Anti-microbials
By
Dr.Mohamed Abd Almoneim Attia
Classifications of antimicrobials
A. According to their antimicrobial spectrum:
*Antibiotics with narrow spectrum:
Drugs primarily effective against gram-positive organisms
e.g. some penicillins, cephalosporins, macrolides,……..
etc.
Drugs primarily effective against gram-negative
organisms e.g. aminoglycosides, monobactam, ……...
*Extended spectrum: both gram –ve and +ve
microorganism.
*Broad-spectrum antimicrobial agents
That affects most gram-positive and most gram-negative
organisms and others(protozoa) e.g chloramphenicol,
tetracyclines, broad-spectrum penicillins, 3rd generation
cephalosporins……….
B.Antimicrobial agents are also classified according
to pharmacological effects as either bacteriostatic
(inhibitory) or bactericidal (lethal) agents.
1-Bacterostatic (stop multiplication of
microorganisms)
e.g. sulfonamides, trimethoprim,
chloramphenicol,…... Most of bacteriostatic drugs
become bactericidal in high concentrations.
2-Bactericidal (act primarily by killing microorganism)
e.g. penicillin, cephalosporins, aminoglycosides……..
C. According to the source and chemistry:
1-Synthetic Chemotherapeutic Agents:
they act selectively on infective organism such as
sulfonamides, isonicotinic acid hydrazide and the
quinolones.
2-Antibiotics:
are those compounds produced by microorganisms
(bacteria, fungi) that, at high dilutions, are inhibitory
or lethal to other microorganisms such as penicillin,
tetracycline and chloramphenicol.
D. Antimicrobial agents are also classified according to their Mechanism of
action:
 Mechanism of action of antimicrobial agents
Antimicrobials affect microbial cells by one or more of the following:
1-Inhibition of bacterial cell wall synthesis, so that the cell absorb water and
bursts
e.g. B lactam antimicrobials , bacitracin, cycloserine, vancomycin.
2-Increased permeability of cell membrane. So that vital metabolites escape
e.g. antifungal (nystatin, amphotericin), antipseudomonas (polymyxin B,
colistin).
3-Inhibition of protein synthesis by an effect on ribosome:
Drugs acting on 30S subunit e.g. aminoglycosides, tetracycline.
Drugs acting on 50S subunit e.g. chloramphenicol, macrolides, fucidin,
lincosamides.
4-Inhibition of nucleic acid synthesis
e.g. rifampicin, quinolones, metronidazole, antivirals, anticancer.
5-Inhibition of intermediary metabolism
e.g. sulfonamides, trimethoprim, pyrimethamine, methotrexate.
• Uses of antimicrobials:…………………………………………
 Adverse effects of antimicrobial agents:
The adverse effects associated with the use of antimicrobial agents
include:
1-Hypersensitivity or allergic reactions: In form of fever, skin rash,
arthralgia, cholestatic jaundice or hemolysis. More serious reactions
are agranulocytosis, bone marrow aplasia or anaphylactic reaction.
2-Resistance
3-Superinfection= (Opportunistic infection): Reactions related to
alterations in normal body flora
Administration of broad-spectrum antibiotics if used for long time
may alter or kill bacterial flora or have incomplete absorption. So,
the bacteria and fungi that are normally inhibited by bacterial flora
will multiply leading to superinfection (its early manifestation may
by diarrhoea). It is caused by staphylococci, Pseudomonas,
proteus, Candida albicans.. etc. Superinfection may be vaginal,
oral, pharyngeal or even systemic infection e.g. staphylococcal
enterocolitis, candidiasis.
The most serious form of superinfection if it is caused by gram+ve
anaerobic organism like closterdil difficile resulting in
pseudmembranous colitis.
Treatment:
Stop the causative agent and give drug, which kill the
organisms responsible for superinfection e.g.
staphylococcal enterocolitis, which is treated by
vancomycin orally, or antifungal nystatin for candidiasis. If
it is in the form of pseudmembranous colitis, it is treated
with antianaerobic e.g. metronidazole. In addition you
must give symptomatic treatment in form of adsorbants
and antidiarrheal.
4-Vitamin B complex deficiency may follow the use of
antimicrobials e.g broad-spectrum antibiotics. It is due
to inhibition of bacterial flora that forms these vitamins.
5-Direct toxic reactions (organ toxicity), resulting from
high doses or drug interactions, on hemopoietic system,
liver, kidney, GIT, nervous system or CVS.
 Resistance to antimicrobial drugs
Biochemical mechanisms:
1-Production of inactivating enzymes:
e.g. -lactamases (by staph. and some gram-negative bacilli)
inactivate -lactam antibiotics.
2-Reduced bacterial permeability to antibiotics:
e.g tetracyclines accumulate by active transport mechanism in
susceptible organisms. Resistant strains lack this mechanism.
3-Modification of the receptor site:
e.g. Loss or alteration of the receptor protein on 30S ribosome
causes resistance to aminoglycosides and 50S ribosome causes
resistance to erythromycin.
4-Development of an alternate metabolic pathway that
bypasses the reaction inhibited by the drugs:
e.g. sulfonamide-resistant bacteria can utilize pre-formed folic
acid.
B. Genetic basis of acquired resistance:
Chromosomal resistance:
Extrachromosomal resistance:
This results from transfer of genetic material from one
bacterium to another.The genetic material may be in the
form of plasmids . The genetic material and plasmids can
be transferred by transformation, transduction,
conjugation, or translocation.
 Prevention of antimacrobial resistance:
1-Choice of proper effective drug.
2-Give the proper dose for sufficient time to maintain
sufficiently high levels of the drug in tissues
3-Drug combination e.g. in TB
4-Avoid unnecessary exposure of microorganism to a
particularly valuable drug by restricting its use (e.g.
rifampicin mainly for TB)
 Combinations of antimicrobials
Clinical values (indications or aims) of antimicrobials combination:
1-To obtain better effect (synergism) or to increase the spectrum e.g.
Sulfamethoxazole plus trimethoprim to form co-trimoxazole.
clavulanic acid plus amoxicillin as clavulanic acid inhibits -lactamase. Another
example is sulbactam with ampicillin
Penicillin plus aminoglycoside.
2-To reduce the toxicity or incidence of adverse effects.
3-To prevent or delay the emergence of resistant strains especially in chronic
infections as tuberculosis in which two or three agents are used.
4-In mixed infections as peritonitis (following colon perforation), a drug
active against anaerobes and gram-positive bacteria (e.g. clindamycin) is
combined with one active against gram-negative bacteria coliforms e.g
aminoglycosides.
5-For emergency treatment of serious infections before laboratory studies
are completed e.g. in suspected septicemia. Anti-staphylococcus (nafcillin)
may be combined with a drug active against aerobic gram-negative bacilli
(aminoglycosides).
Results of antimicrobial combinations:
Combining antimicrobial agents may result in the following:
1-Bactericidal + bactericidal results in synergism:
e.g. combined use of penicillin and an aminoglycoside antibiotic (such as
gentamicin) on the enterococcus. In this example, inhibition of cell wall
synthesis by penicillin permits better penetration of the cell wall by the
aminoglycoside and more effective inhibition of protein synthesis than
either drug alone.
2-Bacteriostatic + bacteriostatic results in addition (summation):
e.g. the use of tetracyclines with sulfonamides or chloramphenicol.
3-Bactericidal + bacteriostatic (antagonism):
e.g. use of penicillin, with tetracyclin in group (A) streptococcal
infection. This because the tetracyclines inhibit protein synthesis and
are bacteriostatic. Penicillin as bactericidal affects cell wall synthesis and
requires that bacteria be actively multiplying in order to be bactericidal.
 Disadvantages of antimicrobial combination:
1-Antagonism:
This may occur if a bacteriostatic (tetracycline,
chloramph-enicol) and a bactericidal (penicillin,
cephalorporins, aminoglycosides) drugs are used
together.
2-Increase incidence of Adverse effects and cost.
3-Efforts toward accurate diagnosis may be neglected.
 General principles of therapy with antimicrobials
1-Antimicrobials should only be given when necessary and after
antimicrobials susceptibility test whenever possible.
2-The pharmacokinetics of the drug should be taken into
consideration e.g. the state of hepatic and renal functions of the
patient.
3-In serious infection it is better to start with a parentral loading
of a bactericidal agent to avoid emergence of resistant strains by
giving adequate dosage for sufficient duration.
4-Antimicrobials should be continued for 3 days after apparent
cure is achieved to avoid relapse.
5-Bactericidal drugs should be used when there is leucopenia or
the phagocytic cells can not get to the site of infection e.g.
endocarditis.
 Causes of failure of antimicrobial therapy
Drug:
Inappropriate choice, in adequate duration or dose,
improper route of administration, poor penetration
into the site of infection.
Host (patient):
Poor host defenses, undrained pus (presence of dead
tissue), retained foreign bodies.
Pathogens: drug resistance, superinfection.
SYNTHETIC ANTIMICROBIALS
The synthetic chemotherapeutic agents available for clinical use include the
sulfonamides, sulfones, quinolones, p-aminosalicylic acid (PAS), trimethoprim,
pyrimethamine, nitrofurantoin, isoniazid and pyrazinamide.
SULFONAMIDES
 Chemistry
sulfonamides comprise a large group of compounds that are structural analogous of
P-aminobenzoic acid (PABA).
 Pharmacokinetics
Absorption and distribution:
Well absorbed and distributed preparations:
the best is sulphadiazine
Poorly absorbed preparations:
unabsorbed part is excreted in the faeces and partly is excreted in milk and bile.
Metabolism and excretion:
The sulfonamides are degraded in the liver by acetylation, oxidation and conjugation
with a glucuronic acid. Both parent compounds and metabolites are excreted in the
urine (so, it is useful for the urinary tract infection). The acetylated form is insoluble in
acid medium and liable to be precipitated in renal tubules (Crystalluria).
 Mechanism of action
The sulfonamides inhibits incorporation of PABA into folic
acid and thereby preventing the synthesis of folic acid, a
compound essential to bacterial growth. Humans can not
synthesize folic acid and must acquire it through their
diet; thus, the sulfonamides selectively inhibit microbial
growth.
 Antibacterial spectrum
They are bacteriostatic chemotherapeutic agents,
effective against gram-positive organisms, some gramnegative organisms and chlamydia.
They also are effective against Toxoplasma gondii
&chloroquine-resistant Plasmodium falciparum.
Therapeutic uses
Systemic uses: shrinking uses due to……………………?
Local uses:
Prevention of infections in burned patients e.g silver sulfadiazine.
Sulfacetamide is used topically for treatment of ocular infections.
 Adverse effects
Mild e.g. nausea, vomiting, headache, cyanosis and arthritis.
Serious:
1-Crystalluria:
it is a precipitation of acetylated form or sulfonamide itself in renal tubules
leading to renal colic, haematuria, oliguria and even anuria
Prevention:
Give excess fluids (at least 2 liters urine/day)
Give alkalinizing agent e.g. citrate, bicarbonate to prevent precipitation (i.e.
increase solubility of sulfonamide and its acetylated form).
2-Allergic reactions
e.g. rash, fever, hepatitis, skin and mucous membrane lesions (Erythema
multiform). After using long acting sulfonamides in children (Stevens-Johnson
syndrome).
• Bone marrow depression leading to aplastic
anaemia (agranulocytosis).
• Haemolytic anaemia (idiosyncrasy)
• especially in patients with defective glucose-6phosphate dehydrogenase.
• Kernicterus
• when given in last 2 weeks of pregnancy or to
neonates and infants. It occurs with long acting
sulfonamides if used for long time because
sulfonamides compete with bilirubin for albumin
leading to high free bilirubin concentration in blood.
• Superinfection (with poorly absorbed sulfa).
 Drug interactions
Through displacement from binding sites on plasma proteins of oral
hypoglycemic drugs, oral anticoagulants (warfarin), methotrexate.
 Preparations of Sulfonamides
Well absorbed from GIT:
Short acting e.g. Sulfadiazine.
Long acting e.g S. Doxine.
Poorly absorbed from GIT: S. Suxidine and S. Thalidine
For local use only :
S. Thiazole for wounds in absence of pus.
Mafenide for wounds and burns in presence of pus.
S. Acetamide: used as eye drops.
Silver sulphadiazeine for infected burns, bed sores, etc.
Others: S. Salazine for chronic ulcerative colitis.
TRIMETHOPRIM
Potent inhibitor of bacterial dihydro folate reductase
 Pharmacokinetics
Absorption and distribution:
Trimethoprim is well absorbed from the gastrointestinal tract.
Because the drug is a weak base, so higher concentration will be
trapped in acidic prostatic and vaginal fluids. It is also penetrate
the cerebrospinal fluid.
 Mechanism of action
Trimethoprim competitively inhibits dihydrofolate reductase,
the enzyme that catalyzes the reduction of dihydrofolic acid
(folic acid) to tetrahydrofolic acid (folinic acid) leading to
decreased tetrahydrofolic acid coenzyme required for purine
and pyrimidine synthesis.
 Antibacterial spectrum
Similar to sulfonamide and more potent.
It can be used alone in treatment of acute urinary tract
infection,bacterial prostatitis (fluoroquinolones are preferred) and
vaginitis.
 Adverse effects
1-Hypersensitivity to trimethoprim.
2-It produces the effects of folic acid deficiency which include
megalobastic anaemia, leucopenia, and granulocytopenia.
Prolonged therapy with full doses can interfere with haemopoiesis
(only in those with initially low folate stores), so macrocytic anaemia
is due to interference with conversion of folic to folinic acid may
occur. Macrocytic anaemia can be reversed by folinic acid and this
will not reverse the antibacterial action of trimethoprim since
bacteria cannot utilize pre-formed folic or folinic acid because they
do not absorb it.
3-Possible teratogenic risk in pregnancy.
 Trimethoprim is contraindicated in pregnancy because it is a folate
antagonist.
SULFONAMIDES COMBINATIONS: CO-TRIMOXAZOLE
It is a combination of trimethoprim and S.
methoxazole:
Either drug alone is bacteriostatic, but in combination
co-trimoxazole is bactericidal (because it inhibits two
successive steps of the enzymatic pathway for the
synthesis of folinic acid), less bacterial resistance
develops and bacteria which were not sensitive to
sulfonamides become sensitive e.g. Salmonella,
Proteus.
It is effective against salmonella, shigella,
staphylococci, proteus, E.coli, haemophilus, Neisseria
(Pseudomonas is usually insensitive).
 Mechanism of action
Sulphamethoxazole acts on the first step in the folic acid synthesis
pathway(see before).
Trimethoprim acts on the second step in the folic acid synthetic
pathway(see before). This step occurs in man, but the sensitivity of
the enzyme that is inhibited is much greater in bacteria than in man,
therefore, the drug is relatively safe.
Uses of Co-trimoxazole
1-Respiratory infection due to H. influenza,pneumonia due to
pneumocystitis carinii (opportunistic infection in patients with AIDS)
2-Urinary tract infection and prostatitis
3-Salmonella infection e.g. enteric fever
4-Shigellosis
5-Gonococcal urethritis.
6-Toxoplasmosis.
Adverse effects
Like sulfonamides and trimethoprim (see before)
 OTHER SULFONAMIDES COMBINATIONS
1-Sulfadoxine + pyrimethamine "Fansidar" (for
treatment of chloroquine-resistant malaria which is
caused by Plasmodium falciparum:
2-Sulfadiazine (or trisulfapyrimidine) + pyrimethamine
for treatment of toxoplasmosis (drug of choice).
3-Silver S.diazine is applied to infected skin lesions
e.g. burn.
QUINOLONES
 Members
1-First generation: Nalidixic acid.
2-Second generation: Pipemidic acid.
3-Third generation: Most are fluorinated. They include ciprofloxacin , ofloxacin
, etc… (Fluorination was found to produce compounds with greater
antibacterial activity, achieving clinically useful drug levels in the blood and
tissues).
4-Fourth generation: e.g. moxifloxacin, trovafloxacin .
 Spectrum
Gram-negative organisms, e.g. E.coli, Proteus, Klebsiella, Shigella, Salmonella,
coliform bacteria, Neisseria, Pseudomonus, and H. Influenza.
Less active on gram-positive bacteria.
Not active on anaerobes.
Fourth generation: they are like third generation with enhanced gram-positive
and antianaerobes activity.
Fluoroquinolones
generation
2nd generation
3rd generation
4th generation
Nalidixic acid
Pipemidic acid
Ciprofloxacin
Trovafloxacin
Levofloxacin
Moxifloxacin
1st
Members
Norfloxacin
Ofloxacin
Spectrum:
Excretion
More active on
G -ve (E.coli,
Shigella, Proteus)
Renal
active onG-ve
& lessactive on
Gm
.
Renal
Active on
G -ve, G+ve, &
Pseudomonas
G -ve, G+ve,
Pseudomonas &
anaerobes
Renal & biliary
Renal & biliary
 Mechanism of action
They inhibit DNA synthesis by inhibition of DNA
gyrase needed for the synthesis of bacterial DNA.
 Pharmacokinetics
They are readily absorbed from GIT, diffuse into
tissues including prostate.
They are metabolized in the liver.
Excretion is renal and biliary (3rd and 4th generations).
Antacids (Mg & Al antacids) & sucralfate decrease
their GIT absorption.
 Therapeutic uses
1-GIT infection caused by salmonella (enteric fever),
shigella, E.coli.
2-Urinary tract infections , genital tract infection e.g
gonorrhea and prostatitis.
3-Third generation can be used in severe systemic
infections.
4-Ciprofloxacin is also used in treatment of meningitis
(due to H. influenza, N. meningitides), respiratory tract
infections.
5-Treatment of skin infections, gonorrhea and
septicaemia.
6-Treatment of bone infection e.g osteomyelitis and
Septicemia.
 Adverse effects
1-GI upset (nausea, vomiting, abdominal pain), and
pseudomembranous colitis.
2-Hypersensitivity reactions and photosensitization.
3-Neurological Adverse effects (headache,
drowsiness, vertigo, and seizures).
4-Fluoroquinolones should not be used in children
up to 17 years as it causes arthropathies in
experimental animals, also it is avoided in
pregnancy and lactation.
5-Interstitial nephritis and crystalluria.
6-Decrease metabolism of theophylline, warfarin and
sulphonylureas leading to increase in their blood
levels.