Bata Lactams Antibiotics & beta lactamase inhibitors Summary

Bata Lactams Antibiotics & beta lactamas inhibitors Summary,
Manual of Clinical Microbiology, 11th Edition

1. Antibacterial Agents
Manual of Clinical Microbiology, 11
th
Edition
Done By: Dr. Abdullatif Al Rashed (Clinical Microbiology Resident)
Best in prevention of Post invasive surgery
IE, due to B-lactamase production, not
active in Pseudomonas,
Enterobacteriaceae, H. influanza and Para
influenza



• Beta Lactams Antibiotics:
1) Penicillins:
Types:
Type Examples
Natural Penicillin G and V.
Penicillinase Resistance (semisynthetic)
Oxacillin, Nafcillin, Cloxacillin, Dicloxacillin, Temocillin
Extended Spectrum Aminopenicillins Amoxicillin, Ampicillin, Mecillinam
Extended Spectrum Carboxypenicillin Ticarcillin (antipseudomonal)
Extended Spectrum Ureidopenicillin Piperacillin (antipseudomonal)
Penicillin–β-lactamase inhibitor combinations
Ampicillin-sulbactam, Ticarcillin-clavulanate
Amoxicillin-clavulanate, Piperacillin-tazobactam

Mechanisms of Action:
1. Inhibits penicillin binding proteins {PBPs} enzymes. (last step in peptidoglycan
synthesis)
2. Binding to bacterial endopeptidases, carboxypeptidases and bifunctional PBPs.
Spectrum of Activity:
1. Penicillin G &V:





2. Penicillinase Resistant:




3. Ampicillin & Amoxicillin: as G & V Plus the following:

Staph.
aureus

S. pneumonia

S. Pyogens,
Viridans



S. bovis

N.
gonorrhea,
N.
Meningitedes


N
Aneorbic cocci and
clostridum

T.pallidum
(Drug of choice)


Actinmoycis (Drug of choice)
Penicllinase Producing
S.aureis

S. pneumonia

S. Pyogens

Not Active Againist: Enterococci,
Enterobacteriacea, Pseudomonas Spp,
And Bacillus Frigalis


Entero
cocci

L. monocytogens

Salmonella
(> in Amox)

Shigella (> in Amp)

2. Antibacterial Agents Manual of Clinical Microbiology, 11
th
Edition

It has > efficacy than ticarcillin against strep,
enterococci and P. aeruginosa.
Act synergistically with aminoglycoside against
P. aeruginosa.


4. Piperacillin:






5. Ticarcillin:
(1) Same as piperacillin, + hemophilus spp & Neisseria spp.
(2) Not active against Klebsiella spp. Unless combined with cluvanic acid. Not
active against enterococci.
Pharmacology:
o Penicillins are well distributed to the lungs, liver, kidneys, placenta, muscles and
bones.
o Distribution to the eye, brain, CSF and prostate is poor in the absence of
inflammation.
o Excreted via the kidneys.

Side effects:
o Skin rash, diarrhea, drug fever.
o Severe anaphylaxis in previous sensitized patients.
o Interstitial nephritis.
o Hypokalemia and Neutropenia. (in high dose for prolonged weeks)
o Thrombocytopenia and coombs test + hemolytic anemia. (RARE)
o Myoclonic twitching and seizure in high dose of Penicillin G.
o Hepatitis in prolonged use of oxacillin.
o Bleeding tendency in Piperacillin & Ticarcillin.
o Pseudomembranous colitis in ampicillin mostly.
Penicllinase
Producing Staph

Streptococci
Not used in
P.pneumonia

Enterococci

ESBL & Non ESBLE Enterobacteriaceae

P. aeruginosa

Anerobes including B.fragalis

A. baumannii
according to
our IPP

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th
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2) Cephalosporins:
Types:
Oral Agents

Parenteral Agents

Others

Mechanisms of Action:
1. Inhibits penicillin binding proteins {PBPs} enzymes. (last step in peptidoglycan
synthesis) as Penicillins.
2. Cephalosporins with anti-MRSA activity have unique chemical structure which is
a thiazole moiety and a vinylpyrrolidinone moiety, at position 3 of the cephem ring.
These chemical side chains facilitate binding of these drugs to the staphylococcal
PBP 2a and pneumococcal PBP 2a and act as a bactericidal against MRSA &
penicillin-and ceftriaxone-resistant pneumococci.

Type Examples
First Generation (Narrow Spectrum) Cephalexin, Cefaclor, Cefadroxil
Second Generation (Broad Spectrum) Cefuroxime, Cefprozil
Third Generation (Extended Spectrum) Cefixime, Cefdinir, Ceftibuten, Cefpodoxime
Type Examples
First Generation (Narrow Spectrum) Cefazolin
Second Generation (Broad Spectrum) Cefuroxime
Third Generation (Extended Spectrum) Ceftriaxone, Ceftazidime, Cefotaxime, Cefoperazone
Fourth Generation Cefepime
Type Examples
Cephamycins (unique Group of 2
nd
Generation) Cefotetan, Cefoxitin
Cephalosporins with anti-MRSA activity Ceftaroline, Ceftobiprole

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th
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Pseudomonas spp., Amp C producer
Enterobacteriaceae are resistant.
Not good acitivity against H. influenzae.


stable against some beta-lactamases found
in Gram-negative bacteria, so they have
more activity against gram negatives



Spectrum of Activity:
1. 1
st
Generation Cephalosporins:




2. 2
nd
Generation Cephalosporins:






3. 3
rd
Generation Cephalosporins:
(1) Much more active against Enterobacteriaceae, due to primarily to their stability
to low-level production of chromosomal β-lactamases and to the early plasmid-
encoded penicillinases. Also, their ability to pass through the outer cell
envelopes of Gram-negative bacilli
(2) Less active than the narrow-spectrum agents against Gram-positive cocci.
(3) All of the 3
rd
generation hydrolyzed by ESBLs and carbapenemases that are
found in Gram-negative pathogens.
Drug Spectrum Comments
eftazidime and
cefoperazone
Active against P. aeruginosa ceftazidime has more potent activity than other expanded-spectrum
cephalosporins or the ureidopenicillins against P. aeruginosa
cefotaxime
and
ceftriaxone
most potent against streptococci,
penicillinase-positive and -negative N.
gonorrhoeae, non-ESBL- or non-CRE
Enterobacteriaceae
N. gonorrhea usually effective as single-dose therapy for infections
caused by this organism.
Ceftriaxone used for Lyme disease. Not active in Serratia marcescens,
Enterobacter cloacae, and Acinetobacter spp.
Oral agents non-ESBL- or non-CRE
Enterobacteriaceae, H. influenzae, M.
catarrhalis, and N. gonorrhoeae,
Not useful againest enterococci, Pseudomonas, Enterobacter, Serratia,
and Morganella spp. and anaerobes.
Penicillin
susceptible
S. aureus

Penicillin
susceptible S.
pneumonia

S. Pyogens,
Viridans



MSSA


N
Anaerobic
streptococci

Non-ESBL E-coli, K. Pneumonia, P. mirabilis


Penicillin susceptible
Anaerobes, except B. fragilis

Anerobes

Aerobic Gram
positives

some
Enterobacter
and Serratia
strains


N
Haemophilus
spp.

Non-ESBL E-coli,
Klebsiella spp ,
Proteus spp.


Neisseria spp.

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Enterobacteriaceae with high
levels of AmpC cephalospo-
rinases, Non ESBL and non CRE.
Staphylococci & Streptococcoi
Acinetobacter spp., enterococci,
or anaerobes.

4. 4
th
Generation Cephalosporin:









5. Ceftaroline & Ceftobiprole:
Drug Active Against Not Active Against
Ceftaroline • Active against all staphylococci (MSSA, MRSA,
hVISA, VISA, VRSA), MDR pneumococci, Viridins
group streptococci and beta-hemolytic streptococci.
• The Gram-negative activity of ceftaroline is limited
mainly to Gram-negative respiratory tract pathogens.
• Clostridium spp. (except Clostridium difficile), Fuso-
bacterium, Lactobacillus, Peptostreptococcus,
Porphyromonas, Propionibacterium acnes, and
Veillonella
• Minimal activity against enterococci.
• weakly active against P. aeruginosa, Acinetobacter
spp., and Gram-negative bacilli with inducible
AmpC β-lactamases. However, its activity against
β-lactamase-producing strains is enhanced by the
addition of avibactam.
• B. fragilis, members of the B. fragilis group, and
Prevotella
Ceftobiprole • Active against all staphylococci (MSSA, MRSA,
hVISA, VISA, VRSA), MDR pneumococci, Viridins
group streptococci and beta-hemolytic streptococci.
• Exhibits good activity against Enterococcus faecalis but
is largely inactive against Enterococcus faecium.
• Clostridium spp. (except Clostridium difficile), Fuso-
bacterium, Lactobacillus, Peptostreptococcus,
Porphyromonas, Propionibacterium acnes, and
Veillonella.
• Weakly active against P. aeruginosa, Acinetobacter
spp., and Gram-negative bacilli with inducible
AmpC β-lactamases.
• inactive against ESBL -producing
Enterobacteriaceae and MDR Acinetobacter
baumannii isolates
• B. fragilis, members of the B. fragilis group, and
Prevotella
6. Cephamycins (Cefoxitin and Cefotetan):



Active
Against
Not
clinicaly
Active
Against
A unique group of 2
nd
Generation Cephalosporins that has extra activity against anerobes
including B. fragilis group, Prevotella spp., Porphyromonas spp., and Gram-positive
anaerobic cocci.

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Pharmacology:
o The parenteral cephalosporins cefotaxime, ceftriaxone, ceftazidime, and cefepime
penetrate into the CSF and may be useful for the treatment of meningitis.
o Cefuroxime penetrates inflamed meninges, but levels in CSF are inadequate in
providing bactericidal activity against susceptible bacteria.
o All cephalosporins except ceftriaxone are excreted primarily by the kidney, and for
these drugs, dosage adjustments are necessary in patients with renal insufficiency.
o Of the cephalosporins, ceftriaxone has the longest elimination half-life, at 6.8 to 8.7
h, permitting once or twice daily drug administration in the treatment of serious
infections.
Side effects:
o Skin rash, diarrhea, drug fever, serum sickness. (Most common)
o Cross-reactions with penicillin-allergic patients occur in only 3% to 7% of cases.
o Interstitial nephritis.
o Elevated serum creatinine and transaminase levels, leukopenia, thrombocytopenia,
and Coombs test-positive hemolytic anemia
o Gallbladder sludge and rarely cholecystitis. (with long use of Ceftriaxone)
o Disulfiram-like reactions (in patients receiving cefotetan and cefoperazone)
o Bleeding tendency & Hypoprothrombinemia.
o Pseudomembranous colitis.
o Neurotoxicity manifest as impaired consciousness or seizures. (in patients receiving
high doses of cefepime with impaired renal function)
3) Monobactams
Types • Aztreonam is the only Monobactam
Mechanism of
Action
• Binds primarily to PBP 3 of Gram-negative aerobes and cause cell wall disruption.
• It is not hydrolyzed by many of the early Bush and Jacoby group 1 and 2 plasmid-encoded and chromosomally
encoded β-lactamases.
• It is susceptible to hydrolysis by ESBLs and serine carbapenemases.
• It has high affinity for the group 1 cephalosporinases but does not induce the production of these enzymes.
• Metallo-β-lactamases are unable to hydrolyze aztreonam, leading to its potential clinical use against
carbapenemase-producing Gram-negative pathogens
Spectrum of
Activity
• Active against Gram Neg. Bacilli including Enterobacteriaceae, Neisseria spp., and Haemophilus spp,
P.aeruginosa (combined with aminoglycoside for synergism).
• Inactive against Acinetobacter spp., Burkholderia cepacia, Stenotrophomonas maltophilia, Gram-positive
bacteria or anaerobes
Pharmacology
• Widely distributed in all body sites and fluids including inflamed meninges. Excreted by kidneys.
Side Effects
• Nausea, diarrhea, skin rash, eosinophilia, mild elevation of LFTs & RFTs.
• Minimal cross-reactivity with other β-lactams.

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4) Carbapenems
Types:
• Doripenem | Ertapenem | Imipenem | Meropenem.
Mechanism of Action:
1. They bind first to PBP 2 then PBP 1a & 1b of gram negatives and causing cell lysis.
2. In staphylococci, they bind to all PBPs except PBP 2a (for MRSA) so it has poor
activity against MRSA.
3. They are stable towards toward most plasmid- or chromosomally mediated β-
lactamases except for the more frequently occurring carbapenemases.
Spectrum of Activity:
Gram
Positives
Active Against: staphylococci (penicillin-
susceptible and -resistant isolates); viridans
group streptococci; group A, B, C, and G
streptococci; pneumococci; enterococcus
faecalis; Bacillus spp.; and L.
monocytogenes.
Inactive Against: MRSA;
enterococcus faecium
Comments: Doripenim and
imipenem are more potent against
MSSA and streptococci. Ertapenem
has poor activity against Enterococcus
faecalis
Gram
Negatives
Active Against: Most Enterobacteriaceae
including ESBL producing; Enterobacter
spp., Citrobacter spp., and Serratia spp; P.
aeruginosa; B. cepacia and Pseudomonas
stutzeri; Acinetobacter baumannii
Inactive Against: S. maltophilia
due to its production of the
chromosomal metallo-β-lactamase
Comments: Ertapenem is inactive
against Acinetobacter and
Pseudomonas. meropenem and
doripenem are the most potent agents
against P. aeruginosa

Anerobes
Active Against: Clostridium spp; B. fragilis
group; Fusobacterium; Porphyromonas;
Prevotella; Actinomyces; Nocardia;
atypical mycobacteria
Inactive Against: NA Comments: Imipenem is more potent
than others against Actinomyces,
Nocardia and atypical mycobacteria

Pharmacology:
o Widely distributed in all sites and body fluids including inflamed meninges (except
Ertapenem has poor penetration in CSF)
o Excreted by kidneys so dose adjustment is necessary for creatinine clearance of ≤50
ml/min.
Side Effects:
o The side effects of carbapenems are similar to those of other β-lactam antibiotics.

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• β-Lactamase Inhibitors:
1. Cluvanic Acid:
2. Sulbactam:
It inhibits penicillinases from staphylococci and many group 2 β-lactamases from Gram-negative bacteria.
It acts synergistically with β-Lactamasagainst β-lactamase-producing staphylococci, klebsiellae, H. influenzae, M. catarrhalis, N. gonorrhoeae, E. coli, Proteus spp., members of the B. fragilis group, Prevotella spp., and Porphyromonas spp
Many plasmid-mediated TEM, SHV, and CTX-M β-lactamases, including ESBLs, present in cephalosporin-resistant strains of K. pneumoniae and E. coli can be inactivated by this drug
Inducible and plasmid-encoded AmpC β-lactamases of Enterobacter, Citrobacter, Proteus, Acinetobacter, Serratia, and Pseudomonas spp. are not inhibited by clavulanic acid
The drug is widely distributed to various body tissues and fluids, but it penetrates uninflamed meninges very poorly. side effects are similar to those reported for amoxicillin or ticarcillin used alone.
It inhibits certain plasmid and chromosomally mediated β-lactamases of S. aureus, many Enterobacteriaceae, H. influenzae, M. catarrhalis, Neisseria spp., Legionella spp., members of the B. fragilis group, Prevotella spp., Porphyromonas spp., and Mycobacterium spp
Sulbactam alone is active against N. gonorrhoeae, N. meningitidis, some Acinetobacter spp., and B. cepacia
Like clavulanic acid, sulbactam does not inhibit the cephalosporinases of Enterobacter, Citrobacter, Providencia, indole-positive Proteus, Pseudomonas spp., or S. maltophilia.
Ampicillin-sulbactam penetrates well into body tissues and fluids, including peritoneal and blister fluids. It enters the CSF in the presence of inflamed meninges.
The most common side effects of the ampicillin-sulbactam combination are nausea, diarrhea, and skin rash. Transient eosinophilia and transaminasemia have been reported. Adverse reactions attributed to ampicillin may also occur with the use of ampicillin-sulbactam.

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3. Avibactam:
4. Tazobactam:
AvibactaminhibitsclassAandCβ-lactamasesaswellassomeclassDenzymesthroughtheformationofreversiblecovalentcarbamoyllinkages
Usedincombinationwithceftazidime,ceftaroline,andaztreonamforthetreatmentofnosocomialGram-negativeinfectionsincludingthoseproducingAmpCβ-lactamases,ESBLsofTEM,SHV,orCTX-Mtypes,andKPCcarbapenemases
Avibactamdoesnotinhibitmetallo-β-lactamases,suchasNDM,IMP,andVIM
Tazobactaminhibitstheβ-lactamasesfoundinstaphylococci,H.influenzae,N.gonorrhoeae,theB.fragilisgroup,Prevotellaspp.,andPorphyromonasspp.
Italsohassomeactivityagainstthegroup1β-lactamasesofAcinetobacter,Citro-bacter,Proteus,Providencia,andMorganellaspp.
TazobactamdisplaysinhibitionofmanyESBL-producingEnterobacteriaceae,especiallyE.coli,Klebdiellaspp.,andP.mirabilis
Piperacillin-tazobactam(Tazocin)istheonemostactiveagainstβ-lacta-mase-producingaerobicandanaerobicGram-negativebacilli
HighconcentrationsofTazocinisachievedintheintestinalmucosa,lung,andskin,withrelativelypoordistributiontomuscle,fat,prostate,andCSF(intheabsenceofinflamedmeninges).
Tazocinhassimilarsideeffectsofpipracillinalone