Antimicrobial Therapy
Dolly Mehta
5-0236
dmehta@uic.edu
Cell Wall Protein syn Cell memb
Nucleic acid
syn
2
Bacterial Cell Wall Components
M
G
M
G
M
G
Peptidoglycan
N acetylmuramic acid (NAMA)
M
M
G
M
M
N acetylglucosamine (NAG) G
G
G
M
M
G
G
M
M
G
Penta peptide Glycine
3
4
1
Biosynthesis of Peptidoglycan
CYTO
Gram +
30 enzymes
M
UDP
M UDP
Proteoglycan (PG) (15-50 nm thick)
Membrane
UMP
Gram -
P-C55 lipid
Lipopolysachrides
and proteins
G UDP
UDP
M P-P-C55
G M P-P-C55
G M P-P-C55
MEMB
PG (2 nm thick)
P
Membrane
P-P-C55 lipid
G M
periplasm
5
WALL
transglycolase
G M G M G M G
6
transpeptidase
Cycloserine (Seromycin) D-4-amino-3-isoxazolidone
V. Absorption, Distribution and excretion
I. structural analog of D-Ala (acts as a competitive inhibitor)
Orally absorbed 70-90%
Peak concentrations in plasma are reached within 3-4 after single dose
distributed throughout body fluids (CSF conc. = plasma)
Metabolism slow, only 50% excreted UNCHANGED in urine
in Ist 12 hrs
renal patients: accumulate to toxic conc, removed by dialysis
II. stable in alkaline solution rapidly destroyed in neutral or acid pH
III Mechanism:
III.
M h i
cycloserine
M UDP
IV. Therapeutic Use: Effective agnst M. tuberculosis (5-20 μg/ml)
used WHEN PRIMARY Anti-Tuberculosis agents (such as
Isoniazid, rifampin) failed
7
VI. Untoward Effects
CNS: headache, tremor, confusion etc
(symtoms disappear after drug is withdrawn)
Large dose or concomitatnt use of alchoholÆseizures
CONTRAINDICATED: Epileptic patients
Caution: patients with history of depression or suicidal
attempts
8
2
Vancomycin
IV. Absorption, Distribution and excretion:
Oral absorption poor; slow IV is preferred, NEVER IM
A single 1 g IV Æ 15-30 ug/ml in plasma after 1-2 hr;
half life~ 6 hrs
appears in body fluids and CSF
90% excreted by glomerular filtration ; accumulates if renal
function is impaired (can be cleared by hemodialysis)
I. Complex tricyclic glycopeptide antibiotic
II. Mechanism: Inhibits polymerization or
transglycolase reaction
( G M )n
G M P-P-C55
G M
(G M )n
+
P-P-C55
III. Antibacterial activity:
Gram (+)
Gram(–) are resistant because D-ala-D-ala (target) is substituted
with D-ala-D-ser or D-ala-D-lactate
9
V. Untoward Effects:
Hypersensitive Reacn (skin rashes, and anaphylaxis, Chills, rash)
Rapid administration causes flushing, tachycardia, hypotension,
erythematous or urticarial reac
auditory impairment (ototoxicity) and nephrotoxicity;
Æcaution with the use of aminoglycosides
cause “red-neck” or “red-man” syndrome by
10
directly inducing toxicity in mast cells
Penicillin: β-Lactam antibiotics
Bacitracin
I. Mechanism:
P-P-C55 lipid
Drug of choice for a large number of diseases
P-C55 lipid
II. Antibacterial Activity: Gram (+) cocci and bacilli.
However, bact strain such as Enterobacteriaceae, Pseudomonas,
Candida spp and Nocardia are resistant
Discovered by Alexander Flemming 1928.
Produced by penicillium
III. Use: Restricted to topical use such as for skin and eye infections
11
12
3
Mechanism:
O
S
=
R
C
2
NH
CH
B
O
=C
CH3
C
CH
A
N
1
CH
Inhibits cross linking of peptidoglycan
CH3
COOH
M G M G M G
M G M G M G M
A Thiazolidine ring
R decides:
B β-lactum ring
1 penicillnase
2 amidase
Penicillin subtype
Antibacterial activity
M G M G M G
resistance to β-lactamase
stability for stomach acids
13
14
PBPs
β-lactum moeity of penicillins binds covalently (irreversibly)
with penicillin-binding proteins (PBPs) at serine residue
PBPs:
belong to the family of acyl serine transferases
high-molecular-weight (HMW) PBPs
low-molecular-weight (LMW) PBPs
ß-lactamases
HMW
β-lactamase
PBP
PBP
15
16
4
LMW
β-lactamase
Class A-B
17
18
PBP’s (40kD-91kD):
β-lactum antibodies
Number of PBPs varies within bacterial strain. i.e.
S aureus has 4 PBPs whereas E coli has 7
Acylation of PBPs
Inhibition of PBPs
1
Apparent
molecular
weight
91000
Binding of
penicillin( %
total )
8.1
2
66000
0.7
20
3
60000
1.9
50
4
49000
4.0
110
5
6
42000
40000
64.7
20.6
1800
570
Protein
Structural irregularities
Cell lysis
19
Molecules/cell
230
20
5
III. Mechanisms of Resistance:
3. Affinity of PBPs to antibiotics is variable
A. Elaboration of altered PBPs
Penicillin (lytic as well as non-lytic)
a) decreased affinity for β-lactams
a1. formed by homologous recombination
between PBPs of different bact sp.
Lytic PBP1; Non-lytic (PBP2/3)
(affect holin-like proteins in bacterial cell memb
which alter membrane potential)
a2. by transposans from unknown org
B. Structural differences in PBPs
21
22
C. Increased expression of efflux pumps i.e E. coli
B. Inability of agent to penetrate to site of action
b1. Gram (-) bact outer layer of LPS
Small hydrophilic antibiotics can pass through channels
porins
i e amoxicillin
i.e.
amoxicillin, ampicillin>Penicillin G
P aeruginosa resistant to most antibiotics lacks
porins
23
24
6
D. Production of β-lactamase
d2. Site of liberation
Hydrolyse β lactam ring of penicillin's
Gram (+), β lactamase is secreted extracellularly in large
amts
d1. β-lactamases class A-D:
Gram (-), β lactamase is located in the periplasmic space,
small amounts.
Class A (extended spectrum β-lactamase): degrade
penicillin,, some cephalosporin's
p
p
p
and
carbapenems
Primary mechanism of acquired resistance!
Class B (Zn-dependent): destroy all β-lactums except
aztreonam
Class C: cephalosporin's
Class D: cloxacillin
d3. Other factors:
surviving bacterial cell,
biofilms produce bacteria in prosthetics
25
27
26
Classification
Spectrum
Natural Penicillins
Penicillin V and G
(phenoxymethyl
penicillin)
Gram (+) cocci, hydrolyzed by penicillinase
so ineffective against most strains of S.
aureus
β-lacatamse resistant
Penicillin; methicillin
(discontinued in US),
nafcillin, isoxazoyl
penicillin
Less active agnst bacteria sensitive to
Penicillin G
First choice for S aureus and S epidermidis
Aminopenicillins (or
modern spectrum)
Ampicillin, amoxicillin
Gram (-) e.g Hemophillus influenzae, E.Coli,
Neissaria sp.
Administered with b-lactamse inhibitor such as
clavanate to prevent hydrolysis
Carboxypenicillin
Cabbenicillin
(discontinued in US)
Ticarcillin
Gram (-) e.g. pseudomonas sp,
enterobacter sp.Inferior to ampicillin
against Gram + cocci
Ureidopenicillins
(extended penicillin)
Mezlocillin, Azliocillin
(discontinued in US),
Piperacillin
Pseudomonas sp, 10 times more effective
than carboxypenicillin
CH2OCH2-
OCH3
OCH3
R1
CH2-
NH2
CH-
COOR
28
7
General features of the Penicillins
Excretion
Distribution
1. Predominantly eliminated unchanged via the
glomerular filtration (10%) and tubular
secretion (90%). Half life short (30-90 min). So
higher urine concentrations.
widely distributed throughout body fluids but conc
varies in diff tissue
Apparent volume of distribution is 0.35L/kg
60% of Penicillin G is bound with albumin
2. Clearance is lower in neonates and infants (3hrs in
y)
1wk old baby)
do not achieve high levels in the CSF when meninges are
normal.
3. Active secretion can be blocked by probenecid.
Donot penetrate living phagocytic cells
4. Renal dysfunction, hepatitis, anuria increases the
half life of G
Active transport process pumps penicillin's from
CSF to the bloodstream. This mechanism is blocked
by Probenecid.
meningitis, inflammation induced increase in the
permeability leads to high levels of penicillin
29
Specific Agents
30
Parenteral administration of Penicillin G
peak conc in plasma reached within 15-30 min
but decline due to 30 min half life
Penicillin G
Low acid stability. Degraded by gastric juices.
Rapid absorbed orally (max conc 30-60 min in blood)
Food interference (30 min before meal)
Repository Forms of Penicillin G:
i.
Peak value 0.3ug/ml after an oral dose of 250 mg in adult
Penicillin V
More acid stable
Yield 2-5 fold more plasma level than G
Peak value 3ug/ml after an oral dose of 500 mg in adult
31
Penicillin G procaine (Wycillin) (benzyl penicillin with
local anasethetic agent procaine
y absorbed after IM injection
j
but an injection
j
of
slowly
300,000 units will maintain adequate plasma levels for
24 hours.
Syphillis, RTI, anthrax
ii. Penicillin G benzathine (Bicillin L-A, Permapen) has the
slowest rate of absorption even after IM absorbtion. An
injection of 1.2 million units will maintain adequate
plasma levels for 10 days.
32
8
β-lactamase resistant Penicillin (narrow spectrum)
(anti-staphylococcal aureus penicillin)
Therapeutic uses
Penicillin G:
Penicillin V:
cellulitis, bacterial endocarditis,gonorrhea
Pneumonia, Steptococcal infections, syphilis,
meningococcal infections
tonsilitis, pharyngitis, skin infection,
odontogenic infection
Isoxazoyl penicillin (oxacillin, cloxacillin, dicloxacillin)
Inhibits the growth of penicillin producing bact
s. aureus (0.05 ug/ml of dicloxacillin than
.
1-3 ug/ml of others)
Relatively stable in an acid medium
Absorbed rapidly but incompletely (30-80%)
increases after empty stomach
Prophylactic uses:
Affords protection agnst
Peak conc in plasma 5-10 ug/ml after an
oral dose of 250 mg in adult
Steptococcal infections
Rheumatic fever
Eliminated rapidly by kidney. Also hepatic
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Aminopenicillins (Moderate spectrum)
Nafcillin
Ampicillin (Principen)
Very effective agnst S aureus (0.06 to 2 ug/ml)
β-lacatamse sensitive
Inactivated in the acidic medium
Acid stable
Peak plasma conc is ~ 8ug/ml after 1-g IM injection;
bile has moe; CSF adequate
Well-absorbed; an oral dose of 500 mg produces peak
plasma conc of about 3 ug/ml at 2hrs
IM injection of 0.5 or 1 g yields 7-10 ug/ml within 1hr
half life 80 min
β-lactamase resistant Penicillin (narrow spectrum)
(anti-pseudomonas aeruginosa or acinetobacter spp)
Food diminishes absorbtion
Renal dysfunction prolongs half life
Appears in bile, undergo enterohepatic circulation
and is excreated in feces
Temocillin
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9
Amoxicillin
Therapeutic Use
β-lacatamse sensitive
Upper respiratory infections, UTI, Meningitis,
salmonella infections
Acid stable
Absorbed quicly and compleletly than ampicillin so incidence
of diarrohea is less
Peak plasma conc is 2-3 fold higher than Ampicillin
Half life = Ampicillin but avl longer in plasma (~x2)
Food does not interfere with absorption
Eliminated in urine; probrnecid delays excreation of drug;
37
Antipseudomonal penicillins: (extended spectrum)
Carboxypenicillin and Ureidopenicillin
38
VIII. Untoward Effects:
Carbenicillin Indanyl sodium (Geocillin)
only used for managing UTI caused by Proteus
Ticarcillin
2-4
2
4 times effective for P aeruginosa than
Carbenicillin, which is toxic
Hypersensitivity: MOST common side effect (0.7%-4%)
Allergy to one penicillinÆ greater risk to other penicillins
O
S
CH3
C CH3
R C NH CH CH
B
A
O =C
N
CH
COOH
Penicillanase
=
β-lacatamase sensitive
O
CH
=
Piperacillin
extends the spectrum of ampicillin to include
most strains of P aeruginosa
R
CH + NH2
CH
O
6-aminopenicillanic acid
39
=C
OH
CH
N
haptens
H
Penicilloic acid
40
IgE Abs
10
Serious hypersensitive reacn:
angiodema (swelling of lips, tongue etc
asthmatic breathing, giant hives)
anaphylaxis (severe hypotension, death)
Decreased platelet aggregation (carbenicillin and
ticarcillin)
Neutropenia (especially the b-lactamase -resistant penicillins)
Convulsions and encephalopathy can occur,
especially at higher doses if administered
intrathecally (NOT advised).
Hypernatremia and hypokalemia (carbenicillin)
Coomb's positive hemolytic anemia
during prolong therapy with Penn/Cephalo
41
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Cephalosporins
IX. Drug-drug Interactions
R1
S
C
O
b. Carboxy- or Ureidopenicillins and aminoglycosides are
synergistic in their anti-pseudomonas activity.
NH
CH
=
i. Chemically antagonize aminoglycosides. MUST NOT be
administered simultaneously through the same I.V. line;
should be staggered by about 1 to 2 hours.
B
O
CH2
CH
=C
R1 decides:
antibacterial activity
resistance to β-lactamase
stability for stomach acids
A
C
N
C
C
=
R2 (effects
metabolism
and
pharmacokinetic)
O
OH
43
44
11
Cephalosporins
Acylation of PBPs
Classification: Best indicated by generation
based on antimicrobial activity
Inhibition of PBPs
Ist -IVth generation
M G M G M G
M G M G M G M
Inhibits cross linking
of peptidoglycan
M G M G M G
Structural irregularities
Cell lysis
45
46
Ist generation
Cefacetrile
Cefadroxyl;Duricef
Cefalexin; Keflex
Cephaloglycin
Cefalonium
Cefaloridine;Keflin
Cefalotin
Cefapirin;Cefadryl
Cefatrizine
Cefazaflur
Cefazedone
Cefazolin;Ancef
Cefradine (Velosef)
Cefroxadine
Ceftezole
IInd generation
good against Gram (+); modest
against Gram (-)
Streptococci (except penn-resistant);
Staphylococcus (except Methicillin
Methicillinresistant strain)
47
Cefonicid;Monocid
Cefprozil;Cefzil
Cefuroxime;Zinnat
Cefuzonam
Cefaclor;Ceclor
Antianaerobe activity:
Cefoxitin
Cefmatazole
Cefotetan
Carbacephems
Cefmetazole;Zefazone
Cefminox;Cefotan
Cefoxitin;mefoxin
Increased activity against
Gram (-) but much less active
than IIIrd generation
Gram (-) e.g., Enterobacter sp,
Klebsiella sp., haemophilus influenza;
Not active against gram + as Ist
generation
48
12
IIIrd generation
Cefeapene
Cefdaloxime
Cefdinir;Omnicef
Cefditoren
Cefetamet
Cefixime;Suprax
Cefmenoxime
C f di i
Cefodizime
Cefoperazone
Cefotaxime
Cefteram
Ceftibuten
Ceftiolene
Ceftizoxime;Cefizax
Ceftriaxone;Rocephin
Less active than Ist generation
against Gram (+) but more active
against Enterobactericeae includingβ-
Ceftriaxone (Rochephin)
Ceftizoxime (Cefizox)
Cefoperazone (Cefobid)
Ceftazidime (Fortaz)
Cephalosporins with
antipseudomonal activity
l
lactamase
producing
d i bacteria
b
i
The following cephems are also sometimes grouped with thirdgeneration cephalosporins:
Oxacephems;latamoxef
49
50
IV generation
Cefelidine
Cefepime;Maxipime
Cefluprenam
Cefoselis
Cefozopran
Cefpironie
Cefquinome
Extended spectrum of activity than
IIIrd generation and have
increased stability against
hydrolysis by β-lactamase
51
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13
General features of the Cephalosporins
Distribution
Mechanism of Resistance:
Same as penicillin's. i.e.ÆAltered PBPs or lactamase
function
First generation cefazolin more susceptible to βlactamase from S aureaus
Most of Cephalosporins such as cephalexin, cefadroxil
etc are absorbed readily after oral administration
Several cephalosporins can penetrate into
CSFÆmeningitis
CSFÆ
i iti
Third generation: susceptible to hydrolysis by inducible
chromosomally encoded (Class 1 β-lactamase)
Can also cross placenta
Fourth generation: less susceptible
High concentrations also seen in synovial, bile and
pericardial fluids
53
54
Specific Agents:
Excretion
Ist generation:
Primarily excreted by kidney
dosage should be adjusted in patients with
renal insufficiency
Cefazolin
Well-tolerated after either IM or IV
Conc in plasma after 1g IM administration reach to 64 ug/ml
Probenecid slows the tubular secreation of
most cephalosporins;
cefoperazone is exception as excreted in bile
Excreted
E
t db
by glomerular
l
l filt
filtration
ti and
d iis b
bound
d tto plasma
l
proteins (85%)
Preferred among Ist generation as can be administered less
frequently due to longer half-life
55
56
14
IInd generation:
Cefotetan
Cefoxitin
Resistant to β-lactamse produced by Gram (-) rods
Gram (+) < active than Ist generation cephalosporins
More active than Ist or IInd generation agents agnst β-fragalis
More active than Cefoxitin agnst Gram (-)
Conc in plasma after 1g IM administration reach to 22 ug/ml;
half life 40 min
III d generation:
IIIrd
ti
Conc in plasma after 1-g IM administration reach to 70 ug/ml;
half life 3.3 hrs
Cefotaxime
Resistant to many β-lactamase and has a good activity
agnst most Gram (+) and (-) bacteria except B. fragilis
Half life in plasma 1 hr
Metabolized Ædesacetylcefotaxime
57
58
IIIrd generation:
Therapeutic Uses:
Ceftazidime
Active agnst Gram (+) excellent for Pseudomonas and
Other Gram (-) bacteria
First generation: skin and soft tissue infections, surgical
prophylaxis of wound infection.
half life 1.5 hrs; not metabolized
Third generation:
infections caused by Klebsiella, Enterobacter, Proteus etc,
ceftriaxone: all forms of gonorrhea, severe lyme diseases
cefotaxime or ceftriaxone: used to treat meningitis due to
pneumococci, meningococci, and Haemophillus influenza
IVth generation:
ti
Cefepime
Active agnst many enterobact which are resistant to
other Cephalo
Excellent penetration in CSF;
Conc in plasma after 2-g IV administration reach to
126-193 ug/ml; half life 2 hrs
Fourth generation noscomal infections where
resistance to β-lactum Antibiotics is expected.
59
60
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Untoward Reaction:
Drug-drug Interactions:
Hypersensitivity: The frequency of cross-reactivity with
penicillin-sensitive individuals is 5 to 15%.
CONTRAINDICATED in patients with a history of anaphylaxis
to a penicillin.
Cephalosporins demonstrate synergistic activity when
combined with an aminoglycoside to treat Klebsiella.
Renal Toxicity
y
Hyperprothrombinemia, Thrombocytopenia, Platelet
dysfunction
Disulfiram-like Effect: cefamandole, cefotetan, moxalactam,
cefoperazone.
61
62
OTHER β-LACTAM Antibiotics
Carbapenems (fused β-lactum ring and a 5-membered ring sys)
Imipenem:
i. Mechanism of action: Binds to PBPs, disrupting cell wall
synthesis and is bactericidal.
ii. Spectrum: Broad-spectrum covers Gram (+) & Gram (-)
e.g. Streptococci, Enterococci.
Resistant to most forms of β-lactamase, including
that produced by staphylococcus.
63
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16
iii. Metabolism:
not absorbed orally.
Rapidly hydrolyzed by dipeptidase, so always
administered with cilastatin, an inhibitor of dipeptidase
iv.
Therapeutic Use:
urinary tract and lower respiratory infections
intraabdominal and gynecological infections
500 mg IV produces 33 ug/ml in plasma, half life 1hr
effective agnst cephallosporin resistant bacteria
70% recovered in urine as the active drug; Ærenal
insufficiency
iv. Side effects:
patients allergic to the penicillins may demonstrate
cross-reactivity with imipenem.
nausea and vomiting.
Seizures have been reported with high doses.
65
66
Aztreonam: A monocyclic β-lactam (a monobactam).
Meropenem:
i. Mechanism of action: Interacts with PBPs and induces the
formation of long filamentous bacteria
does not require cilastatin
toxicity~imipenem
Therapeutics equivalent to Imipenem but less likely
to cause seizures
ii. Spectrum: It more closely resembles the spectrum of the
aminoglycosides. No activity against Gram (+) and
anaerobic bacteria are resistant.
Aztreonam is resistant to the β-lactamase produced
by Gram (-) organisms.
Ertapenem:
long serum half life than imipenem or meropenem
thus once daily dose
iii. Side effects: well tolerated. Penicillin allergic patients do
not exhibit cross-reactions with aztreonam.
Gram (+) bacteria
67
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17
β-Lactamase Inhibitors:
Mechanism of action:
i. Inhibits β-lactamase.
ii. Poor antimicrobial activity.
Included in combination with amoxacillin
(Augmentum) or with ticaricillin
iii. clavulanic acid also called as “SUICIDE" inhibitor of βlactamase because it binds irreversibly with βlactamase from both gram (+) or gram (-) bact
69
70
Summary
Cycloserine
Inhibits enzymes inducing cell wall
Vancomycin
synthesis
bacitracin
*Penn/cepha
Carbapenems
Affects bact.
bact growth by
Aztreonam
binding PBP’s and/or β-lactamase
β-lactamse inhibitors
Common Side effect: Hypersensitivity
Resistance is developed
PBPs, efflux pumps, cell wall, location of β-lacatamase
71
18