Introduction to Antibiotic Therapy

1. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
Review I: Antibiotic Sites of ActionReview I: Antibiotic Sites of Action
Gram negative: Klebsiella Gram positive: Bacillus
From Essentials of Medical Microbiology, 2nd edition; W.A. Volk, ed.
Review II: Morphological DifferencesReview II: Morphological Differences
Between Gram+ and GramBetween Gram+ and Gram-- BacteriaBacteria

2. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
Review III: Differences Between Gram+Review III: Differences Between Gram+
and Gramand Gram-- Cell Walls and MembranesCell Walls and Membranes
I. The Bacterial Cell WallI. The Bacterial Cell Wall
A. Not present on mammalian cells,A. Not present on mammalian cells,
and therefore an excellent targetand therefore an excellent target
for selective toxicity toward bacteriafor selective toxicity toward bacteria
B. ComponentsB. Components
1.1. Gm+ organismsGm+ organisms
a. crossa. cross--linkedlinked peptidoglycanpeptidoglycan (3(3--D)D)
b.b. teichoicteichoic acidsacids-- essential foressential for
appropriate cell separationappropriate cell separation
c. rarely, polysaccharidesc. rarely, polysaccharides
** d. inner membrane with proteinsd. inner membrane with proteins
((PBP: penicillinPBP: penicillin--binding proteinsbinding proteins))

3. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
2.2. GmGm-- organismsorganisms
a. 3a. 3--layered outer envelopelayered outer envelope
i. outer membranei. outer membrane
--phospholipidsphospholipids
--proteins (proteins (PorinsPorins))
--lipopolysaccharidelipopolysaccharide (LPS)(LPS)
ii. thinii. thin peptidoglycanpeptidoglycan layerlayer
iii.iii. periplasmicperiplasmic spacespace
b. inner membrane with proteinsb. inner membrane with proteins
((PBPsPBPs))
II.II. Cell WallCell Wall PeptidoglycanPeptidoglycan
A.A. FunctionFunction: provides support to: provides support to
maintain cell integrity undermaintain cell integrity under
conditions of osmotic stressconditions of osmotic stress
B.B. Disruption ofDisruption of peptidoglycanpeptidoglycan
synthesis leads to cell deathsynthesis leads to cell death
due to osmotic shockdue to osmotic shock
(the intracellular(the intracellular
environment isenvironment is
hypertonichypertonic; the cell wall; the cell wall
restricts the volume ofrestricts the volume of
water taken up)water taken up)
From Essentials of Medical Microbiology, 2nd edition; W.A. Volk, ed.

4. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
From Basic & Clinical
Pharmacology, 8th edition,
B.G.Katzung, ed.
Antimicrobial inhibition
of cell wall synthesis can
be effected at several steps
in the pathway:
1.1. FosfomycinFosfomycin
2.2. CycloserineCycloserine
3.3. BacitracinBacitracin
4.4. VancomycinVancomycin **
glycolipidglycolipid
5.5. bb--lactamslactams andand
vancomycinvancomycin
C.C. Biosynthesis ofBiosynthesis of peptidoglycanpeptidoglycan
and its inhibition by drugsand its inhibition by drugs
1. overview1. overview
2.2. peptidoglycanpeptidoglycan crosscross--linking: anlinking: an
activity of a plasma membrane PBPactivity of a plasma membrane PBP
From Essentials of Medical Microbiology, 2nd edition; W.A. Volk, ed.
*
*

5. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
3.3. peptidoglycanpeptidoglycan crosscross--linking:linking:
differences between Gm+ and Gmdifferences between Gm+ and Gm--
From Essentials of Medical Microbiology, 2nd
edition; W.A. Volk, ed.
Gm- Gm+
III.III. Cell Wall Synthesis InhibitorsCell Wall Synthesis Inhibitors
A.A. FosfomycinFosfomycin
--structural analog ofstructural analog of phosphoenolphosphoenol
pyruvatepyruvate (PEP), the(PEP), the lactyllactyl donor fordonor for
synthesis ofsynthesis of muramicmuramic acidacid
--binds the active site ofbinds the active site of enol pyruvateenol pyruvate
transferasetransferase to block addition of PEPto block addition of PEP
and UDPand UDP--NN--acetylglucosamineacetylglucosamine
--oral administration onlyoral administration only
--renal excretionrenal excretion
--used for treatment of recurrent UTI;used for treatment of recurrent UTI;
effective on Gram + and Grameffective on Gram + and Gram --

6. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
B.B. DD--CycloserineCycloserine
-structurally similar to D-alanine; a
competitive inhibitor of 2 steps
in cell wall synthesis
alanine racemase: L-Ala to D-Ala
D-alanyl-D-alanine synthetase: D-Ala—D-Ala
--administered orally; 70administered orally; 70--90% absorbed90% absorbed
rapidly; good CNS penetrationrapidly; good CNS penetration
--toxicity: CNS (reversible)toxicity: CNS (reversible)
--used with otherused with other tuberculostatictuberculostatic
drugs when firstdrugs when first--line agents failline agents fail
C.C. BacitracinBacitracin
--inhibitsinhibits dephosphorylationdephosphorylation ofof undecaundeca--
prenylprenyl pyrophosphate topyrophosphate to undecaprenylundecaprenyl
phosphate + Pphosphate + Pii; accumulation of the; accumulation of the
substrate deprives the cell of the lipidsubstrate deprives the cell of the lipid
carrier necessary for synthesis ofcarrier necessary for synthesis of
peptidoglycanpeptidoglycan,, teichoicteichoic acid, andacid, and
OO--linkedlinked sidechainssidechains of LPSof LPS
--topical application ONLYtopical application ONLY
--ophthalmologicalophthalmological uses: conjunctivitis;uses: conjunctivitis;
corneal ulcercorneal ulcer
--Gram +;Gram +; NeisseriaNeisseria;; T.T. pallidumpallidum

7. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
D.D. VancomycinVancomycin (&(& teichoplaninteichoplanin) *****) *****
--glycopeptides bind with high affinityglycopeptides bind with high affinity
to the Dto the D--AlaAla——DD--Ala terminus of cellAla terminus of cell
wall precursor units; block transwall precursor units; block trans--
peptidationpeptidation
--onlyonly vancomycinvancomycin is used in the U.S.is used in the U.S.
--I.V. administration; renal excretionI.V. administration; renal excretion
--adverse effects:adverse effects: 1. Red Man Syndrome1. Red Man Syndrome
2.2. ototoxicityototoxicity
--good against Gram +;good against Gram +; critical agent forcritical agent for
treatment of infections by MRSAtreatment of infections by MRSA; poor; poor
or no impact on Gramor no impact on Gram ––
D.D. VancomycinVancomycin (&(& teichoplaninteichoplanin) continued) continued
1.1. mechanisms of resistancemechanisms of resistance
a.a. enterococcienterococci carry resistancecarry resistance
gene on a conjugativegene on a conjugative
plasmidplasmid; transfer to other; transfer to other
enterococcienterococci and Gram +and Gram +
b.b. bacteria can synthesize abacteria can synthesize a
pentapeptidepentapeptide with Dwith D--alaala--DD--
lactatelactate terminus, rather thanterminus, rather than
DD--alaala--DD--ala (reduced affinity)ala (reduced affinity)
c.c. bacteria canbacteria can overexpressoverexpress DD--
alaala--DD--ala; acts as a competitorala; acts as a competitor
to bind up the drugto bind up the drug

8. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
E.E. ββ--Lactam antimicrobialsLactam antimicrobials
1.1. as structural analogs ofas structural analogs of
terminal Dterminal D--AlaAla——DD--Ala on theAla on the
peptidoglycanpeptidoglycan strand,strand,
covalently bind to thecovalently bind to the PBPsPBPs
mediatingmediating transpeptidationtranspeptidation..
Competitively block transCompetitively block trans--
peptidationpeptidation ofof peptidoglycanpeptidoglycan..
2.2. also cause the release ofalso cause the release of
teichoicteichoic acids from Gm+ cellsacids from Gm+ cells
--this process precedesthis process precedes
hydrolysis, which involves thehydrolysis, which involves the
release ofrelease of murein hydrolasesmurein hydrolases
involved in cell wall divisioninvolved in cell wall division
IV.IV. ββ--Lactam AntimicrobialsLactam Antimicrobials:: PenicillinsPenicillins
A.A. Penicillin was the first truePenicillin was the first true
antibiotic discoveredantibiotic discovered
B.B. Penicillins GPenicillins G (benzylpenicillin)(benzylpenicillin)
andand VV (phenoxymethylpenicillin)(phenoxymethylpenicillin)
are the penicillin prototypesare the penicillin prototypes
1.1. the usefulness of penicillin Gthe usefulness of penicillin G
is limited by:is limited by:
a.a. acid instabilityacid instability (i.e., less effective(i.e., less effective
upon oral administration)upon oral administration)
b. its very rapid renal excretionb. its very rapid renal excretion
(t(t½½=~30 min);=~30 min); ProbenecidProbenecid??

9. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
3.3. susceptibility to inactivation bysusceptibility to inactivation by
penicillinasespenicillinases
C.C. There are also penicillinaseThere are also penicillinase--
resistant and extendedresistant and extended--spectrumspectrum
penicillins, which are either usedpenicillins, which are either used
alone or withalone or with ββ--lactamaselactamase
inhibitorsinhibitors
D.D. Penicillin chemistryPenicillin chemistry
1.1. all penicillins have the same 6all penicillins have the same 6--
aminopenicillanicaminopenicillanic acid nucleusacid nucleus
this nucleus is synthesized bythis nucleus is synthesized by
PenicilliumPenicillium molds andmolds and
contains acontains a ββ--lactam ringlactam ring ——
essential for antibacterialessential for antibacterial
activityactivity
b-lactam ring
COOHCH
CHCH
CH3
C
S
NCO
CH3
2
NH
thiazolidine ring

10. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
2.2. thethe ββ--lactam ring is also presentlactam ring is also present
inin cephalosporinscephalosporins,, carbapenemscarbapenems,,
carbacephemscarbacephems, and, and monobactamsmonobactams
cleavage of the ring bycleavage of the ring by
penicillinasespenicillinases ((ββ--lactamaseslactamases))
results in the conversion of theresults in the conversion of the
penicillin into an inactivepenicillin into an inactive
penicilloicpenicilloic acidacid
am
idases
am
idases
b-lactam ring
penicillinspenicillins
66--aminopenicillanic acidaminopenicillanic acid
penicilloic acidspenicilloic acids
penicillinases
penicillinases
((bb––lactam
ases
lactam
ases))
COOHCH
CHCH
CH3
C
S
NCO
C
O
NH
CH3
R
COOHCH
CHCH
CH3
C
S
NCO
O
CH3
C OH 2
R NH+
COOH
CHCH
CH3
C
S
NC
C
O
NH
CH3
O
R
CH
OH H
Penicillins: chemistry (continued)

11. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
3.3. hydrolysis of the amide bondhydrolysis of the amide bond
between the acyl sidebetween the acyl side--chain andchain and
the 6the 6--aminopenicillanic acid moietyaminopenicillanic acid moiety
by amidases results in theby amidases results in the
liberation ofliberation of 66--aminopenicillanicaminopenicillanic
acidacid-- has significant, but less,has significant, but less,
antibacterial actionantibacterial action (NOT used(NOT used
therapeutically)therapeutically)
COOHCH
CHCH
CH3
C
S
NCO
O
CH3
C OH 2
R NH+
4.4. the semisynthetic penicillins havethe semisynthetic penicillins have
different acyl sidedifferent acyl side--chain substituents (chain substituents (RR))
a.a. each substituent imparts specificeach substituent imparts specific
chemical, pharmacologic, and antichemical, pharmacologic, and anti--
bacterial properties to the penicillinbacterial properties to the penicillin
moleculemolecule-- acid stability, degree ofacid stability, degree of
binding to plasma proteins, antibinding to plasma proteins, anti--
bacterial spectrum, and resistance tobacterial spectrum, and resistance to
penicillinasepenicillinase
COOHCH
CHCH
CH3
C
S
NCO
C
O
NH
CH3
R

12. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
E.E. Mechanism of actionMechanism of action
1.1. penicillins and otherpenicillins and other ββ--lactamlactam
antibiotics bind to and interfereantibiotics bind to and interfere
with bacterial cell membranewith bacterial cell membrane
proteins called penicillinproteins called penicillin--bindingbinding
proteins (proteins (PBPsPBPs))
a.a. PBPsPBPs include transpeptidasesinclude transpeptidases
and carboxypeptidases thatand carboxypeptidases that
catalyze reactions involvedcatalyze reactions involved
in the final step of cell wallin the final step of cell wall
synthesissynthesis, the cross, the cross--linking oflinking of
peptidoglycan polymerspeptidoglycan polymers
b.b. ββ--lactam antibiotics preventlactam antibiotics prevent
the formation of a complete,the formation of a complete,
intact cell wall, and this resultsintact cell wall, and this results
in the lysis of the bacterial cellin the lysis of the bacterial cell
in the relatively hypoin the relatively hypo--osmoticosmotic
environment in mostenvironment in most
mammalian tissues and fluidsmammalian tissues and fluids
c.c. thus, the penicillins and otherthus, the penicillins and other
ββ--lactam antibiotics arelactam antibiotics are
bactericidal and require thatbactericidal and require that
bacteria be growing andbacteria be growing and
synthesizing cell walls to besynthesizing cell walls to be
effectiveeffective

13. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
From Essentials of Medical Microbiology,
2nd edition; W.A. Volk, ed.
murein hydrolasesmurein hydrolases
act hereact here
cell wall synthesiscell wall synthesis
is blockedis blocked
inin hypotonichypotonic medium,medium,
thethe spheroblastspheroblast burstsbursts
==--cidalcidal
in isotonic medium,in isotonic medium,
thethe spheroblastspheroblast is stableis stable
==--staticstatic
e.g., renal medulla

14. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
F.F. Antibacterial spectrumAntibacterial spectrum
1.1. penicillins G and Vpenicillins G and V (natural(natural
penicillinspenicillins) have a relatively) have a relatively
narrow antibacterial spectrumnarrow antibacterial spectrum
they mainly affect:they mainly affect:
gramgram--positive aerobespositive aerobes
facultative aerobesfacultative aerobes
some gramsome gram--negative coccinegative cocci
some anaerobes (esp. in oral cavity)some anaerobes (esp. in oral cavity)
spirochetes (spirochetes (T.T. pallidumpallidum))
penicillin V is widely used for softpenicillin V is widely used for soft
tissue infections,tissue infections, cellulitiscellulitis,,
periodontal infectionsperiodontal infections
G.G. BacterialBacterial resistance toresistance to penicillinspenicillins
develops slowly by 1 of 4 mechanismsdevelops slowly by 1 of 4 mechanisms
1.1. production ofproduction of penicillinasespenicillinases (most(most
common)common)—— >100>100 ββ--lactamaseslactamases havehave
been identified; some act on allbeen identified; some act on all ββ--
lactamslactams, while others exhibit some, while others exhibit some
degree of substrate specificitydegree of substrate specificity
a.a. Gm+Gm+ penicillinasespenicillinases areare
inducible andinducible and exocellularexocellular
GmGm-- penicillinasespenicillinases may bemay be
inducible or constitutive, and lieinducible or constitutive, and lie
within thewithin the periplasmicperiplasmic spacespace

15. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
b.b. this is the most importantthis is the most important
mechanism of resistance, sincemechanism of resistance, since
the ability to synthesizethe ability to synthesize ββ--
lactamaselactamase can be transferredcan be transferred
to other microbes viato other microbes via transductiontransduction
this is why most strains ofthis is why most strains of
StaphylococcusStaphylococcus today aretoday are
resistant to most penicillinsresistant to most penicillins
and why the number ofand why the number of
penicillinpenicillin--resistant organisms isresistant organisms is
steadily increasingsteadily increasing
2.2. alteration of targetalteration of target PBPsPBPs —— thisthis
usually results a decreasedusually results a decreased
affinity for the penicillinaffinity for the penicillin
3.3. alteration of the outer membranealteration of the outer membrane
proteinsproteins of susceptible gramof susceptible gram--
negativenegative coccicocci —— prevents the drugprevents the drug
from reaching the target PBPfrom reaching the target PBP
4.4. efflux pumpefflux pump activityactivity —— transportstransports
ββ--lactamslactams across the bacterialacross the bacterial
outer membraneouter membrane

16. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
H.H. AbsorptionAbsorption
1.1. penicillin Gpenicillin G —— because of its acidbecause of its acid
labilitylability, only a portion of an orally, only a portion of an orally
administered dose is absorbedadministered dose is absorbed ——
this is why it is administeredthis is why it is administered
parenterallyparenterally, usually by IM injection, usually by IM injection
(IV for serious infections)(IV for serious infections)
ΒλοοδΛεϖελ
2 4 6 12 18 24
Τιµε (ηουρσ)
Βενζατηινε
πενιχιλλιν Γ
Προχαινε
πενιχιλλιν Γ
Πεν Γ (οραλ)
Πεν ς (οραλ)
Πεν Γ (ιντραµυσχυλαρ)
I.M.
can give I.V.None penetrate CNS
well when meninges
are intact;
better penetration
when meninges are
inflamed.
2.2. penicillin Vpenicillin V is acid stable and isis acid stable and is
much more effective after oralmuch more effective after oral
administrationadministration
3.3. procaineprocaine andand benzathinebenzathine penicillinpenicillin
GG are waterare water--insoluble depot, orinsoluble depot, or
repository, forms that arerepository, forms that are
administered IMadministered IM
the penicillin is absorbed slowlythe penicillin is absorbed slowly
and continuously over a longand continuously over a long
period of time to produce aperiod of time to produce a
prolonged duration of actionprolonged duration of action

17. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
becausebecause procaineprocaine andand benzathinebenzathine
penicillin Gpenicillin G yield low blood titers,yield low blood titers,
they are used only against highlythey are used only against highly
susceptible microorganismssusceptible microorganisms
ΒλοοδΛεϖελ
2 4 6 12 18 24
Τιµε (ηουρσ)
Βενζατηινε
πενιχιλλιν Γ
Προχαινε
πενιχιλλιν Γ
Πεν Γ (οραλ)
Πεν ς (οραλ)
Πεν Γ (ιντραµυσχυλαρ)
I.I. Metabolism and excretionMetabolism and excretion
1.1. most penicillinsmost penicillins are notare not
significantly metabolized andsignificantly metabolized and
are very rapidly eliminated byare very rapidly eliminated by
the kidney (penicillin tthe kidney (penicillin t1/21/2=30 min)=30 min)
a.a. therefore, the dose must betherefore, the dose must be
decreased in patients withdecreased in patients with
impaired renal functionimpaired renal function
b.b. but, because most penicillinsbut, because most penicillins
are primarily excretedare primarily excreted
unchanged in the urine, theyunchanged in the urine, they
are useful in the treatment ofare useful in the treatment of
urinary tract infectionsurinary tract infections

18. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
J.J. Therapeutic usesTherapeutic uses
1.1. the penicillins are among thethe penicillins are among the
most effective and mostmost effective and most
extensively used antibioticsextensively used antibiotics
(narrow spectrum; high selective(narrow spectrum; high selective
toxicity)toxicity)
2.2. however, their use is becominghowever, their use is becoming
limited due to the emergence oflimited due to the emergence of
resistant organismsresistant organisms
K.K. Adverse effectsAdverse effects
1.1. the penicillins and otherthe penicillins and other ββ--
lactamlactam antibiotics exhibitantibiotics exhibit
maximal selective toxicitymaximal selective toxicity
--mammalian cells do not havemammalian cells do not have
cell wallscell walls
2.2. they are relatively nonthey are relatively non--toxic but:toxic but:
a.a. are irritating to tissues and canare irritating to tissues and can
cause phlebitis when given IVcause phlebitis when given IV
b.b. can lead to superinfectioncan lead to superinfection

19. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
c.c. penicillin G can produce apenicillin G can produce a
dosedose--dependentdependent neurotoxicityneurotoxicity
leading toleading to epileptiformepileptiform seizuresseizures
3.3. the most common adverse effect ofthe most common adverse effect of
penicillin therapy ispenicillin therapy is allergicallergic
reactionsreactions
--the incidence of allergic reactionsthe incidence of allergic reactions
has decreased with the availabilityhas decreased with the availability
of highly purified preparationsof highly purified preparations
a.a. allergic reactions seen today areallergic reactions seen today are
primarily due to breakdownprimarily due to breakdown
products of the 6products of the 6--aminoamino--
penicillanicpenicillanic acid molecule andacid molecule and
usually occur after parenteralusually occur after parenteral
administrationadministration —— but canbut can
sometimes be seen after oralsometimes be seen after oral
administrationadministration
b.b. occur in 1occur in 1--10% of patients and10% of patients and
may result in crossmay result in cross--sensitizationsensitization
among all penicillins as well asamong all penicillins as well as
to chemicallyto chemically--related drugs suchrelated drugs such
as the cephalosporinsas the cephalosporins

20. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
c.c. incidence depends on the type ofincidence depends on the type of
penicillin and its route ofpenicillin and its route of
administrationadministration
i.i. procaine penicillin Gprocaine penicillin G ——
causes significant incidencecauses significant incidence
of allergyof allergy, probably because, probably because
procaine also is allergenicprocaine also is allergenic
ii.ii. topical administration is mosttopical administration is most
likely to cause sensitizationlikely to cause sensitization ——
this is why thethis is why the penicillinspenicillins
should never be used topicallyshould never be used topically
(except in ophthalmology)(except in ophthalmology)
d.d. the presence of penicillins inthe presence of penicillins in
food products (milk, beef, andfood products (milk, beef, and
poultry) can also result inpoultry) can also result in
sensitization, as can exposure tosensitization, as can exposure to
PenicilliumPenicillium moldsmolds
e.e. 3 types of allergic reactions3 types of allergic reactions
i.i. acute reactionsacute reactions such assuch as
anaphylactic shockanaphylactic shock —— occuroccur
within 30 minutes ofwithin 30 minutes of
administrationadministration
-- lifelife--threatening: treatthreatening: treat
with epinephrine with orwith epinephrine with or
without a corticosteroidwithout a corticosteroid

21. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
ii.ii. accelerated reactionsaccelerated reactions —— occur 30occur 30
min to 48 hrs after administrationmin to 48 hrs after administration
and generally are not lifeand generally are not life--
threateningthreatening
iii.iii. delayed reactionsdelayed reactions —— occur two oroccur two or
more days after administration andmore days after administration and
generally are mild and reversible,generally are mild and reversible,
e.g., a rashe.g., a rash
-- account for 80account for 80--90% of90% of
all allergic reactions toall allergic reactions to
penicillinspenicillins
LL.. PenicillinasePenicillinase--resistant penicillinsresistant penicillins
cloxacillincloxacillin K,BK,B
dicloxacillindicloxacillin K,BK,B
methicillinmethicillin XX
nafcillinnafcillin BB
oxacillinoxacillin K,BK,B
1.1. may eliminate penicillinasemay eliminate penicillinase--
producing strains ofproducing strains of S. aureusS. aureus ——
but arebut are much less active againstmuch less active against
some gramsome gram--positive species andpositive species and
inactive against graminactive against gram--negativenegative
organismsorganisms

22. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
2.2. bacterial resistance occursbacterial resistance occurs
primarily with methicillin and isprimarily with methicillin and is
due to the appearance of a PBPdue to the appearance of a PBP
having a lowered affinity forhaving a lowered affinity for
methicillin and some othermethicillin and some other ββ--
lactam antibioticslactam antibiotics
3.3. pharmacokineticspharmacokinetics
a.a. methicillinmethicillin is unstable inis unstable in
acidic environments and wasacidic environments and was
only usedonly used parenterallyparenterally-- not innot in
use, due touse, due to nephrotoxicitynephrotoxicity
b.b. cloxacillin, dicloxacillin, andcloxacillin, dicloxacillin, and
oxacillinoxacillin are acid stable andare acid stable and
effective wheneffective when given orallygiven orally
c.c. nafcillinnafcillin is somewhat lessis somewhat less
stable in acidic media andstable in acidic media and isis
commonly administeredcommonly administered
parenterallyparenterally for treatingfor treating
serious systemic infectionsserious systemic infections
d.d. clearance?clearance?
4.4. major therapeutic usesmajor therapeutic uses
treatment of infections causedtreatment of infections caused
by penicillinaseby penicillinase--producing strainsproducing strains
ofof S. aureusS. aureus

23. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
5.5. adverse effectsadverse effects
generally the same as forgenerally the same as for
penicillinspenicillins G and V except that:G and V except that:
a.a. methicillin causes a highmethicillin causes a high
incidence of interstitialincidence of interstitial
nephritisnephritis due to an allergicdue to an allergic
reactionreaction
b.b. oxacillin may cause hepatitisoxacillin may cause hepatitis
after the administration ofafter the administration of
very high dosesvery high doses
MM.. ExtendedExtended--spectrum penicillinsspectrum penicillins
1.1. 3 groups of drugs3 groups of drugs
a.a. amino penicillinsamino penicillins —— includeinclude
amoxicillinamoxicillin*, ampicillin,*, ampicillin, andand
bacampicillinbacampicillin (which is a(which is a
prodrug, being convertedprodrug, being converted
into ampicillininto ampicillin in vivoin vivo))
b.b. carboxy penicillinscarboxy penicillins —— includeinclude
carbenicillin,carbenicillin, ticarcillinticarcillin
c.c. ureidopenicillinsureidopenicillins:: azlocillinazlocillin,,
mezlocillinmezlocillin andand piperacillinpiperacillin

24. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
2.2. the antibacterial spectra of boththe antibacterial spectra of both
groups are generally similar togroups are generally similar to
that of penicillin G with thethat of penicillin G with the
following major differencesfollowing major differences
a.a. amino penicillinsamino penicillins areare --cidalcidal
for both gramfor both gram--positive andpositive and
gramgram--negative bacterianegative bacteria (upper(upper
respiratory tract, urinary tract,respiratory tract, urinary tract,
andand SalmonellaSalmonella infections;infections;
meningitis)meningitis)
b.b. carboxy penicillins are effectivecarboxy penicillins are effective
against strains ofagainst strains of PseudomonasPseudomonas,,
ProteusProteus,, H.H. influenzaeinfluenzae, and, and E.E.
colicoli;; ureidopenicillinsureidopenicillins also arealso are
effective against Gmeffective against Gm-- bacillibacilli
3.3. bacterial resistance developsbacterial resistance develops
to all due to the inducedto all due to the induced
production ofproduction of penicillinasespenicillinases
4.4. pharmacokineticspharmacokinetics
a.a. in general,in general, amino penicillinsamino penicillins
are stable in acidare stable in acid and areand are
well absorbed after oralwell absorbed after oral
administrationadministration
b.b. carboxy penicillins are notcarboxy penicillins are not
well absorbed from the GIwell absorbed from the GI
tracttract

25. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
5.5. major therapeutic usesmajor therapeutic uses
a.a. amino penicillinsamino penicillins —— treatmenttreatment
of infections due toof infections due to susceptiblesusceptible
gramgram--negative microbes andnegative microbes and
treatment of mixed infectionstreatment of mixed infections
caused by susceptible gramcaused by susceptible gram--
positive and grampositive and gram--negativenegative
organisms;organisms; periodontitisperiodontitis
i.i. amoxicillinamoxicillin —— drug of choicedrug of choice
for prophylaxis againstfor prophylaxis against
bacterialbacterial endocarditisendocarditis
(What alternatives for allergic pts?)(What alternatives for allergic pts?)
(Mono(Mono--associated rash?)associated rash?)
b.b. carboxy penicillinscarboxy penicillins ——
treatment of urinary tracttreatment of urinary tract
infections caused byinfections caused by
susceptiblesusceptible PseudomonasPseudomonas sp.sp.
6.6. adverse effects of the extendedadverse effects of the extended--
spectrum penicillinsspectrum penicillins are similarare similar
to those of the other penicillinsto those of the other penicillins
butbut they cause a greaterthey cause a greater
incidence of superinfectionsincidence of superinfections

26. Introduction to Antibiotic Therapy II
Dr. N. Lill, 71:111
February 11, 2004
N.N. ExtendedExtended--spectrum penicillin/spectrum penicillin/ββ--
lactamase inhibitor combinationslactamase inhibitor combinations
(augmented(augmented penicillinspenicillins))
1.1. extendedextended--spectrum penicillinsspectrum penicillins
often are administered togetheroften are administered together
with awith a ββ--lactamase inhibitorlactamase inhibitor toto
prevent the inactivation of theprevent the inactivation of the
penicillinpenicillin
-- overcomes resistance due toovercomes resistance due to
the production ofthe production of penicillinasepenicillinase
by many microbial strains thatby many microbial strains that
are otherwise susceptible toare otherwise susceptible to
penicillinpenicillin
2.2. 33 ββ--lactamase inhibitors are used:lactamase inhibitors are used:
clavulanic acid, sulbactamclavulanic acid, sulbactam, and, and
tazobactamtazobactam
theythey resembleresemble ββ--lactams structurally butlactams structurally but
have very weak antibiotic activityhave very weak antibiotic activity
each is used in a fixed combination witheach is used in a fixed combination with
specific penicillins: e.g., amoxicillinspecific penicillins: e.g., amoxicillin--
clavulanate (Augmentinclavulanate (Augmentin®®), ampicillin), ampicillin--
sulbactam, piperacillinsulbactam, piperacillin--tazobactamtazobactam