PRINCIPLES OF ANTIMICROBIAL

THERAPY
N Ngcobo
• Antibiotics are designed to advantage of the biochemical
differences that exist between microorganisms and human
beings.
• Antimicrobial drugs are effective in the treatment of
infections because of their selective toxicity.
• They have the ability to injure or kill an invading
microorganism without harming the cells of the host.
 How do we select the correct antimicrobe?
• Identity of the organism
• Identify the susceptibility of the organism to a particular agent/s
• Identify the site of the infection
• Look at patient factors
• Consider the safety and efficacy of the agent
• Depending on the setting, one may need to look the cost of therapy
• However, most patients require empiric therapy (immediate administration of drug(s) prior to
bacterial identification and susceptibility testing.
• Drug of choice in such instances (empirical therapy) is influenced by the site of infection, the
patient history (for example, previous infections, age, recent travel history, recent antimicrobial
therapy, immune status, whether the infection was hospital- or community-acquired), and local
susceptibility data.
BACTERIOSTATIC VERSUS BACTERICIDAL
DRUGS
Bacteriostatic drugs
• Temporarily inhibit growth of the microorganism
• Require the host defence mechanisms to eradicate the infection as they do not kill the
organism.
• These include protein synthesis inhibitors

Bactericidal drugs
• They cause the death of the microorganism
• They eradicate the infection in the absence of the host defence mechanisms
• These include cell wall , DNA synthesis inhibitors and aminoglycosides.
ANTIBIOTIC RESISTANCE

Intrinsic Resistance
• The natural ability of a bacteria to resist activity from certain antibacterial agents.
• May occur due to different functional or structural features such as the production of enzymes
that metabolise the drug or the inability of the drug to enter/penetrate the bacterial.

Acquired Resistance
• Occurs when bacteria develop the ability to resist activity from certain antimicrobial agent/s.
• May occur due to spontaneous chromosomal mutations which lead to changes in the structural
receptor for an antibiotic or a protein involved in drug transport.
CLASSIFICATION OF ANTIMICROBIALS
1. Chemical structure
2. Spectrum
• Narrow spectrum: acting only on a single or a limited group of microorganisms e.g. isoniazid (TB)
• Extended spectrum: modified to be effective against gram-positive organisms and also against a
significant number of gram-negative bacteria e.g. ampicillin

3. Mode of action (MOA)

• Cell wall synthesis inhibitors
• Protein synthesis inhibitors
• Nucleic acid synthesis inhibitors
Gram + vs gram - bacteria
• The cell envelope of both gram(+) and gram(-)
bacteria consists of a cytoplasmic membrane
surrounded by a cell wall
• Gram(-) bacteria also have an outer membrane
not found on other types of bacteria
• The cell wall is much thicker in gram(+) bacteria
than in gram(-) bacteria
• The cytoplasmic membrane contains several
transport proteins to facilitate the uptake of
substances used by bacteria, and it contains the
enzymes that synthesize the bacterial cell wall –
these enzymes are inhibited by penicillins and
other beta-lactam antibiotics and are collectively
known as PBP
• The cell wall maintains the shape of the
bacterium and protects it from osmotic lysis
Gram + vs gram - bacteria
• Without a cell wall the bacterium is unprotected
• Because a cell wall is not found in higher
organisms, inhibition of the cell wall synthesis
has no effect on host (human/animal) cells
• The cell wall is synthesized during bacterial
replication, and the drugs that inhibit cell wall
synthesis are more active against rapidly dividing
bacteria than they are against bacteria in the
resting or stationary phase
• For this reason the effectiveness of cell wall
inhibitors is sometimes reduced by concurrent
administration of antibiotics that slow the growth
of bacteria (protein synthesis inhibitors / nucleic
acid synthesis inhibitors)
 Cell Wall Inhibitors

• Selectively interfere with synthesis of the bacterial cell wall resulting in weakened cell wall and
ultimately cell death.
• The interference with the enzymes results in the formation of porins in the cell wall leading to cell death..

1. Penicillins (amoxicillin, ampicillin)

2. Cephalosporins (cefazolin, ceftriaxone)
3. Carbapenems (meropenem, imipenem)
4. Beta lactamase inhibitor + antibiotic combinations (tazobactam + pipercallin, clavulanic acid +
amoxicillin)
5. Others (vancomycin, colistin)
When you complete this section, you
should be able to:
• Describe the MOA of beta-lactam antibiotics
• Describe the 3 mechanisms underlying the resistance
of bacteria to beta-lactam antibiotics
• Identify the drugs in each subclass of penicillins and
describe their antibacterial activity and clinical uses
• Identify the 4 subclasses of cephalosporins and
describe their antibacterial activities and clinical uses
• List the major adverse effects of the penicillins and
cephalosporins
• Identify the important features of aztreonam,
imipenem and meropenem
• Describe the clinical uses and toxicities of
vancomycin
 PENICILLINS

• Interfere with the last step of bacterial cell wall synthesis, which is the cross-linking of adjacent
peptidoglycan strands by a process known as transpeptidation.
• Compete for and bind to enzymes called penicillin-binding proteins (PBPs), which catalyze
transpeptidase and facilitate cross-linking of the cell wall.
• Gram-positive microorganisms have cell walls that are easily traversed by penicillins, and,
therefore, in the absence of resistance, they are susceptible to these drugs.
• Penicillins have a beta-lactam ring; the integrity of the beta-lactam ring is required for
antibacterial activity
• Penicillins are absorbed rapidly after oral administration and parenteral administration
• GI absorption may be decreased in the presence of food
• Penicillins do not cross the BBB, except in meningitis; Meningitis increases the permeability
of the BBB, but even then very high doses of penicillin must be administered
• Some bacteria, such as staphylococci, become resistant to penicillins as they produce the beta-
lactamase enzyme, penicillinase, which inactivates the penicillins
• Bactericidal
 PENICILLINS

ADVERSE EFFECTS
• Hypersensitivity
• Diarrhoea
• Nephritis
• Neurotoxicity
• Hematologic hepatoxicities

THERAPEUTIC INDICATIONS
• Respiratory infections
• UTIs
• Endocarditis
• Otitis media
• Pneumonia
• Hospital-acquired infections
 PENICILLINS

CLINICAL CONSIDERATIONS
• Dose reductions are necessary in cases of renal impairment as penicillins excreted by
kidney.
• Avoid where there is a history of penicillin allergy (if a patient is allergic to one
penicillin, will be allergic to ALL penicillins – CROSS allergy).
• Penicillins reduce the elimination of methotrexate (used in cancer treatment)
Broad spectrum drugs increase C difficile infection risk
C difficile – anaerobic bacteria C difficile colonize the human colon without
symptom; antibiotic treatment can produce overgrowth
Produce diarrhoea and inflammation
Antibiotic treatment is difficult due to antibiotic resistance and physiological factors
of the bacteria (spore formation, protective effects of the pseudomembrane)
 Except for oral amoxicillin, penicillins should be given 1-2 hrs before or after a meal; they
should not be given with food to minimize binding to food proteins and acid inactivation

Resistance to penicillins occur because of:

• 1 ) inactivation of the antibiotic by the bacterial enzyme, β-lactamse

• 2) modification of target PBP’s so penicillins cannot bind to these
• 3) impaired penetration of drug to target PBP’s (cannot reach target site in
bacterial cell)

Penicillins • 4) efflux (bacterial cell pumps antibiotic out, so antibiotic cannot reach PBP)

Combinations of penicillins and beta-lactamse inhibitors:

• amoxicillin + clavulanic acid (beta-lactamase inhibitor) = co-amoxiclav

• Clavulanic has minimal intrinsic antibacterial action, but the combination has
extended the spectrum of amoxicillin
• Piperacillin + tazobactam (beta-lactamase inhibitor)
• Tazobactam extends the spectrum of piperacillin to include beta-lactamase
producing bacteria, including many nosocomial infections

Synergy with aminoglycosides against pseudomonal and enterococcal species

CLASSES OF PENICILLINS

iii) Broad spectrum iv) Antipseudomonal

Narrow-spectrum penicillins ii) Penicillinase resistant
penicillins penicillins
• Pen G (IV) – measured in • Cloxacillin (PO / IV / IM) • Amoxicillin (PO) • Piperacillin
units • Flucloxacillin (PO) • Ampicillin (IM / IV) • Tazobactum
• Benzylpenicillin • Dicloxacillin (PO) • Piperacillin (IV / IM)
• Benzathine • Nafcillin (IV) • Ticarcillin (IV)
benzylpenicillin (IM; long • Oxacillin (IV)
acting)
• Procaine benzylpenicillin
(IM; long acting)
• Pen V (PO)
• Phenoxymethylpenicillin
SUMMARY
MOA
All living cells are surrounded by a
cell membrane, but bacterial cells
are also surrounded by a firm cell
wall essential for their normal
growth and development
Β-lactams inhibits cell wall synthesis
by binding to penicillin binding
protein (PBP) preventing cross-
linking of peptidoglycan
Lysis of the bacterial cells takes
place after exposure to penicillins
PK
Oral absorption of the penicillins is
poor, but there are exceptions
Most of the penicillins only cross the
BBB if it is inflamed
Penicillins are, for the most part,
excreted by tubular secretion; dose
reduction only needed in major
renal dysfunction
AE
Most important adverse effect of
penicillins as a group is the
hypersensitivity reaction
Assume complete cross-allergy
between individual penicillins
GI distress such as nausea and
diarrhea (especially ampicillin)
Cholestatic jaundice (rare – most
linked to co-amoxiclav)
 CEPHALOSPORINS

• Closely related both structurally and functionally to penicillins.

• Have the same mode of action as penicillins, and they are affected by the same resistance
mechanisms. However, they tend to be more resistant than the penicillins to certain β-lactamases.

• Classified as first, second, third, fourth, and advanced generation, based largely on their bacterial
susceptibility patterns and resistance to β-lactamases

• First generation has a narrow spectrum. The 2 nd, 3rd and 4th generations have a wider spectrum.

• Cephalosporins are classified into generations – first generation mainly effective against gram-
positive cocci; second generation more gram-negative coverage incl. anaerobes; 3 rd generation
both gram-positive and gram-negative coverage; fourth generation wider spectrum than 3 rd
• Cephalosporins are widely distributed in body fluids;
selected agents (cefuroxime, cefotaxime, ceftizoxime)
penetrate the CSF
• Orally administered cephalosporins are second- and third-
line in the treatment of respiratory and urinary tract
infections
THERAPEUTIC
• IV administered cephalosporins are used in the treatment
of more severe infections, including antibiotic-resistant INDICATIONS
infections
• Earlier cephalosporin generations have greater activity
against Gram-positive organisms; their Gram-negative
activity can be summarized by the mnemonic PEcK –
Proteus mirabilis, some E coli and Klebsiella pneumoniae
• As cephalosporin generations progress, they become more
and more active against Gram-negative organisms
• Second generation have less activity against Gram-positive
organisms, however, they have greater Gram-negative
activity: HEN – Haemophilus influenza, Enterobacter, and THERAPEUTIC
some Neisseria (in addition to PEcK)
INDICATIONS
• Each newer generation is increasingly resistant to
penicillinases
• Third generation cephalosporins are sensitive to the
cephalosporinases
ADVERSE EFFECTS
• Generally well tolerated.
• Allergic reactions are a concern
• Patients who have had an anaphylactic response, Stevens-Johnson
syndrome, or toxic epidermal necrolysis to penicillins should not
receive cephalosporins.
• Should be avoided or used with caution in individuals with
penicillin allergy.
Cephalosporin generations
(spectrum increases with newer generations)
First generation
cephalosporins
• Cefadroxil / Cephalexin (PO)
• Cefazolin (IV)
• Have good activity against
some gram-positive and
some gram-negative
organisms
• Used mainly for Klebsiella
and penicillin- and
sulfonamide-resistant UTI
• Used prophylactically in
surgical procedures
• Do not penetrate the CSF
Second generation
cephalosporins
• Cefuroxime / Cefoxitin /
Cefamandole
• Cefaclor / Cefprozil (PO)
• Have somewhat broader
spectrum than first-
generation
• Used in the treatment of
streptococcal infections
• Active against most
anaerobes
• Used primarily in UTI, RTI,
bone and soft tissues
infections and surgical
prophylaxis
• With exception of
cefuroxime, these agents do
not penetrate CSF
Third generation Fourth-generation
cephalosporins cephalosporins
• Ceftriaxone / Cefotaxime / • Cefepime / Cefpirome (IV /
Ceftazidime (IM / IV) IM)
• Cefixime / Cefpodoxime
(PO) • Coverage against
Pseudomonas as well as
• Enhanced activity against other gram-negative
gram-negative organisms bacteria
• These agents penetrate the
CSF
• Most are excreted by the
kidney except cefoperazone
and ceftriaxone which are
excreted through the biliary
tract
 • Used for Staph and Strep infections, respiratory
tract infections (RTIs), meningitis, pneumonia
• Organisms not covered by cephalosporins = LAME

Spectrum • Listeria monocytogenes

• Atypicals (Chlamydia, mycoplasma)
• MRSA
• Enterococci

• MOA and resistance mechanisms – identical to

penicillins
Summary
MOA • They inactivate bacterial transpeptidases and
prevent the cross-linking of peptidoglycan polymers
that is essential for bacterial cell wall integrity

• Cephalosporins are relatively nontoxic

• Hypersensitivity (cross-hypersensitivity with
penicillins)

AE
• Some cephalosporins can cause disulfiram-like
reactions because they block alcohol oxidation
causing acetaldehyde to accumulate
• Some cephalosporins have anti-vit K effects (may
result in increased bleeding)
 Include
• Imipenem / Meropenem / Ertapenem / Doripenem

MOA
• similar to other beta-lactams carbapenems inhibit bacterial cell wall synthesis by binding to PBP
• carbapenems are relatively resistant to beta-lactamases and do not demonstrate cross-resistance
with other antibiotics

PK
• Important agents in hospital for empiric treatment in life-threatening conditions
• Imipenem is formulated with an equal amount of cilastatin, a specific enzyme inhibitor that blocks
renal metabolism of imipenem and enhances its urinary concentration; cilastatin has no

CARBAPENE
antibacterial action
• Imipenem is not suitable for treating meningitis as seizures may occur with higher doses
• Meropenem: more stable to renal inactivation than imipenem and thus given without cilastatin.

MS • Imipenem, meropenem, and doripenem are administered IV and penetrate well into body tissues and
fluids, including the CSF when the meninges are inflamed.
• Meropenem is known to reach therapeutic levels in bacterial meningitis even without inflammation.

T/I
• infections caused by penicillinase-producing S aureus, E coli, Klebsiella, Enterobacter
• Also used for Pseudomonas (except ertapenem)

AE
• Hypersensitivity reactions; Penicillin cross-allergy
• Excessive levels of imipenem may result in seizures in patients with renal failure
• GI distress
• Potential to cause CNS effects including seizures (high risk with imipenem)
 MONOBACTAMS
E.g. Aztreonam

• IM / IV
• Mainly used against gram - rods

Spectrum

• Active against aerobic gram-negative bacteria, incl Pseudomonas

• Ineffective against gram-positive bacteria and anaerobes

MOA

• Although azatreonam has a monobactam ring, the MOA is the same as penicillins and cephalosporins – inhibit bacterial cell wall
synthesis by binding to PBP
• Resistant to beta-lactamases

A/E

• No cross-allergy with penicillins or cephalosporins

• Possible skin rash and increased serum liver transaminases
 GLYCOPEPTIDES
E.g. vancomycin, telavancin, dalbavancin, oritavancin

MOA

• Bind to the terminal end of the growing peptidoglycan; prevent further elongation and cross-linking due to inhibition of transglycosylase
• This results in decreased cell membrane activity and increased cell lysis

Pharmacological properties and indications

• Vancomycin only penetrates CSF during inflammation

• Tricyclic glycopeptide active against aerobic and anaerobic gram-positive bacteria etc

Bactericidal

• Commonly used in patients with skin and soft tissue infections, infective endocarditis, and nosocomial pneumonia.
• Vancomycin is only active against gram-positive organisms, incl MRSA
• Oral vancomycin is used to treat C difficile colitis
• Televancin, dalbavancin and oritavancin are used to treat skin and skin-structure infections

A/E

• Rapid infusion of vancomycin cause red-man syndrome, which is an infusion-related reaction caused by the release of histamine; it is not considered a drug allergy – prolonging the
infusion to 1-2hrs will prevent this reaction
• High levels of vancomycin may cause nephrotoxicity and ototoxicity
• Televancin and dalbavancin are potentially teratogenic
 LIPOPEPTIDE

Daptomycin

MOA
• Daptomycin binds to the cell membrane via calcium-dependent insertion of its lipid tail
• This results in depolarization of the cell membrane with potassium efflux and rapid cell death

Spectrum & T/I

• Daptomycin has antibacterial actions similar to vancomycin
• Covers gram-positive bacteria and may be active against MRSA and vancomycin-resistant strains
• Cannot be used for the treatment of pneumonia as it is inactivated by pulmonary surfactant and does not achieve sufficient
concentrations in the respiratory tract

A/E
• May cause myopathy
• May result in eosinophilic pneumonia
OTHER CELL WALL SYNTHESIS INHIBITORS
Fosfomycin

• Inactivates pyruvyl transferase, an enzyme that is critical in the synthesis of bacterial cell wall
• Active against both gram-positive and gram-negative infections
• Treatment of uncomplicated UTIs
• A/E may include headache and GI distress

Bacitracin

• Prevents the transfer of mucopeptides into the growing cell wall

• Most active against gram-positive bacteria
• Highly nephrotoxic, thus only used topically; used in combination with neomycin or polymyxin for
minor infections
• Adverse effect may include allergic reactions

Colistin (polymixin)

• This unlicensed drug has become important as the only treatment available for highly resistant
Acinetobacter infections;
• Not registered in SA, but can be obtained from the company on a named-patient basis after MCC
approval
• Nephrotoxicity / Neurotoxicity
Summary of important points

The beta-lactam antibiotics
Beta-lactam antibiotics,
inhibit the transpeptidase
vancomycin, bacitracin, and
reaction that cross-links the
fosfomycin are drugs that inhibit
peptidoglycan component of the
bacterial cell wall synthesis
cell wall
Beta-lactamase inhibitors
(clavulanic acid, sulbactam,
Narrow-spectrum penicillins are
tazobactam) are administered in
primarily active against gram-
combination with a beta-lactam
positive cocci and spirocheted
antibiotic to prevent degradation
of the antibiotic by bacteria

Most penicillins are eliminated

Penicillinase-resistant peicillins
are used to treat staphylococcal
infections
Extended-spectrum penicillins are
primarily by renal tubular
active against various gram-
secretion, a process that is
negative bacilli
inhibited by probenecid
Summary of important points cont’
Cephalosporins are subdivided
into 4 generations on the basis of
their antimicrobial spectrum; the
activity against gram-negative
organisms increase from the first
to the fourth generation
Aztreonam is a monobactam
antibiotic that is active against
aerobic gram-negative bacilli; it
does not show cross-sensitivity
with other beta-lactam antibiotics
Some cephalosporins are
eliminated by renal tubular
secretion, whereas others are
eliminated in the bile
Vancomycin is active against
gram-positive organisms incl
MRSA and Clostridium difficule
Ceptriaxone has a much longer
Carbapenems are active against a
half-life than the other
broad spectrum of bacteria incl
cephalosporins, enabling it to be
many strains of gram-negative
used as a single-dose treatment
bacteria resistant to other
for certain infections, incl
antibiotics
gonorrhea
Bacitracin is used topically for Fosfomycin is administered as a
infections caused by gram- single dose for uncomplicated
positive cocci UTI’s case by E coli or enterococci