College of Nursing

1st Semester (S.Y. 2023-2024)

 Anti-Bacterials III

Terro Nikko M. Baluyut, RN, CRN, MD

Clinical Instructor
 Bacterial Cell Wall Synthesis
Inhibitors

Penicillins Cephalosporins Miscellaneous

Narrow Wider Narrow Wider

Carbapenems Aztreonam Vancomycin
Spectrum Spectrum Spectrum Spectrium
Bacterial Cell Wall Synthesis Inhibitors

Penicillins Cephalosporins

Wider Narrow Wider

Narrow Spectrum
Spectrum Spectrum Spectrum

Penicillinase- Peniciillinase- 1st Higher

susceptible resistant Generation Generation
Bacterial Cell Wall Synthesis Inhibitors

Miscellaneous

Carbapenems

Aztreonam Vancomycin

Imipenem Meropenem Ertapenem

Season 2, Episode 1

BETA-LACTAM ANTIBIOTICS
 Beta-Lactam Antibiotics
• Penicillins

• Cephalosporins

• Carbapenems

– Not really a beta-lactam but retains its ring

structure
 Penicillins
• Derivatives of 6-aminopenicillanic acid

• Contains a beta-lactam ring essential for

antibacterial activity

• Have additional chemical substituents which

confer differences (antimicrobial activity,
susceptibility to acid, enzymatic hydrolysis,
and biodisposition)
 Penicillins
• Pharmacokinetics

– Vary in resistance to gastric acid (and thus have

variable bioavailability)

– Not metabolized extensively (in effect excreted

unchanged in the urine via glomerular filtration
and tubular secretion)

• Tubular secretion is inhibited by probenecid

 Penicillins
• Pharmacokinetics:

– Nafcillin (excreted mainly in bile)

– Ampicillin (undergoes enterhepatic recycling)

 Penicillins
• Pharmacokinetics: half-lives of mostly 30
minutes to 1 hour

– Procaine and Benzathine have longer half-lives

(given IM 🡪 active drug has slow release into the
bloodstream)

Note: most penicillins are able to cross the

blood-brain barrier only when meninges
are inflamed
 Penicillins
• Mechanism of Action: bactericidal

– Inhibits cell wall synthesis by the following steps:

• Drug binds to specific enzymes (penicillin-binding proteins

[PBPs] located in the bacterial cytoplasmic membrane

• Inhibition of the transpeptidation reaction that crosslinks

the linear peptidoglycan chain constituents of the cell wall

• Activation of autolytic enzymes that cause lesions in the

bacterial cell wall
 Penicillins
• Resistance:

– Enzymatic hydrolysis of the beta-lactam ring

results in the loss of antibacterial activity

– Formation of beta-lactamases (penicillinases) by

mostly staphylococci and many gram-negative
organisms is the major cause of resistance
 Penicillins
• Resistance:

– To combat this development, inhibitors of these

bacterial enzymes are often used in combination with
penicillins to prevent their inactivation

• Clavulanic acid

• Tazobactam

• Sulbactam
 Penicillins
• Resistance:

– In the case of MRSA 🡪 structural changes in the

target PBPs (also in resistance to penicillin G in
pneumococci)

– In some gram-negative rods (pseudomonas),

changes in porin structures in the outer cell wall
may contribute resistance (it prevents penicillins
from accessing and binding to the PBPs)
 Clinical Uses
• Narrow spectrum Penicillinase-susceptible
agents

• Very narrow spectrum penicilllinase-resistant

agents
 Narrow Spectrum Penicillinase-Resistant

• Penicillin G

– Prototype of a subclass of penicillins with limited

spectrum of antibacterial activity (and susceptible
to beta-lactamases)

– Used against common streptococci, meningococci,

gram-positive bacilli, and spirochetes
 Narrow Spectrum Penicillinase-Resistant

• Penicillin G

– Many strains of pneumococci are now resistant to

penicillins (PRSP)

– Most strains of S. aureus and N. gonorrhea are

resistant due to beta-lactamse production

• No longer DOC for gonorrhea, but still for syphilis

 Narrow Spectrum Penicillinase-Resistant

• Penicillin G

– Activity against enterococci is enhanced by co-

administration of aminoglycosides
 Narrow Spectrum Penicillinase-Resistant

• Penicillin V

– Used for oropharyngeal infections (given orally)

 Very Narrow Spectrum Penicillinase-Resistant

• Subclass of penicillins which includes:

– Methicillin (prototype, but rarely used due to its

nephrotoxic potential)

– Nafcillin

– Oxacillin
 Very Narrow Spectrum Penicillinase-Resistant

• Primary use: staphylococcal infections

Note: MRSA and MRSE (S.

epidermidis) are resistant to all
penicillins, and often against
multiple antimicrobials
 Wider Spectrum Penicillinase-Susceptible

• Ampicillin and Amoxicillin:

– Subgroup that has wider spectrum of antibacterial

activity compared to penicillin G (but still
susceptible to penicillinase)
 Wider Spectrum Penicillinase-Susceptible

• Ampicillin and Amoxicillin:

– Clinical use similar to penicillin G, as well as

against:

• Enterococci, L. monocytogenes, E. coli, P. mirabilis, H.

influenzae, and M. catarrhalis

– Some resistant strains have developed

 Wider Spectrum Penicillinase-Susceptible

• Ampicillin and Amoxicillin:

– Activity is enhanced when used with penicillinase

inhibitors (e.g. clavulanic acid 🡪 Co-Amoxiclav)

– Synergistic with aminoglycosides in enterococcal

and listerial infections (ampicillin)
 Wider Spectrum Penicillinase-Susceptible

• Piperacillin and Ticarcillin:

– Activity against some gram-negative rods,

including:

• Pseudomonas

• Enterobacter

• Klebsiella
 Wider Spectrum Penicillinase-Susceptible

• Piperacillin and Ticarcillin:

– Often used with penicillinase inhibitors

(tazobactam and clavulanic acid) to enhance their
activity
 Penicillins
• Toxicity:

– Allergic reactions

– Gastrointestinal disturbances
 Penicillins
• Toxicity: allergic reactions

– Urticaria, severe pruritus, fever, joint swelling,

hemolytic anemia, nephritis, and anaphylaxis

– Allergic response occurs if given penicillin again (in

5-10% of persons)
 Penicillins
• Toxicity: allergic reactions

– Maculopapular skin rash (but mimics an allergic

reaction) 🡪 ampicillin
 Penicillins
• Toxicity: gastrointestinal disturbances

– Nausea and diarrhea (oral penicillins)

• May be due to direct irritation or by overgrowth of

gram-positive organisms or yeasts

• Pseudomembranous colitis (ampicillin)

 Penicillins
• Toxicity: gastrointestinal disturbances

– Nausea and diarrhea (oral penicillins)

• May be due to direct irritation or by overgrowth of

gram-positive organisms or yeasts

• Pseudomembranous colitis (ampicillin)

 Penicillins
• Toxicity: miscellaneous

– Neutropenia (nafcillin)

– Interstitial nephritis (methicillin)

 Cephalosporins
• Derivatives of 7-aminocephalosporanic acid
and contain the beta-lactam ring structure

• Many members are in clinical use

– Vary in antimicrobial activity and are designated

according to their generations (in order of their
introduction into clinical use)
 Cephalosporins
• Pharmacokinetics:

– Many are available for oral use (mostly parenteral)

– Those with sidechains may undergo heptaic

metabolism but majority undergo renal excretion
via active tubular secretion

• Only Cefoperazone and Ceftriaxone are excreted mainly

in the bile
 Cephalosporins
• Pharmacokinetics:

– Most cephalosporins do not enter the

cerebrospinal fluid even when meninges are
inflamed
 Cephalosporins
• Mechanism of Action

– Bind to penicillin-binding proteins to inhibit

bacterial cell wall synthesis (just like penicillins)

• bactericidal

– Some structural differences make them less

susceptible to penicillinase produced by
staphylococci
 Cephalosporins
• Resistance

– Some bacteria are able to produce beta-lactamases

which can inactivate cephalosporins

– May occur from decreases in membrane permeability

to cephalosporins or from changes in PBPs

– MRSA is resistant
 1 Generation
st

• Cefazolin (parenteral) and Cephalexin (oral)

– Active against gram-positive cocci (staphylococcus

and common streptococci)

– Effective against many strains of E. coli and K.

pneumoniae

– Usually used as surgical prophylaxis

 1 Generation
st

• Cefazolin (parenteral) and Cephalexin (oral)

– Minimal activity against:

• Gram-negative cocci

• Enterococci

• MRSA

• most gram-negative rods

 2 Generation
nd

• Lesser activity against gram-positive microbes

versus 1st generation drugs

– But have extended gram-negative coverage

– Marked differences between usefulness between

drugs in the group
 2 Generation
nd

• Examples:

– Bacteroides fragilis (cefotetan and cefoxitin)

– Sinus, ear, and respiratory infections caused by H.

influenzae or M. catarrhalis (cefamandole,
cefuroxime, and cefaclor)
 3 Generation
rd

• Increased activity against gram-negative

microbes resistant to other beta-lactam
medications

– Plus the ability the penetrate the blood-brain

barrier (except for cefoperazone and cefixime)
 3 Generation
rd

• Most active against:

– Providencia, serratia marcescens, and beta-

lactamase-producing strains of H. influenzae and
Neiserria
 3 Generation
rd

• Less active against:

– Enterobacter strains that produce extended-

spectrum beta-lactamases
 3 Generation
rd

• Most drugs in this class are reserved usually

for serious infections:

– Pseudomonas 🡪 cefoperazone, ceftazidime

– B. fragilis 🡪 cetizoxime

• Except for: ceftriaxone (parenteral) and

cefixime (oral) 🡪 for gonorrhea
 4 Generation
th

• Cefepime 🡪 more resistant to beta-

lactamases produced by gram-negative
microorganisms:

– Enterobacter, haemophilus, neisseria, and some

penicillinase-resistant pneumococci
 4 Generation
th

• Cefepime 🡪 combines:

– Gram-positive activity of 1st generation

– Wider gram-negative spectrum of 3rd generation

 4 Generation
th

• Ceftaroline 🡪 has activity against infections

caused by MRSA
5 Generation
th
 Cephalosporins
• Toxicity:

– Allergies (skin rashes to anaphylactic shock)

• Between cephalosporins is complete (100%)

• Between a cephalosporin and penicillin is incomplete

(5-10%)
 Cephalosporins
• Other Adverse Effects:

– May cause pain at IM injections (as well as

phlebitis if given IV)

– May increase nephrotoxicity of aminoglycosides (if

given together)
 Cephalosporins
• Other Adverse Effects:

– Some may cause hypoprothrombinemia and

disulfiram-like actions with ethanol (cefamandole,
cefoperazone, and cefotetan)

• Due to their methylthiotetrazole group

Season 2, Episode 1

OTHER BETA-LACTAM DRUGS

 Other Beta-Lactam Drugs
• Aztreonam

• Carbapenems (Imipenem, Meropenem, and

Ertapenem)

• Beta-Lactamase Inhibitors (Clavulanic acid,

Sulbactam, and Tazobactam)
 Aztreonam
• monobactam resistant to beta-lactamases
produced by some gram-negative rods
(including Klebsiella, pseudomonas, and
serratia)

• No activity against gram-positive bacteria or

anaerobes
 Aztreonam
• Cell wall synthesis inhibitor (preferentially
binds with penicillin-binding protein (PBP3)

• Synergistic with aminoglycosides

 Aztreonam
• Given intravenously and is eliminated via renal
tubular secretion

• Half-life is prolonged in renal failure

 Aztreonam
• Adverse effects include GI upset with possible
superinfection, vertigo, headache, and rarely
hepatotoxicity

– Skin rash may occur but there is no cross-

allergenicity with penicillins
 Carbapenems
• Imipenem

• Doripenem

• Meropenem

• Ertapenem
 Carbapenems
• Chemically different from penicillins but retain the
beta-lactam ring structure

• Have low susceptibility to beta-lactamases which

makes them useful against:

– Gram-positive cocci

– Gram-negative rods

– anaerobes
 Carbapenems
• All are active against P. aeruginosa and
acinetobacter spp, except for ertapenem

– Often paired with an aminoglycoside if used

against pseudomonas
 Carbapenems
• Given parenterally, are useful against microbes
resistant to other antibiotics

• X MRSA

• Co-drugs of choice for:

– Enterobacter, citrobacter, and serratia spp

 Imipenem
• Rapid inactivation by renal dehydropeptidase I

• Administered in fixed combination with cilastatin

(an inhibitor of the enzyme above)

– Increases its half-life and inhibits the formation of a

metabolite toxic to the kidneys

Note: other carbapenems are not significantly degraded

by the kidneys
 Imipenem-Cilastatin
• PRIMAXIN
• Partial cross-allergenicity with penicillins
• Adverse effects:

– GI distress, and skin rash

– CNS toxicity 🡪 confusion, encephalopathy, and

seizures (at very high plasma levels)
 Meropenem
• Similar to imipenem but not metabolized by
renal dehydropeptidases

• Less likely to cause seizures

 Ertapenem
• Long half-life but less active against
enterococci and pseudomonas

• Intramuscular route causes pain and irritation

 Beta-Lactamase Inhibitors
• Clavulanic acid

• Sulbactam

• Tazobactam
 Beta-Lactamase Inhibitors
• Used in fixed combinations with certain
hydrolyzable penicillins

• Most active against plasmid-encoded beta-

lactamases (produced by gonococci,
streptococci, E. coli, and H. influenzae)
 Beta-Lactamase Inhibitors
• Not useful against enterobacter,
pseudomonas, and serratia

– Their type of beta-lactamase is chromosomal (and

not plasmid-encoded)
Season 2, Episode 1

OTHER CELL WALL OR MEMBRANE-

ACTIVE AGENTS
 Other Agents
• Vancomycin

• Fosfomycin

• Bacitracin

• Cycloserine

• Daptomycin
 Vancomycin
• Bactericidal glycoprotein which inhibits
transglycosylation

– Prevents elongation of the peptidoglycan chain

and interferes with cross-linking

– Resistance 🡪 due to decreased affinity for the

binding site
 Vancomycin
• Narrow spectrum of activity

– Used for serious infections caused by drug-

resistant gram-positive organisms

• Methicillin-resistant staphylococci (MRSA)

• Penicillin-resistant pneumococi (PRSP) 🡪 in

combination with a 3rd generation cephalosporin
(usually ceftriaxone)
 Vancomycin
• Narrow spectrum of activity

– Used for serious infections caused by drug-

resistant gram-positive organisms

• Backup drug 🡪 Clostridium difficile infection

 Vancomycin
• Not absorbed in the GI tract (and may be
given orally for bacterial enterocolitis)

• Given parenterally, it penetrates most tissues

and is eliminated unchanged in the urine
 Vancomycin
• Dosage modification is mandatory in renal failure
patients

• Toxicity:

– Chills, fever, phlebitis, ototoxicity, and nephrotoxicity

– Rapid intravenous infusion 🡪 Red Man Syndrome (due

to histamine release)
Vancomycin
 Fosfomycin
• Antimetabolite inhibitor of cytosolic
enolpyruvate transferase

– Prevents formation of N-acetylmuramic acid (an

essential precursor for peptidoglycan chain
formation)

– Resistance 🡪 decreased intracellular accumulation

of the drug
 Fosfomycin
• Excreted by the kidney in urinary levels higher
than minimum inhibitory concentrations (MIC)
🡪 makes it useful against UTIs

• In multiple dosing, diarrhea is common

• May be synergistic with beta-lactam and

quinolone antibiotics in some infections
 Bacitracin
• Peptide antibiotic which interferes with a late
stage in cell wall synthesis in gram-positive
organisms

• Limited to topical use because of its marked

nephrotoxicity
 Cycloserine
• Antimetabolite that blocks incorporation of
amino acids into the side chain of the
peptidoglycan

• Highly neurotoxic (tremors, seizures, and

psychosis)

– Limited use to tuberculosis that is resistant to first-

line antituberculosis drugs
 Daptomycin
• Novel cyclic lipopeptide with spectrum similar
to vancomycin (but active against vancomycin-
resistant strains of enterococci and
staphylococci)

• Eliminated via the kidney

• Monitor creatinine since it causes myopathy

THANK YOU.