7/24/2019 abx part I 2015

1/39

Pharmacology of Antibacterial

and Antifungal Agents

Part IDana Whitney, Pharm.D., BCPS

Clinical Pharmacy Specialist Infectious DiseasesBoston Medical Center

dana.whitney@mc.or!

7/24/2019 abx part I 2015

2/39

Learning Objectives

"ecall the mechanisms of action, pharmacodynamic

and pharmaco#inetic properties of the ma$or classes

of antiiotics

Identify the representati%e spectrum for antiioticprototypes

Identify the ad%erse effects for the ma$or antiiotic

classes

Descrie common mechanisms of resistance toantiiotics

7/24/2019 abx part I 2015

3/39

Antibiotic prescriptions by dentists

represent what percentage of the totalvolume of outpatient antibiotic

prescriptions?

&. '()B. *')

C. +()

D. +)

7/24/2019 abx part I 2015

4/39

Structure

Lecture IIntroduction

Cell wall synthesis inhibitors

ecture II-ancomycin

Protein synthesis inhiitors

ucleic acid structure inhiitors

ecture III&ntifolates

&ntimycoacterials

&ntifun!al a!ents

7/24/2019 abx part I 2015

5/39

7/24/2019 abx part I 2015

6/39

Principles of Antibiotic herapy

reatmentof infection /mpiric

ased on most li#elymicroes and theirproale susceptiility

Documented0definiti%e y culture of microes and

determination ofsusceptiility to dru!s

Prophylactictherapy topre%ent infection

1se the most narrow, leastto2ic, most cost3effecti%ea!ent

&ntiiotics aid the ody4s

defenses in clearin! theinfection /liminate the or!anism y

physical means 5i.e. incisionand deridement6

7/24/2019 abx part I 2015

7/39

Antibiotic Selection

&ntiiotic

7actorsSpectrum

PK/PDAdverse effects

Drug interactions

Cost

Patho!enLikely organisms

Susceptibility

8ost 7actorsAge

Immune status

Renal and epatic function

Recent antibiotic e!posure

Allergy/IntoleranceDisease severity

Pregnancy and Lactation

7/24/2019 abx part I 2015

8/39

Pharmaco!inetics "P#$ of Antibiotics

P9 :descries what theody does to the dru!; & &sorption

D Distriution

-d 5

7/24/2019 abx part I 2015

9/39

7/24/2019 abx part I 2015

10/39

Pharmacodynamics "P%$ of Antibiotics

PD :descries what the dru! does to the ody Aor

microor!anism; Descries antimicroial effect

Bactericidal Bacteriostatic

Post antiiotic effect 5P&/6

PD parameters

ime dependent acti%ity 5MIC, &1CMIC6 Concentration dependent acti%ity 5Cma2MIC, &1CMIC6

7/24/2019 abx part I 2015

11/39

&actericidal vs' &acteriostatic

LogBacteria

Time

Static

Cidal

Antibiotic

Log

Immune &ssistance

Cell wallsynthesisinhibitors

7/24/2019 abx part I 2015

12/39

Pharmacodynamics

Rybak M. Am J Med 2006;119:S37-

7/24/2019 abx part I 2015

13/39

() y*o woman with estimated

CrCl +) ml*min, being treated for

peridontal abscess

Dru! & 5concentration dependent6 *'(m! E+*h

Dru! & 5concentration dependent6 '((m! E*Fh

Dru! B 5time dependent6 +! EFh

Dru! B 5time dependent6 *! EGh

7/24/2019 abx part I 2015

14/39

Bactericidal

Bacteriostatic

Cma2MIC

MIC

&. Concentration dependent

acti%ity

B. "eEuires immune

assistance to clear

infectionC. Cell wall synthesis

inhiitors

D. ime dependent acti%ity

7/24/2019 abx part I 2015

15/39

Cell -all Synthesis Inhibitors

Penicillins Beta lactamase inhiitor cominations

Cephalosporins

Carapenems

-ancomycin

Beta 3

lactams

7/24/2019 abx part I 2015

16/39

.echanism of Action

Inhiits PBPs

In%ol%ed in the cross lin#a!e of peptide chains Pre%ents the de%elopment of normal peptido!lycan structure

Cell lysis Hsmotic pressure or acti%ation of endo!enous autolysins

7/24/2019 abx part I 2015

17/39

&asic beta/lactam structure

Manipulations of side chain alter spectrum, susceptiility andpharmaco#inetic properties

oal "apidly actericidal, nonto2ic, ioa%ailale, resistant to de!radation,

hi!h affinity for PBPs

7/24/2019 abx part I 2015

18/39

Penicillins Cephalosporins

Carbapenems

7/24/2019 abx part I 2015

19/39

Penicillins "spectrum$

MSS& streptococci

S" pneumoniae

" influen#ae

/nteric ramne!. 5$"coli%

Klebsiella%Proteus6

anaeroes

atural PCspenicillin -9

J only

Penicillinase

resistant PCs

J only

&minopenicillinsamo2icillin

J only

&mo2icillin0

cla%ulanic acid

Caro2yPCs,ureidoPCs

J only

arrow spectrum

Broader Spectrum

7/24/2019 abx part I 2015

20/39

Average .IC

7/24/2019 abx part I 2015

21/39

Penicillin and amo0icillin1 P#

&sorption Difficult to achie%e hi!h serum concentrations with PH formulations &mo2icillin penicillin

ood penetration into most tissues, e2cept prostate, eye,and uninflamed CS7

Primarily e2creted y #idneys &d$ust with moderate3se%ere renal impairment

In !eneral, shorter half3life than most antimicroials &mo2icillin penicillin

Proenecid loc#s renal e2cretion and causes increasedserum le%els of penicillin

7/24/2019 abx part I 2015

22/39

P#

2 3 Proteinbinding3

ime toPea!"hr$

Pea!"mcg*mL$

ime torough"hr$

Pencillin I- 33 '( (.'3+ *'3'( F3K

Penicillin -9 K( G( + *.'3' F

Penicillin procaine 33 '( *3F +( +*

Penicillin en=athine 33 '( *F3FG (.* L3F w#s

&mpicillin I- 33 *( (.'3+ *'3'( K

&mo2icillin '3N( *( + 3+( K3G

7/24/2019 abx part I 2015

23/39

Penicillins "Adverse effects$

8ypersensiti%ity 5+3+()6&naphyla2is 5(.((F to (.(+')6 Cross3reacti%ity with cephalosporins '3+()

Phleitis 5+3+()6 I disturances 5+3+()6 8ematolo!ic 5O+)6 /lectrolyte disturances 5O+)6

eurolo!ic 5O+)6 "enal 5interstitial nephritis6 5O+)6

7/24/2019 abx part I 2015

24/39

Case 4 A&

F' y0o male with recent aortic %al%e replacement. Cardiolo!ist instructs him to call you prior to his

ne2t dental appointment for a prescription for

antiiotics. What type of therapy is this

7/24/2019 abx part I 2015

25/39

American 5eart Association 6uidelines for

the Prevention of Infective 7ndocarditis "I7$

Prophyla2is is recommended for dental proceduresthatin%ol%e

Manipulation of !in!i%al tissues or periapical re!ion of

teeth

Perforation of oral mucosa Prophyla2is is only for patients with

1nderlyin! cardiac conditions associated with the

hi!hest ris# of ad%erse outcome from I/

Circulation"*((Q++'

7/24/2019 abx part I 2015

26/39

8nderlying cardiac conditions

associated with the highest ris!

Prosthetic cardiac %al%e Prior history of infecti%e endocarditis Con!enital heart disease 5C8D6

1nrepaired cyanotic C8D

Completely repaired, during the first 6 months after theprocedure "epaired C8D with residual defects

Cardiac transplantation recipients who de%elop cardiac%al%ulopathy

Circulation"*((Q++'

7/24/2019 abx part I 2015

27/39

9ecommended 9egimens Co%era!e ofStreptococcus viridans Hral re!imens + hour prior to procedure I- re!imens L( min prior to procedure

Standard !eneral prophyla2is &mo2icillin *!m PH

1nale to ta#e oral medications &mpicillin *!m IM or I-

&ller!ic to penicillin Clindamycin K((m! PHCephale2in *!m PHR&=ithromycin '((m! PHClarithromycin '((m! PH

&ller!ic to penicillin and unale to ta#e oralmedications

Clindamycin K((m! I-Cefa=olin +!m I-RCeftria2one +!m I-R

R should not e used in indi%iduals with immediate3type hypersensiti%ity reaction 5urticaria,

an!ioedema, or anaphyla2is6 to penicillins

Circulation"*((Q++'

7/24/2019 abx part I 2015

28/39

Case 4 A&

F' y0o male with recent aortic %al%e replacement. Which prophylactic antiiotic should e !i%en

&mo2icillin * ! PH 2 + 5ta#e + hour prior to procedure6

What should e considered prior to writin! the

prescription&ller!ies if aller!ic to PC, assess aller!y and consider

alternati%es

Which ad%erse effects should he e made aware of

7/24/2019 abx part I 2015

29/39

Antimicrobial 9esistance

Intrinsic characteristics of the dru! pre%ent reachin! thetar!et site or the dru! is inacti%ated

&cEuired resistance which de%elops 5hori=ontally or%ertically6

Mechanisms Dru! cannot reach the tar!et site Dru! is inacti%ated ar!et site is altered

7/24/2019 abx part I 2015

30/39

9esistance to beta/lactam Antibiotics

Dru! is inacti%ated 3 beta&lactamases

7/24/2019 abx part I 2015

31/39

&eta Lactamase Inhibitors

Cla%ulanic acid Compounded with some

penicillins

Binds to eta lactamase,

pre%ents the destruction of

the parent dru! /nhances the spectrum of

the parent dru! if the

decreased acti%ity is a result

of eta3lactamases

7/24/2019 abx part I 2015

32/39

R&u!mentin amo2icillin J cla%ulanic acid

7/24/2019 abx part I 2015

33/39

Penicillins

Cephalosporins

7/24/2019 abx part I 2015

34/39

Cephalosporins "spectrum$

MSS& streptococci

S" pneumoniae

" influen#ae

/nteric ramne!. 5$"coli%Klebsiella%Proteus6

anaeroes

+st!enerationcephale2in

*nd!eneration

*nd!enerationcephamycins

Lrd!enerationcefpodo2ime

Fth!eneration

arrow spectrum

Broader Spectrum

7/24/2019 abx part I 2015

35/39

Cephalosporins

Pharmaco#inetics &sorption

I- for se%ere infections

PH for mild0moderate

infections

Distriution

Similar to penicillins

Metaolism

/2cretion

renal

&d%erse /ffects enerally well tolerated

I disturances 5+3+()6

Phleitis 5+3+()6

8ypersensiti%ity 5O +)6 8ematolo!ic 5O +)6

"enal 5O +)6

euroto2icity 5O +)6

7/24/2019 abx part I 2015

36/39

9esistance to beta/lactam Antibiotics

Dru! is inacti%ated 3 beta&lactamases Penicillinases Cephalosporinases /2tended spectrum eta lactamases 5/SBs6

Dru! cannot reach the tar!et site 3 alterations inmembrane permeability or efflu!

ar!et site is altered 3 alterations in P'P Penicillin resistant S" pneumoniae 5P"SP6

Methicillin resistant S" aureus5M"S&6

7/24/2019 abx part I 2015

37/39

Carbapenems

Mechanism of action similar to PCs Broad spectrum a!ent 3 reser%ed as last line for

resistant or!anisms ram positi%e, !ram ne!ati%e, anaeroes

Pharmaco#inetics I- only ood distriution "enally e2creted 3 reEuires dose ad$ustment in patients with

renal dysfunction

&d%erse effects 8ypersensiti%ity, sei=ures 5caution in patients with sei=urehistory or renal disease6

-hich of the following is true of

7/24/2019 abx part I 2015

38/39

-hich of the following is true of

beta 4 lactam agents?

a6 Primarily acteriostatic6 Common mechanisms of resistance include en=ymatic

inacti%ation, altered tar!et sites

c6 Intra%enous and oral formulations are eEually ioa%ailale

d6 "esponsile for many dru! dru! interactions due toinhiition of CTP F'(, isoen=yme L&F

e6 &ntiacterial acti%ity is concentration dependent 5hi!her

pea#s ha%e !reater antiacterial acti%ity

Summary

7/24/2019 abx part I 2015

39/39

Summary

cell wall synthesis inhibitors

beta lactams Penicillins 5penicillin, amo2icillin6

Cephalosporins

cephale2in cefpodo2ime

Carapenems