Penicillins, Beta-Lactam

Inhibitors and Cephalosporins

PENICILLINS
 CHEMISTRY:
 Basic structure : nucleus containing a
thiazolidine ring, Beta lactam ring and a side
chain
PENICILLINS

 Discovered by Alexander Fleming (1928) from

Penicillium notatum
 Commercial production made possible from
the works of Florey, Chain and associates
 The modern “antibiotic era” was initiated by
the general availability of penicillin G in the
U.S. by the middle of the 1940’s
PENICILLINS

 Core ring structures esp. the β-lactam ring

 essential for antibacterial activity
 Side chain: determines antibacterial
spectrum and pharmacologic properties of a
particular penicillin
PENICILLINS

 Emergence of β-lactamase producing

organisms – Staphylococcus aureus
 Prompted development of compounds that are
resistant to hydrolysis by beta-lactamases
 Prompted the search for agents that are more
active than penicillin G against gram (-) species
PENICILLINS
 The isolation of the penicillin nucleus (6-
amino penicillanic acid) from a precursor –
depleted fermentation of Penicillium
chrysogenum made possible the production
and testing of semisynthetic penicillins:
 Methicillin – active against β-lactamase-producing
S.aureus
 Ampicillin – active against selected GNB
 Carbenicillin – active against Pseudomonas
aeruginosa
MECHANISM OF ACTION of β-lactams

 Penicillin inhibits enzymes that catalyze the

final step in bacterial cell wall assembly which
is the formation of the cross-links that bridge
peptidoglycan
 Final common pathway of bactericidal
antibiotics: stimulation of the production of
deleterious hydroxyl radicals that irreversibly
damage the cell
 It is this transpeptidase reaction that is sensitive to
the inhibition action by penicillin
 The penicillin sensitive reactions are catalyzed by
proteins called Penicillin-Binding-Proteins (PBP)
PENICILLINS

 Penicillin receptor PBPs transmit a

transmembrane signal that give rise to β-
lactamases
 β-lactamases are PBPs
 β-lactamases ‘catalyze’ the hydrolysis of the
β-lactam ring
 PBPs are membrane bound except for β-
lactamases which may be secreted or
membrane associated
PENICILLINS

 PBPs are inhibited by β-lactam antibiotics by

covalent binding of the active site serine residue
 Because the high molecular weight PBPs carry
the essential functions for survival of the cell, it
is the binding to and inhibition of the high
molecular weight PBPs that mediate the
antibacterial activity of β-lactam antibiotics
 Low molecular weight PBPs play a role in the
maintenance of cell shape and septum
formation
PENICILLINS

 PBPs account for 1% of the membranes protein

 The PBPs vary in the amount present and in the
physiologic functions they serve in cell wall
assembly
 PBPs differ in their affinity to bind to β -lactam
antibiotics
 The differences in affinity for binding can
explain in part why β-lactam antibiotics differ in
antibacterial properties and spectrum of activity
PENICILLINS
 The ‘lethal’ effect of β-lactam antibiotics on
bacteria involve the simultaneous inactivation of
multiple PBPs
 Note: inhibition of cell wall synthesis, ‘by itself’ ,
is not necessarily lethal. ex) non-growing cells
and osmotically protected cells can survive in the
presence of penicillins
 The unopposed action of autolysins that occur
when PBPs are inhibited by β-lactam antibiotics
contribute to the antimicrobial effects in some
organisms
PENICILLINS
 Cell ‘lysis’ is not required for cell ‘death’,
although it is ‘lethal’ and often accompanies cell
wall inhibition
 The ‘lethal effect’ in both gram (+) and gram (-)
organisms is ‘cell-cycle dependent’ where the
inhibition of PBPs leads to the disruption of
some ‘crucial’ event during the time of cell
division
 It is from this ‘disturbed morphogenesis’ event
that it is hypothesized the initiation of cell death
takes place
BACTERIAL RESISTANCE

 4 MECHANISMS:
 Account for clinically significant bacterial
resistance to penicillins and other β-lactam
antibiotics
 1) Destruction of antibiotic by β-lactamase
 2) Failure of antibiotic to penetrate the outer
membrane of GNB to reach PBP targets
BACTERIAL RESISTANCE

 3) Efflux of drug across the outer membrane

of GNB
 4) Low affinity binding of antibiotic to target
PBPs
BACTERIAL RESISTANCE

 The most common mechanism of resistance:

 The β-lactamase destruction of the antibiotic
 This is often accompanied by efflux in GNB
(particularly P.aeruginosa)
 β-lactamase covalently react with the β-
lactam ring, rapidly hydrolyze it then
subsequently destroy the activity of the drug
BACTERIAL RESISTANCE

 β-lactamases can be categorized in to 4

classes
 Ambler classes A, B, C, D
 The classes are based on amino acid
sequence similarity and molecular structure
BACTERIAL RESISTANCE

 CLASS A, C and D:
 Contain penicillin binding motifs
 They are PBPs
 Compared to other PBPs:
 smaller in size
 not cell synthetic enzymes
 As with other PBPs: they react with penicillin
through the same series of reactions
BACTERIAL RESISTANCE

 Biochemically: main distinction between cell

wall ‘synthetic’ PBPs and β-lactamases is the
rate of deacylation
 Deacylation of β-lactamase is much faster
that leads to rapid hydrolysis and turn over of
β-lactam molecules
BACTERIAL RESISTANCE

 CLASS B:
 They hydrolyze the β-lactam ring like the
other classes
 But, structurally, are unrelated to PBPs
 They are ‘Zinc’ dependent enzymes
 They use a ‘different’ series of reactions to
open the β-lactam ring
BACTERIAL RESISTANCE

 Most clinically important β-lactamases are Class A

and C
 Class A:
 - are penicillinases but also have cephalosporinase or
carbapenemase activity in some
 - are inhibited by β-lactamase inhibitors (ex.
Clavulanic acid)
 - point mutations can render the enzyme inhibitor
resistant or extend the spectrum of activity to
include 3rd generation cephalosporins and
monobactams (extended spectrum β-lactamases)
BACTERIAL RESISTANCE

 Class C:
 - are cephalosporinases ‘NOT’ inhibited by
clavulanic acid
 - are encoded on the chromosome and
inducible
 Inhibited by cloxacillin and monobactams
BACTERIAL RESISTANCE

 Class B:
 - are the broadest spectrum enzymes
 - are inhibited by chelating agents
 - are able to hydrolyze all β-lactams ‘except’
monobactams
BACTERIAL RESISTANCE
 The outer membrane of GN organisms is an
important barrier to drug penetration and an
important component to resistance
 The β-lactamases of GN bacteria are found in the
periplasmic space between the inner cytoplasmic
membrane and the outer lipopolysaccharide
membrane
 The location of the β-lactamases in the GN help
protect target PBPs from exposure to active β-
lactam antibiotics
 But, small polar molecules can cross this barrier
through protein channels called ‘porins’
BACTERIAL RESISTANCE

 ‘porins’ can constrain the entry of molecules into

the cell according to size, structure and charge
 β-lactam antibiotics can be made that satisfy
and meet the standards of entry requirement by
the porins and can enter and traverse the porin
channels and gain entry to the periplasmic space
and bind to target PBPs
 The ‘absence’ or ‘deletion’ of a critical porin in
the presence of β-lactamase activity can result in
‘resistance’
BACTERIAL RESISTANCE

 3rd mechanism: EFFLUX

 The drug that enters the periplasmic space is
pumped back across the outer membrane
 Efflux can operate independantly of other
mechanisms but the exclusion of antibiotic by
porins , the destruction of antibiotic by β-
lactamases or both can contribute to
resistance by limiting the periplasmic
antibiotic concentration
BACTERIAL RESISTANCE

 Species differences in porins, pumps, β-

lactamases and target PBPs will determine
whether an organism is susceptible or
resistant to a particular antibiotic
 ‘mutations’ that affect protein structure or
protein expression can cause a strain that was
initially susceptible to certain β-lactam
antibiotic to become resistant to it
BACTERIAL RESISTANCE

 4th mechanism: Low affinity binding between

antibiotic and target PBPs
 - may be the result of mutation of PBP genes
that lower affinity to binding (ex. Penicillin
resistant pneumococci or Neisseris species)
 - may be the result of an extra, low affintiy
PBP (ex. PBP 5 of Enterococci faecium, PBP
2a of Methicillin resistant staphylococci)

BACTERIAL RESISTANCE

 The low affinity binding produces unfavorable

interactions between antibiotic and protein
that lead to failure of inactivation or failure to
block cell wall synthesis and bacterial growth
CLASSIFICATION

 5 CLASSES
 Based on the antibacterial activity
 Considerable overlap between classes
 1) natural penicillins, penicillin G and penicillin
 2) penicillinase-resistant penicillins, methicillin,
nafcillin and isoxazolyl penicillins
 3) aminopenicillins, ampicillins, and amoxicillin
 4) carboxypenicilins, carbenicillin, and ticarcillin
 5) acyl ureidopenicillins,azlocillin, mezlocillin and
piperacillin
CLASSIFICATION

 Differences between classes are

pharmacologic, although one compound in
one class may be more active than another
PHARMACOLOGIC PROPERTIES
 Penicillins differ markely in their oral
absorption
 Acid labile compounds, penicillin G,
methicillin, and anti pseudomonal penicillins
are poorly absorbed
 Acid stable compounds can have major
differences in oral absorption
 Semi-synthetic penicillins are well absorbed
(except nafcillin)
PHARMACOLOGIC PROPERTIES

 Ampicillin is only partially absorbed (30-60%);

food decreases absorption
 Amoxicillin is almost totally absorbed
 Orally absorbed penicillins yield peak
concentrations 1-2hrs after ingestion but
delay with ingestion of food
PHARMACOLOGIC PROPERTIES

 Penicillins are bound by serum proteins with

varying degress (17% aminopenicillins to 97%
dicloxacillin)
 The major protein to which penicillins bind is
albumin
 Only the ‘unbound’ drug exerts the
antimicrobial activity; however, protein
binding is reversible and it is possible for
bound penicillin to be released and the newly
unbound penicillin can kill bacteria
PHARMACOLOGIC PROPERTIES

 The major mechanism by which most drugs

are removed by the body is by excretion via
the kidney as intact molecules
 Penicillins are metabolized to a minor degree;
but it is important to note that even in minor
metabolic differences, clinically significant
differences can result in the half-life for those
suffering from renal failure
 Biliary excretion of penicillins occurs
(nafcillin, antipseudomonal penicillin)
PHARMACOLOGIC PROPERTIES
 Penicillins are rapidly excreted by renal tubular
cells with a short half life of 30min for penicillin
to 70min for carbenicillin
 Ability of renal tubular cells to excrete penicillin
varies
 Excretion can be blocked by probenicid
 Probenicid is an inhibitor of organic acid
secretion by tubular cells that subsequently
prolongs the half life of all penicillins
 Probenicid also competes for binding sites on
albumin and therefore there is more free drug in
the presence of probenicid
PHARMACOLOGIC PROPERTIES
 Renal excretion of penicillins in newborns is less
than in older children because tubular function is
not fully developed
 Dosage programs for penicillins must be
modified for newborns and low birth weight
infants
 Dosage adjustments must also be taken into
account for poor renal function and creatinine
clearance
 Peritoneal dialysis removes variable amounts of
penicillins
PHARMACOLOGIC PROPERTIES
 Penicillins are well distributed to most tissues
(lung, liver, kidney, muscle, bone, placenta)
 Most penicillins are insoluble in lipid and
penetrate cells poorly
 Inflammation alters normal barriers and permits
the entry of penicillins
 Urinary concentrations of penicillins are high
even with moderately reduced renal function
 Most penicillins are actively secreted into the bile
that yield biliary concentrations in excess of
those in the serum
UNTOWARD REACTIONS
 Major adverse reactions: hypersensitivity
reactions (rash  anaphylaxis)
 Major determinants of penicillin allergy:
 Penicilloyl determinant – produced through
opening of the β-lactam ring thereby allowing
amide linkage to body proteins
 Penicillanic acid and its derivatives are produced
when reconstituted penicillins break down in
solution from acidity or temperature elevation
UNTOWARD REACTIONS
 Minor determinants of allergy:
 Benzyl penicillin and sodium benzyl penicilloate:
can act as sensitizing agents or can elicit an
allergic reaction
 Both major and minor determinants may be
involved in anaphylactic and urticarial
reactions
 Reactions are mediated by IgE antibody
 The minor determinants are the major cause
of anaphylactic reactions
UNTOWARD REACTIONS

 Penicillin allergy quite common

 Less than 2% will have an allergic reaction if
challenged
 Risk is higher for those with history of an
immediate hypersensitivity reaction or a
positive skin test
UNTOWARD REACTIONS
 Serum sickness – uncommon
 characterized by fever, urticaria, joint pains and
angioneurotic edema
 Rare forms of allergic reactions:
 exfoliative dermatitis and Stevens-Johnsons
syndrome
 Allergic vasculitis
 extremely rare allergic reaction with formation of
cutaneous and visceral lesions
 Epinephrine IM or IV aborts hypersensitivity
reaction
UNTOWARD REACTIONS

 Antihistamines and corticosteroids

 no benefit shown
 Hemotologic toxicity – rare
 Neutropenia – when large doses are used
 Returns to normal when agent is discontinued
 Coombs positive hemolytic anemia - rare
 UNTOWARD REACTIONS
 Renal toxicity
 Clinical syndrome: fever, macular rash, eosinophilia,
proteinuriam eosinophiluria, hematuria
 ranges from allergic angitis to interstitial nephritis
 Interstitial nephritis most common with methicillin
 Initial reaction : nonoliguric reanl failure with
decreased CrCl, increased BUN and Creatinine
UNTOWARD REACTIONS

 Renal toxicity

 Progress to anuria and renal failure

 Bx of kidney: interstitial infiltrate of mononuclear
and eosinophilic cells with tubular damage but no
glomerular lesions
 Discontinuation of penicillin results in return of
renal function to normal in most cases
UNTOWARD REACTIONS

 Hypokalemia – massive doses of Penicillin,

most often Ticarcillin
 Due to the large doses of non reabsorbable anion
presented to the distal renal tubules which alters
hydrogen ion excretion and secondarily results in
potassium loss
 UNTOWARD REACTIONS
 CNS Toxicity – myoclonic seizures after
massive doses of Penicillin G ( 40 – 100 M
units/day)
 More likely if there is decreased renal function, the
drug accumulate and this toxicity becomes more
likely
UNTOWARD REACTIONS

 Gastrointestinal disturbances – oral forms

 More pronounced with ampicillin
 Antibiotic ass’d colitis due to Clostridium difficile
has followed the use of each of the penicillins

 Abolishment of normal bacterial flora – high

doses for prolonged periods
 Results in colonization of GN bacilli or with fungi
such as Candida
UNTOWARD REACTIONS

 Abnormalities in liver function test results

 Elevation of alkaline phosphatase and
aminotransferase (transaminase) levels
 Most often after oxacillin and flucloxacillin

 Major hepatic injury - uncommon

CLINICAL USE

 Penicillin G primary agent for infections from:

S. pyogenes, penicillin susceptible strains of S.
pneumoniae, and enterococci
 IV penicillin G: pneumococcal and
meningococcal meningitis, streptococcal and
enterococcal endocarditis and neurosyphilis

CLINICAL USE

 Penicillin G is the primary agent for infections

from: S. pyogenes, penicillin susceptible
strains of S. pneumoniae, and enterococci
 IV penicillin G is the tx of choice for
pneumococcal and meningococcal
meningitis, streptococcal and enterococcal
endocarditis and neurosyphilis
 Newer penicillins or agents in other classes
have not shown to be more effective
CLINICAL USE
 Penicillin susceptible strains of S. pneumoniae
are inhibited at concentrations of less than
0.1 ug of penicillin
 Other penicillins are highly active but theire
minimal inhibitory concentration (MIC) are
greater than that of penicillin G
 The activity of the penicillins in the other
groups is maintained against penicillin
resistant strains of S. pneumoniae but at
higher MICs
CLINICAL USE
 Penicillin, ampicillin and amoxicillin are the
most active compounds. Their MICs rarely
exceed 4ug/ml
 Ticarcillin - effective action at MICs of
128ug/ml or greater against highly penicillin
resistant strains
 Infections caused by penicillin resistant
pneumocci respond to penicillin G in high
dose. However, clinical failures in cases with
pneumococcal meningitis
CLINICAL USE

 Vancomycin or another non β-lactam is

preferred over penicillin or other β-lactam
antibiotic for serious pneumococcal
infections caused by penicillin resistant
strains with MICs greater than 1ug/ml
 Penicillin should only by used to treat
pneumococcal meningitis if the isolate if fully
penicillin susceptible
CLINICAL USE: Pen G
 All Neisseria meningitidis strains are
susceptible
 N. gonorrhoeae strains are frequently
resistant to penicillin - no longer
recommended to treat gonorrhea
 drug of choice for treating syphilis
 puerperal infections from anaerobic
streptococci or group B streptococci and to
treat genital clostridial infections
CLINICAL USE: Penicillin G
 treat anaerobic mouth infections that include GP and
GN cocci and actinomycetes
 Penicillinase resistant penicillins - Drug of choice of
infections from methicillin susceptible strains of
staphylococci
 More active against viridans, streptococci, S. pyogenes,
other hemolytic streptocci, penicillin susceptible
strains of S. penumoniae, anaerobic GP cocci and
anaerobic GP bacilli
 Preferred drug although penicillinase resistant
penicillins can cover these organisms
CLINICAL USE

 The penicillinase resistant penicillins and

penicillins compounds are inactive against
Listeria monocytogenes, Enterococcus spp and
methicillin resistant strains of Staphylococci
 The production of PBP 2a is the basis of
methicillin resistance in staphylococci where
there is low affinity for binding methicillin
 The penicillinase resistant penicillins and
penicillins lack GN activity
CLINICAL USE
 Aminopenicillins – URTI, LRTI, bacterial
gastroenteritis, bacterial endocarditis, meningitis,
UTIs caused by susceptible organisms
 Amoxicillin
 excellent bioavailability
 preferred agent for oral administration
 highly tolerated even in high doses in children when
given 3 times a day
 recommended as one component of a triple drug
combination regimen for tx of ulcers and gastric
infections caused by H. pylori
CLINICAL USE
 Antipseudomonal and extended spectrum
penicillins - infections caused by resistant GN
bacilli
 Should be used in combi with another
antipseudomonal agent, typically
aminoglycoside, for non-UT pseudomonal
infections
 Ureidopenicillins (piperacillin) - active against
many strains of Klebsiella spp., Enterobacter spp.,
Serratia marcescens and providentia
CLINICAL USE

 Ticarcillin
 less active against enterococci than
ureidopenicillins and ampicillin
 should not be used to treat documented infections
caused by these organisms
 fallen into disuse
 Piperacillin - still widely used
 often given as a combination with Tazobactam
because of the prevalence of β-lactamase
producing strains
CLINICAL USE

 The activity of piperacillin, however, against

GN (P. aeruginosa, Enterobacter, Citrobacter,
Serratia, Providentia) is not improved by the
combination with Tazobactam because of a
class C -lactamase they produce that is not
inhibited by β-lactamase inhibitors
 Piperacillins can be used alone without
Tazobactam to ward off infections by these
organisms
PROPHYLACTIC USE

 Penicillins have been used in several manners

to prevent infection
 Oral and IM injections of penicillins help to
control the onset and spread of infection
 Recurrent Rheumatic Fever: 200,000U of
Penicillin G or Penicillin V orally q 12hrs; 1.2-
2.4 M U of Benzathine Penicillin IM once
monthly
PROPHYLACTIC USE

 Outbreaks of infection by S. pyogenes:

aborted by the prophylactic use of 200,000U
Penicillin G or V orally BID x 5days or by IM inj
single dose of procaine Penicillin OD or of
Benzathine Penicillin
 For asplenic children or children with
agammaglobulinemia: oral ampicillin or
amoxicillin prevents infection caused by H.
influenzae and S. pneumoniae
PROPHYLACTIC USE
 Prophylaxis of bacterial endocarditis: a single
2G oral dose of Penicillin is recommended
 Penicillin prophylaxis has not shown to be of
benefit
 Meningococcal infection
 bacterial infection after a viral respiratory infection
 pneumonia after coma
 Shock
 CHF
PROPERTIES OF INDIVIDUAL
PENICILLINS
 NATURAL PENICILLINS: Penicillin G
 Available as a salt for oral and parenteral
administration and as repository salts for IM
injection
 unstable in acid and therefore penicillin V
(amoxicillin) should be used for oral
administrations
 Crystallin form of pen. G in aqueous solution can
be used IM, SC, IV and intrathecally
PROPERTIES OF INDIVIDUAL
PENICILLINS
 Pen. G given IM in an aqueous sol’n is cleared
very rapidly by the body and may be
preferably used in a repository form
 Repository penicillins give tissue depots from
which the drug is absorbed over several hours
to several days
 Repository penicillins are for IM use only
PROPERTIES OF INDIVIDUAL
PENICILLINS
 PENICILLIN V
 only for oral use as a sodium or potassium salt in
suspension form or tablets in doses of 125, 250
and 500mg
 For children dose: 25-50mg/kg/day in 3 or 4
divided doses
 For adult dose: 1-4 G/day in 3 or 4 divided doses
PROPERTIES OF INDIVIDUAL
PENICILLINS
 PENICILLIN V
 The potassium salt produces higher blood levels
than the other salts
 Serum levels are from 2-5 times that obtained
with pen G
 an adult dose of Pen V 500 mg orally will reach
blood levels equal to an IM injection of 600,00U of
procaine penicillin
PROPERTIES OF INDIVIDUAL
PENICILLINS
 PENICILLIN V
 can be used in place of Pen G for cases of serious
infections where treatment by oral route is
reasonable
 less active than Pen G against Haemophilus,
Neisseria, and enteric organisms
PROPERTIES OF INDIVIDUAL
PENICILLINS
 PENICILLINASE RESISTANT PENICILLINS
 antibiotic spectra is identical among the members
of this group
 Active against methicillin susceptible strains of
staphylococci, penicillin susceptible strains of
streptococci, and most anaerobic GP cocci
 Not active against MRSA, high level penicillin
resistant streptococci, enterococci, Listeria
monocytogenes, aerobic GN cocci or bacilli, or
anaerobic GN bacteria
PROPERTIES OF INDIVIDUAL
PENICILLINS
 PENICILLINASE RESISTANT PENICILLINS
 ‘METHICILLIN’
 first of many penicillinase resistant penicillins
developed
 least active by weight
 acid labile and therefore can only be administered
parenterally
 more likely to cause interstitial nephritis
 no longer used clinically because of this
PROPERTIES OF INDIVIDUAL
PENICILLINS
 NAFCILLIN
 Has more intrinsic activity than methicillin against
susceptible organisms
 Highly protein bound
 Oral absorption is erratic
 Circulating levels after IM injection are low
 IV route is the only practical administration route
PROPERTIES OF INDIVIDUAL
PENICILLINS
 NAFCILLIN
 Primarily excreted by the liver and to a lesser
extent by the kidney
 Combination with probenacid will elevate serum
levels and prolong the half life
 Adult dose: 6-12 G/day depending on infection
severity
 Child dose: 100-200 mg/kg/day
PROPERTIES OF INDIVIDUAL
PENICILLINS
 NAFCILLIN
 ‘Isoxazolyl Penicillins’
 Absorbed following oral administration but
absorption is affected with food
 Oxacillin, cloxacillin, dicloxacillin, and flucloxacillin
 Dicloxacillin and flucloxacillin yield the highest
total drug serum concentration
PROPERTIES OF INDIVIDUAL
PENICILLINS
 NAFCILLIN
 ‘Isoxazolyl Penicillins’
 IV infusion of 1G over 15min will produce serum
levels of 25ug/mL after 1hr and less than 1ug/mL
after 6 hrs
 Excreted primarily by the kidney with some biliary
excretion
 Oxacillin undergoes more rapid degradation than
cloxacillin and dicloxacillin
PROPERTIES OF INDIVIDUAL
PENICILLINS
 NAFCILLIN
 ‘Isoxazolyl Penicillins’: OXACILLIN
 Sodium for injection can be IM or IV
 Adult dose: 2-12 G/day
 Child dose: 100-300 mg/kg/day q 4-6 hrs
 higher incidence for hepatotoxicity and rash than
with nafcillin or other antistaphylococcal agents
PROPERTIES OF INDIVIDUAL
PENICILLINS
 NAFCILLIN
 ‘Isoxazolyl Penicillins’: CLOXACILLIN
 Sodium by oral solution (125mg/5mL) or capsules
(250mg, 500mg)
 Adult dose: 1-4 G/day in four equal doses
 Child dose: 25-50mg/kg/day in four equal doses
PROPERTIES OF INDIVIDUAL
PENICILLINS
 NAFCILLIN
 ‘Isoxazolyl Penicillins’: DICLOXACILLIN
 Sodium as a suspension (62.5mg/5mL) and as
capsules (125mg, 250mg)
 Adult dose: 250mg-1 G q 6hrs depending on
infection severity
 Child dose: with weight < 40kg 25-50mg/kg/day in
four doses
PROPERTIES OF INDIVIDUAL
PENICILLINS
 NAFCILLIN
 ‘Isoxazolyl Penicillins’: FLUCLOXACILLIN
 Sodium as an oral suspension (125mg/5mL,
500mg/5mL), capsule (250mg, 500mg), and
powder form
PROPERTIES OF INDIVIDUAL
PENICILLINS
 AMINOPENICILLINS
 Antibacterial activities among group are similar
 not stable to β-lactamases
 Their activity is identical to pen G against penicillin
susceptible organisms except that they are more
active against enterococci
 Non-β-lactamase producing strains of H.
influenzae and H. parainfluenzae are susceptible
PROPERTIES OF INDIVIDUAL
PENICILLINS
 AMINOPENICILLINS
 Due to β-lactamase production, strains of E.coli,
Shigella sonnei, and Salmonella spp. are resistant
 Klebsiella, Serratia, Acinetobacter, indole (+)
Proteus, Pseudomonas and strains of Bacteroides
fragilis are resistant
PROPERTIES OF INDIVIDUAL
PENICILLINS
 AMINOPENICILLINS: AMPICILLIN
 Moderately well absorbed with oral
administration but peak levels are lowered and
delayed with food
 0.5 G orally give peak blood levels of 3 ug/mL 1-
2hrs after ingestion; delayed peak levels for
diabetics and pts with renal failure
 0.5 G injected IM give peak levels of 10ug after 1 hr
PROPERTIES OF INDIVIDUAL
PENICILLINS
 AMINOPENICILLINS : AMPICILLIN
 Elimination half life is 80 min
 Well distributed to body compartments
 acheives therapeutic concentrations in CSF, and in
pleural, joint and peritoneal fluids in the presence
of inflammation after parenteral administration
 undergoes enterohepatic circulation with
significant levels found in bile and stool
PROPERTIES OF INDIVIDUAL
PENICILLINS
 AMINOPENICILLINS : AMPICILLIN
 Urinary levels are high even in reduced renal
function
 Peritoneal dialysis is ineffective in removing this
drug
 Hemodialysis can remove up to 40% of the agent
in 6 hrs
 Half life of 3hrs during continuous venovenous
hemofiltration
PROPERTIES OF INDIVIDUAL
PENICILLINS
 AMINOPENICILLINS : AMPICILLIN
 Available for oral use as a sodium salt as a capsule
(250mg, 500mg), oral suspension
(125mg/5mL,250mg/mL)
 The salt can be used IM or IV
 Oral ampicillin has been replaced in favor of oral
amoxicillin for most indications of infection
because of greater bioavailability
PROPERTIES OF INDIVIDUAL
PENICILLINS
 AMINOPENICILLINS : AMPICILLIN
 Effective for tx of URTIs, LRTIs by S.pneumoniae,
B-hemolytic strep., and non-B-lacatamase
producing strains of H.influenzae
 Effective in tx of meningitis by group B strep.,
Listeria monocytogenes, N.meningitidis, and
penicillin susceptible strains of S.pneumoniae
PROPERTIES OF INDIVIDUAL
PENICILLINS
 AMINOPENICILLINS : AMPICILLIN
 Ampicillin should not be used until susceptibility
of organisms are documented due to high level of
B-lactamase producing strains
 Dose administration will vary according to age of
pt, renal function status and disease severity
PROPERTIES OF INDIVIDUAL
PENICILLINS
 AMINOPENICILLINS : AMPICILLIN
 Adult dose: oral 2-4G/day q 6hrs; parenteral dosage
6-12G/day q 4hrs for severe infection
 Child dose: >1 month old. Oral 50-100mg/kg/day in
four doses; IM or IV 100-300mg/kg/day in 4 or 6
doses
PROPERTIES OF INDIVIDUAL
PENICILLINS
 AMINOPENICILLINS : AMOXICILLIN
 Structurally differs from ampicillin by the presence
of a hydroxyl group in the para position of the
benzene side chain
 identical in vitro activity as ampicillin
 Significantly better absorption than ampicillin when
administered orally; and preferred over ampicillin
because of this
 Peak blood levels are 2-2.5x those achieved by
ampicillin for a similar dose
 food does not affect absorption
PROPERTIES OF INDIVIDUAL
PENICILLINS
 AMINOPENICILLINS : AMOXICILLIN
 Oral form of amoxicillin produces blood levels
similar to the IM injection form of ampicillin
 Elimination half life is 80 min for adults with
normal renal function
 Urinary excretion is greater vs. ampicillin
 Tissue distribution is similar to ampicillin
 Parenteral form is pharmacologically identical to
parenteral ampicillin
PROPERTIES OF INDIVIDUAL
PENICILLINS
 AMINOPENICILLINS : AMOXICILLIN
 Clinical studies of use is extensive
 Tx for: otitis media, bronchitis, pneumonia,
typhoid, gonorrhea and UTI
 High doses (80-90kg/mg) effective and 1st line tx
for otitis media in children because its spectrum
range covers penicillin resistant pneumococci
 1G TID orally is effective and recommended for
CAP
PROPERTIES OF INDIVIDUAL
PENICILLINS
 AMINOPENICILLINS : AMOXICILLIN
 Acheives concentrations that exceed MICs
effective for nonmeningeal infections caused by
penicillin resistant strains of S.pneumoniae
 Not useful for tx of shigellosis
 Adult dose: 0.5mg-1G q 8-12hrs
 Child dose: 20-40mg/kg/day up to 90mg/kg/day in
2-3 divided doses q8hrs
PROPERTIES OF INDIVIDUAL
PENICILLINS
 CARBOXYPENICILLINS: CARBENICILLIN
 Large doses required to achieved effectiveness
 Greater potential for toxicity because of large
doses
 Availability of more potent alternative
 Agent is no longer used because of these reasons
PROPERTIES OF INDIVIDUAL
PENICILLINS
 CARBOXYPENICILLINS: TICARCILLIN
 Not available as a single agent
 Is susceptible to β-lactamase
 Used in a fixed combination with clavulanate
 Less active than aminopenicillins against penicillin
resistant strep
 Inactive against enterococci but more active
against many GNB
PROPERTIES OF INDIVIDUAL
PENICILLINS
 CARBOXYPENICILLINS: TICARCILLIN
 3G IV dose produces serum levels of 250ug/mL
 Excreted by renal tubules
 Use of probenicid will delay excretion and
consequently increases serum concentration
 Tissue distribution similar to ampicillin but CSF
concentrations are inadequate to treat menigitis
PROPERTIES OF INDIVIDUAL
PENICILLINS
 CARBOXYPENICILLINS: TICARCILLIN
 Half life is 70min; but accumulates in renal failure
and even greater accumulation with combined
hepatic and renal dysfunction
 Hemodialysis and continuous venovenous
hemofiltration reduce plasma concentrations
 Side effects similar to those with penicillin and can
interfere with platelet function because of binding
to ADP receptor site on platelets that prevents
normal contraction
 Bleeding can result from high serum levels and in
renal failure
PROPERTIES OF INDIVIDUAL
PENICILLINS
 UREIDOPENICILLINS
 All members within this group have similar
spectrum of activity and pharmacologic property
 PROPERTIES OF INDIVIDUAL
PENICILLINS
 UREIDOPENICILLINS: PIPERACILLIN
 Similar to ampicillin in activity against GPB
 Excellent activity against Strep, Neiserria,
Haemophilus and members of family
Enterobacteriaceae
 Excellent activity against anaerobic species of both
cocci and bacilli
 Like ampicillin, it is hydrolyzed by class A β-
lactamases
PROPERTIES OF INDIVIDUAL
PENICILLINS
 UREIDOPENICILLINS: PIPERACILLIN
 Resistance to piperacillin is due to selection of
mutants that express high levels of ampC β-
lactamase
 It acts synergistically against Pseudomonas and
some Enterobacteriaceae sp. when combined with
aminoglycoside
 antibacterial activity is additive when combined
with a fluoroquinolone
PROPERTIES OF INDIVIDUAL
PENICILLINS
 UREIDOPENICILLINS: PIPERACILLIN
 4G IV gives peak levels above 350ug/mL
 kinetics are dose dependant
 Accumulation of the agent is less with renal failure
compared with carbenicillin
 Half life is only 4-6hrs with creatinine clearance <
10mL/min
 It can be removed by hemodialysis and should be
dosed after dialysis
PROPERTIES OF INDIVIDUAL
PENICILLINS
 UREIDOPENICILLINS: PIPERACILLIN
 Half life with continuous venovenous
hemofiltration is 5hrs; with recommended dose of
4G BID
 Adverse reactions are similar to the other
penicillins
 Neutropenia can result from prolonged
administration with high doses
 Alteration with bleeding time and hypokalemia
are infrequent
PROPERTIES OF INDIVIDUAL
PENICILLINS
 UREIDOPENICILLINS: PIPERACILLIN
 Clinical studies have revealed usefulness in tx of
many infections
 Adult dose: 12-18G daily
 Available as a single agent but usually used in
combination with Tazobactam to extend activity
against class A β-lactamase producing strains

PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS
 Are clavulanic acid and penicillanic acid sulfone
derivatives and are themselves β-lactam
compounds
 Have weak antibacterial activity
 Potent inhibitors of many class A β-lactamases
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS
 prevent hydrolysis of the antibiotic when
combined with a β-lactam antibiotic that is
substrate for class A β-lactamases and therefore
inactive against bacteria producing them, thereby
restoring its activity
 They primarily act as a suicide substrate that
forms a stable intermediate that consequently
renders the enzyme inactive
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS
 3 in clinical use: clavulanic acid, sulbactam and
tazobactam
 Each is only available as fixed combination
preparation with an active β-lactam antibiotic
 It is this active β-lactam antibiotic that combines
with these inhibitors that determines the
antibacterial spectrum of activity
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS
 Effective only against Ambler class A β-
lactamases (penicillinase), which are often
plasmid encoded
 Class A β-lactamases are produced by S.aureus,
H.influenzae, M.catarrhalis, Bacteroides sp., and
Enterobacteriaceae
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS
 They also inhibit extended spectrum β-lactamases
(ESBL) which are mutant class A β-lactamases
 Ambler class C β-lactamases are not inhibited by
β-lactamase inhibitors
 β-lactamase inhibitors do not inhibit class D
enzymes or class B metallo-β-lactamases
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS: ‘CLAVULANATE’
 Formulated in combination with amoxicillin
 Available in oral and parenteral preparations
 Available in combination with Ticarcillin in IV
administration
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS: ‘CLAVULANATE’
 Moderately well absorbed from the GI
 Peak serum concentrations of 4ug/mL achieved
40-120min after ingesting 125mg
 Combniation with amoxicillin does not alter the
pharmacologic properties of either drug
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS: ‘CLAVULANATE’
 Absorption is unaffected by food, milk and
aluminum containing antacids
 Serum half life is 1 hr
 No accumulation of drug until Crcl is <10mL/min
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS: ‘CLAVULANATE’
 Degraded in vivo with metabolites excreted via
lungs, feces, urine
 20-60% remains unchanged in urine 6hrs after
oral dose
 Therapeutic levels are achieved in the bile, middle
ear fluid and tonsil tissue
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS: ‘CLAVULANATE’
 Crosses the placenta
 found on cord blood of newborns and amniotic
fluids but not in breast milk
 It does not penetrate non-inflamed meninges
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS: ‘CLAVULANATE’
 Diarrhea, nausea are adverse reactions
 Maximum dose: 125mg BID-TID
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS: ‘AMOXICILLIN-
CLAVULANATE’
 effective tx for acute otitis media in children
caused by β-lactamase producing H.influenzae
and M.catarrhalis
 Effective in sinusitis or pneumonia caused by
susceptible β-lactamase producing or non-β-
lactamase producing bacteria
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS: ‘AMOXICILLIN-
CLAVULANATE’
 Particularly useful in tx of polymicrobial infections
in which B-lactamase producing organisms are
present (ex. bite wounds, diabetic foot infections)
 Skin structure infections by Strep and Staph
respond with this combination
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS: ‘AMOXICILLIN-
CLAVULANATE’
 Formulated in tablet (200mg,500mg, 875mg
amoxicillin) (125mg clavulanate)
 also a sustained release formulation (1000mg
amoxicillin:62.5mg clavulanate)
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS: ‘AMOXICILLIN-
CLAVULANATE’
 Adult dose: 250mg amox. Q 8hrs – 875mg q 12hrs
orally; 500/125 mg and 875/125 mg dosage forms
are effective as BID regimens
 Child dose: 20-45mg/kg/day in 2-3 divided doses
 Extended Release formulation effective in tx of
bacterial sinusitis and CAP with 2 tabs of
1000/62.5mg BID
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS: ‘AMOXICILLIN-
CLAVULANATE’
 In pts with CAP with comorbidities, guidelines by
the Infectious Disease Society of America
recommend 2000/125mg BID ‘in combination’
with a macrolide as an alternative to
fluoroquinolones for empirical out pt tx
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS: ‘TICARCILLIN-
CLAVULANATE’
 A broad spectrum of activity
 Spectrum includes GP cocci other than
enterococci and MRSA, Enterobacteriaceae,
P.aeruginosa and GP, GN anaerobes
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS: ‘TICARCILLIN-
CLAVULANATE’
 Effective in tx: CAP, hospital acquired and
ventilator acquired pneumonia, gyne. infections,
intra-abdominal infections, skin and skin structure
infections and osteomyelitis
 Dose: 3.1 G q4-6hrs
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS: SULBACTAM
 A broader spectrum β-lactamase inhibitor the
clavulanate, but less potent
 In combination form with ampicillin as parenteral
formulation for IV use
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS: SULBACTAM
 Avg. peak serum level after 1G IV infusion is
68ug/mL
 Serum half life 1 hr
 Excreted by the kidney with a 70-80% urinary
recovery rate
 Minimal biliary excretion
 metabolism <25%
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS: SULBACTAM
 Renal excretion blocked by probenicid
 Half life altered when creatinine clearance
<30mL/min
 Penetration into inflamed meninges is low
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS: SULBACTAM
 Adverse reactions: no major hema., renal, hepatic
or CNS; some diarrhea, skin reactions; occassional
elevation of transaminases
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS: SULBACTAM
 Clinical Use: tx of mixed bacterial infxns (intra
abdominal, ob-gyne, soft tissue and bone)
 Because it is only available in combination use, its
clinical utility is independent of the companion β-
lactam for tx of certain organisms
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS: TAZOBACTAM
 Mean peak concentration 25ug/mL after 30min
with infusion of 375mg
 Cleared primarily by kidney with dosage
adjustment when Cr Cl < 40mL/min
 Half life is 1hr with normal renal function;
 3.6hrs with CrCl<20mL/min;
 7hrs with end stage renal disease
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS: TAZOBACTAM
 A penicillanic acid sulfone β-lactamase inhibitor
 Spectrum of β-lactamase inhibition similar with
sulbactam but its potency is more like clavulanic
acid
 Available only in parenteral formulation only in
combination with Piperacillin
PROPERTIES OF INDIVIDUAL
PENICILLINS
 β-LACTAMASE INHIBITORS AND INHIBITOR
COMBINATIONS: TAZOBACTAM
 Penetrates inflamed meninges
 No significant adverse rxs
 Clinical use: in combination with Piperacillin has
the broadest spectrum