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Antibacterial

Drugs
Taufik Nur Yahya, MD
Resident
Div. Of Thoracic And Cardiovascular Surgery
Faculty Of Medicine, Airlangga University/Soetomo General Hospital

Antimicrobial Drugs
Chemicals used to treat microbial infections
Before antimicrobials, large number of people died from
common illnesses
Now many illnesses easily treated with antimicrobials
However, many antimicrobial drugs are becoming less
useful

Antimicrobial Drugs
Chemotherapeutic agent = Antimicrobial drug
Different types of antimicrobial drugs:

Antibacterial drugs
Antifungal drugs
Antiprotozoan drugs
Antihelminthic drugs

There are Three in this Relationship

Host defence

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Infection

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Drug

Bacteria

Features of Antimicrobial Drugs

1.
2.
3.
4.

Most modern antibiotics come from species of


microorganisms that live in the soil
To commercially produce antibiotic:
Select strain and grow in broth
When maximum antibiotic concentration reached,
extract from medium
Purify
Chemical alter to make it more stable

Features of Antimicrobial Drugs:

Antimicrobial Action
Bacteriostatic: inhibit growth of
microorganisms
Bactericidal: Kill microorganisms
All antibiotics require the immune system to
work properly

Bactericidal appropriate in poor


immunity

Bacteriostatic require intact


immune system

Features of Antimicrobial Drugs:

Spectrum of Activity
Antimicrobial medications vary with respect to the range
of microorganisms they kill or inhibit
Some kill only limited range : Narrow-spectrum
antimicrobial
While others kill wide range of microorganisms: Broadspectrum antimicrobial

Features of Antimicrobial Drugs:

Adverse Effects
1. Allergic Reactions: some people develop
hypersensitivities to antimicrobials
2. Toxic Effects: some antimicrobials toxic at high
concentrations or cause adverse effects
3. Suppression of normal flora: when normal flora killed,
other pathogens may be able to grow to high numbers

Features of Antimicrobial Drugs:

Resistance to Antimicrobials
Some microorganisms inherently resistant to effects of a
particular drug
Other previously sensitive microorganisms can develop
resistance through spontaneous mutations or acquisition
of new genes

Mechanisms of action of
Antibacterial Drugs
1.
2.
3.
4.
5.

Inhibit cell wall synthesis


Inhibit protein synthesis
Inhibit nucleic acid synthesis
Injury to plasma membrane
Inhibit synthesis of essential metabolites

Figure 20.2

Inhibition of Cell Wall Synthesis:


-Lactam Drugs
Irreversibly inhibit enzymes involved in the final steps of
cell wall synthesis
These enzymes mediate formation of peptide bridges
between adjacent stands of peptidoglycan
-lactam ring similar in structure to normal substrate of
enzyme
Drug binds to enzyme, competitively inhibit enzymatic
activity

Lactam Drugs
Some bacteria produce -lactamase- enzyme that breaks
the critical b-lactam ring
-lactam drugs include: penicillins and cephalosporins

Penicillins (Benzylpenicillin)

Acid-labile.
Gram+ bacteria.
So, take phenoxymethylpenicillin.
Large Vd, but penetration into brain: poor, except
when the meninges are inflammed.
Broad spectrum penicillins: amoxicillin and
ampicillin are more hydrophillic and therefore,
are active against gram- bacteria.

Penicillins (Benzylpenicillin)
Penicillinase-resistant penicillins Flucloxacillin
Indicated in infections caused by penicillinase-producing penresistant staphlococci.
Has an isoxazolyl group at R1 sterically hinders access of the
enzyme to the -lactam ring.
Less effective than benzylpen.
So, should be used only for pen-resistant infections.

Well-absorbed orally, but in severe infections, should be i.v. and not


alone.
Staphlococci aureas-resistant strains to flucloxicillin and MRSA
(methicillin-resistant Staph aureas) increasing problem.

Broad-Spectrum Penicillins
Ampicillin and amoxicillin very active against non--lactamase-producing
gram+ bacteria.

Because they diffuse readily into Gram- bacteria, also very active against many
strains of E. coli, H. influenzae, and Salmonella typhimurium.

Orally, amoxicillin is better because absorption is better.


Ineffective against penicillinase-producing bacteria (e.g., S. aureus, 50% of E.
coli strains, and up to 15 % of H. influenzae strains.

Many baterial -lactamases are inhibited by clavulaic acid amoxicillin (coamoxiclav) antibiotic is effective against penicillinase-producing organisms.

Co-amoxiclav indicated in resp and UT infections, which are confirmed to be


resistant to amoxicillin.

Cephalosporins

Used for treatment of meningitis, pneumonia, and


septicemia.
Same mech and pcol as that of pens.
May allergic rxn and cross-reactivity to pen.
Similar to pens in broad-spectrum antibacterial activity.

Vancomycin

Not well absorbed orally.


Inhibits peptidoglycan formation.
Active against most gram+ organisms.
I.v. treatment for septicemia or endocarditis caused
by MRSA.
Used for pseudomembranous colitis (superinfection
of the bowel by Clostridium difficile produces a
toxin that damages the colon mucosa)

Antibacterial Drugs
that Inhibit
Cell Wall Synthesis

Antibacterial Medications that


Inhibit Protein Synthesis
Target ribosomes of bacteria
Aminoglycosides: bind to 30S subunit causing it to
distort and malfunction; blocks initiation of translation
Tetracyclines: bind to 30S subunit blocking attachment
of tRNA.
Macrolides: bind 50S subunit and prevents protein
synthesis from continuing.

Aminoglycosides

Against many gram- and some gram+.


Narrow TI very potentially toxic.
Most important adverse side-effect: VIIIth cranial n.
(ototoxicity) and kidney damage.
Resistance several mechs: inactivation of the drug
by acetylation, phos, or adenylation, envellope to
prevent drug access, and the binding site of the 30S
subunit (streptomycin only).

Aminoglycosides

Gentamicin used for acute, life-thretening gram- infections. Has synergism


with pen and van and combo.

Amikacin used for bact that are gent-resistant.


Netilmicin less toxic than gentamicin.
Neomycin too toxic for parenteral use. Used for topically for skin infections
and orally for sterilizing bowel before surgery.

Streptomycin active against Mycobacterium tuberculosis. But bec of its


ototoxicity, rifampicin replaces.

Rifampicin resistance develops quickly alone; so, with TB, combine with
isoniazid, ethambutol, and pyrazinamide for the 1st 2 mos of treatment,
followed by another 4 mos with rifampicin and isoniazid.

Macrolides
Very safe drugs.
Ususally given orally.
Erythromycin and clarithomycin
Effective against gram- bact and can be used as an alt to pen-sensitive
patients, esp in infections caused by streptococci, staphylococci,
pneumococci, and clostridia.

Dont cross the BBB ineffective against meningitis.


Resistance- occurs bec of plasmid-controlled of their receptor on the 50S
subunit.

Erythromycin in high doses, may cause nausea and vomiting (less so with
clarithromycin and azithromycin).

Azithromycin very long t1/2 (~40-60 hr) and a single dose is as effective in
treating chlamydial non-specific urethritis as tretracycline admin over 7
days,

Tetracyclines

Broad-spectrum.
Penetrate microorganisms well.
Sensitive organisms accumulate it through partly passive

diffusion and partly through active transport.


Resistant organisms develop an efflux pump and do not
accumulate the drug.
Genes for tet-resistance transmitted by plasmids.
Closely assoc with those for other drugs to which the
organisms will also be resistant (e.g., sulphonamides,
aminoglycosides, chloramphenicol).
Tets bind to Ca in growing bones and teeth can discolor
teeth. So, should be avoided in children < 8 yrs old.

Chloramphenicol

Broad-spectrum.
Serious side-effects: bone marrow aplasia,

suppression of RBCs, WBCs, encephalopathy, optic


neuritis.
So, periodic blood counts required, esp in high doses.
Large Vd, including CNS.
Inhibits the actions of other drugs and may incr the
actions of phenytoin, sulphonlureas, and warfarin.
Neonates cannot met the drug rapidly accum
grey baby syndrome (pallor, abdominal distension,
vomiting, and collapse).

Antibacterial
Drugs that Inhibit
Protein Synthesis

Antibacterial Medications that


Inhibit Nucleic Acid Synthesis
Target enzymes required for nucleic acid synthesis
Fluoroquinolones: inhibit enzymes that maintain the
supercoiling of closed circular DNA
Rifamycins: block prokaryotic DNA-dependent RNA
polymerase from initiating transcription

Sulphonamides

Sulfadiazine well-absorbed orally. Used to treat UTIs.


But many strains of E. coli are resistant.
So, use less toxic drugs instead.
Adverse effects: allergic rxns, skin rashes, fever.
Trimethoprin used for UTIs and Resp TIs
Co-trimoxazole (trimethoprin + sulfamethoxazole) used
mostly for pneumonia, neocarditis, and toxoplasmosis.

Antibacterials Competitive Inhibitors


Sulfonamides (Sulfa drugs)
Inhibit folic acid synthesis
Broad spectrum

Figure 5.7

Figure 20.13

Quinolones (GABA antagonists)


Inhibit DNA gyrase.
Nalidixic acid used only for UTIs.
Ciprofloxin (6-fluoro substituent) that
greatly enhances its effectiveness against
both gram- and gram+ bacteria.
Well-absorbed both orally and i.v.
Eliminated largely unchanged by the
kidneys.
Side-effects (headache, vomiting, nausea)
are rare; but convulsions may occur.

5-Nitroimidazoles
Wide-spectrum
Metronidazole against anaerobic bacteria and protozoan
infections.
Tinidazole longer duration of action.
Diffuses into the organism where the nitro group is
reduced chemically reactive intermediates are formed
that inhibit DNA synthesis and/or damage DNA.

Antibacterial Drugs that Inhibit Nucleic Acids

Antibacterial medications that


Injure Plasma Membrane
Polymyxin B: binds to membrane of G- bacteria
and alters permeability
This leads to leakage of cellular contents and cell
death
These drugs also bind to eukaryotic cells to some
extent, which limits their use to topical
applications

Antibacterial Drugs that Inhibit


Synthesis of Essential Metabolites
Competitive inhibition by substance that
resembles normal substrate of enzyme
Sulfa drugs

Resistance to Antimicrobial Drugs


Drug resistance limits use of ALL known antimicrobials
Penicillin G: first introduced, only 3% of bacteria resistant
Now, over 90% are resistant

Mechanisms Responsible for Resistance to


Antimicrobial Drugs Include the Following:
1. Inactivating enzymes that destroy the drug (e.g., lactamases).
2. Decreased drug accumulation (e.g., tet).
3. Altering the binding sites (e.g., aminoglycosides and
erythromycin).
4. Development of alternative metabolic pathways
(sulphonamides ( dihydropteroate synthease) and
trimethoprim (dihydrofolate reductase).

How do Bacteria Become Resistant?


1. Spontaneous Mutation: happen as cells replicate
Within a pop, there will be some bact with acquired
resistance. The drug then elim the sensitive
organisms, while the resistant ones proliferate.
2. Gene Transfer or Transferred resistance: Usually
spread through conjugative transfer of R plasmid
( may be virally mediated).

Antibacterial Drugs in
Surgery

Classification of Surgery and Risk


Of Infection

It is important to emphasise that surgical


antibiotic prophylaxis is an adjunct to, not
a substitute for, good surgical technique.

Definition
Prophylactic antibiotic treatment
The use of antibiotics before, during, or after a diagnostic, therapeutic, or
surgical procedure to prevent infectious complications

Therapeutic antibiotic treatment


The use of substances that reduce the growth or reproduction of bacteria,
including eradication therapy.

This term is used to describe antimicrobial therapy prescribed to clear


infection by an organism or to clear an organism that is colonising a patient
but is not causing infection.

Common Principles
Ideally, an antimicrobial agent for surgical prophylaxis should
(1)prevent surgical site infection (SSI),
(2)prevent SSI-related morbidity and mortality,
(3)reduce the duration and cost of health care (when the costs
associated with the management of SSI are considered, the costeffectiveness of prophylaxis becomes evident),
(4)produce no adverse effects, and
(5)have no adverse consequences for the microbial flora of the
patient or the hospital

Timing
The antimicrobial agent should be started within 60 minutes before surgical incision

(120 minutes for vancomycin or fluoroquinolones).


Single-dose prophylaxis is usually sufficient, the duration of prophylaxis for all
procedures should be less than 24 hours.
If an agent with a short half-life is used (e.g., cefazolin, cefoxitin), it should be
readministered if the procedure duration exceeds the recommended redosing interval
(from the time of initiation of the preoperative dose).
Readministration may also be warranted if prolonged or excessive bleeding occurs or
if there are other factors that may shorten the half-life of the prophylactic agent (e.g.,
extensive burns).
Readministration may not be warranted in patients in whom the half-life of the agent
may be prolonged (e.g., patients with renal insufficiency or failure).

To achieve these goals, an antimicrobial agent should be


(1) active against the pathogens most likely to contaminate the surgical
site,
(2) given in an appropriate dosage and at a time that ensures adequate
serum and tissue concentrations during the period of potential
contamination,
(3) safe, and
(4) administered for the shortest effective period to minimize adverse
effects, the development of resistance, and costs.
In general, a first-generation cephalosporin (cefazolin) fulfills these criteria
and is regarded as sufficient prophylaxis for the majority of procedures.

Recommendations for Surgical


Antimicrobial Prophylaxis

Kirby-Bauer Method for


Determining Drug Susceptibility
1. Bacteria spread on surface of agar plate
2. 12 disks, each with different antimicrobial drug, placed
on agar plate
3. Incubated- drugs diffuse outward and kill susceptible
bacteria
4. Zone of inhibition around each disk
5. Compare size of zone to chart

Figure 21.10

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