topical treatment of orolabial HSV lesions

24

-Ribavirin (aerosol / PO) -> Virazole / Rebetol


-Virazole is used in children infected with RSV -Rebetol is used in conjunction with interferon-o products to treat HCV -main SE includes -teratogenicrty (pregnant women should not be exposed to aerosolized ribavirin) -systemic ribavirin may cause hemolytic anemia

-Rimantadine

(PkJFlUgadin

![rophylaxis or treatment (if started within 48 hrs. of exposure) -main SE include GI intolerance and CNS effects (less than amantadine)
-used for(qfluenza

-Valacyclovir (PO) -> Valtrex -used to treat HSV and VZV infections -once absorbed its converted to acyclovir -main SE include GI intolerance and HA -Valganciclovir (PO) -> Valeyte -used for CMV infections
-once absorbed its converted to ganciclovir

-main SE is myelosuppression

-Zanamivir (oral inhalationl -GeieEza -used for influenz@@ilph-ylaxis or treatment (if started within 36 hrs. of
symptom onset) -main SE is nasai / throat discomfon; bronchospasm has been reported in patients with reactive airway disease

25

-Systemic Antifungals

-Amphotericin B (w) -> Fungizone -used for invasive aspergillosis and other deep fungal infections -main SE include fever / chills and nephrotoxicity

- I Flcwitir apep, hydrocortisone, and meperidine - i nephrotoxicity with sodiumJoading


-watch for I Mg+ and K+

-Liposomal Arnphotericin B Products -example -amphotericin B lipid compiex -> Abelcet (ABLC) -amphotericin B cholesteryl sulfate complex -> Amphotec (ABCD) Jiposomal arnphotericin B -> Ambisome -less nephrotoxic than amphotericin B -generally used for deep fungal infections in patients not tolerating amphotericin B -Caspofungin (trV) -> Caneidas -used for invasive aspergillosis & Candida spp. -generally well tolerated with few drug interactions
-Fiuconazole (PO / tR -> Diflucan -used for various infections causedfty{gldj!:yp -main SE include rash and GI intolerance -watch flcr drug-drug interaction (immunosuppressants, rifabutin, phenytoin, AZT, indinivir, warfarirl and sulfonylureas)

Lcinn;S, \ firt" Ut'7t -Itraconazole (PO / tV) -> Sporonox AJur^; tic -used prirnarily for invasive aspergillus infections & onychomycosis -main SE include GI intolerance -watch for drug-drug interaction as this drug is a potent CY3A4 inhibitor (immuno suppressant s, rifabutin, digoxin, benzo diazepines, etc. )
-Voriconazole (PO / n}-> Vfend -used for invasive aspergillosis and other deep fungal infections -main SE is reversibie visual disturbances (photophobi4 altered color perception, etc ) -similar drug interactions as other -azole rirugs

he