Antiinfective drugs
Chemotherapy: is the treatment of a disease by the use of pur chemicals
which have specific antagonistic effects on the organism causing the disease.
Selective toxicity: substances or drugs which selectively destroy the organism
which cause the disease with no or little effect on the host.
Antibacterial: An agent that inhibits bacterial growth impedes replication of
bacteria or kills bacteria.
Antibiotic: An agent produced by a microorganism or semi synthetically that
has the ability to inhibit the growth or kill microorganisms.
Antimicrobial: An agent that kills microorganisms or suppresses their
multiplication or growth.
Antibiotic failure
The most important reasons for unsuccessful antibiotic therapy are:
1- bacterial resistance.
2- Lack of adequate immune response by host.
3- Physical barriers to drug pentration.
4- Inappropirate dose or duration of therapy.
Classifications of antibacterials:
I- Antimicrobial drugs can be divided into two categories according to the
effectivness:
1- Bactericidal: An agent with the capability to kill bacteria like penicillins,
cephalosporins and aminoglycosides.
2- Bactriostatic: An agent that inhibits the growth or reproduction of bacteria
like sulphonamides, tetracyclines and chloramphenicol.
There are different types of bacteria like gram-positive, gram-negative,
acid-fast staining, aerobic and anaerobc bacteria. Not all antimicrobials have
the same degree of effectiveness against microorganism.
II- According to the spectrum antibitics are divided into:
1-
Narrow spectrum: their antibacterial effect is restricted to a relatively
small number of organism’s type, gram-positive or gram-negative
bacteria. Examples: penicillin which is active mainly against gram
positive organism and polymyxin B which is active only against gram
negative bacteria.
2- Broad spectrum: antibacterials which are effective against a wide
variety of organisms gram-positive and gram-negative organism,
possibly Rickettsiae and chlamydia and even protozoa. e.g.
tetracyclines.
3- Extended spectrum: in addition to effect on gram-positive and gramnegative bacteria it is effective against mycoplasma and pseudomonus.
Example: enrofloxacin, sulphonamide + trimethoprim, ticarcillin +
clavulanic acid.
III- According to the echanism of action:
123abc4-
antibacterials which inhibit cell wall synthesis. Examples: penicillins,
cephalosporins, bacitracins, vancomycin.
Antibacterials which inhibit permeability of cell membrane. Example:
polymyxin B.
Antibacterials which inhibit protein synthesis (effect on ribosomes 30S
or 50S) and it subdivided into:
Irreversible binding to 30S (bactericidal). Example: streptomycin
Reversible binding to 30S (bacteriostatic). Examples: tetracyclines.
Reversible binding to 50S. example: chloramphenicol and erythromycin.
Antibacterial which inhibit metabolism (inhibit folic acid synthesis).
Example: sulphonamides and trimethoprim.
5-
Antibacterial which inhibit nucleic acid functio or synthesis, and it
subdevided into:
a- Antibacterial which inhibit RNA synthesis. Example: rifampin.
b- Antibacterial which inhibit DNA synthesis. Example: fluoroquinolones
and nitrofurans.
After the diagnosis of the disease is made and the type of bactera is
distinguished, a sesnsitivity test should be performed. Several tests are
available for testing the susceptibility of an organism to a specific
antimicrobial drugs, including disk susceptibility test and broth dilution
susceptibility test. The lowest concentration that inhibits the growth of an
organism is the minimum inhibitory concentration (MIC). The antimicrobials
that are effective in vitro may not always be the best choice for use in vivo.
Penicillins:
Penicillin was developed dring the 1940s and remains very important as
an antimicrobial drug. There are natural and semisynthetic compounds that
display varied antimicrobial spectra. Many penicillin formulations may
precipitate and must be shaken well before use and must stored in the
refrigerator. Oral preperations are stable for only 7-14 days after dilution.
Pharmacokinetics:
Oral penicillins are absorbed in the stomach and small intestine. Injected
penicillins are absorbed rapidly at the site of injection and distributed rapidly
through most tissues. Penicillins are metabolized in the liver and excreted by
the kidneys and through the milk in dairy cows and withdrawal period shoud
be considered.
Pharmacodynamics:
Mechanism of action:
Penicillin binds reversibly with penicilline-binding proteins (PBPs),
which involved in cell wall synthesis and cell division. It impair the
development of bacterial cell wals by interfering with transpeptidase
enzymes responsible for the formation of the cross-links between
peptidoglycan resulted in defective cell wall development.
Some baceria produce beta-lactamase (pencillinase) which increase the
resistance of bacteria by converting penicillin to inactive penicillic acid.
Penicillins are usually very effective against gram-positive bacteria, but gramnegative bacteria have an outer membrane around the cell wall that limits
PBP permeability, but this membrane can be pentrated by some penicillins to
be more effective against gram-negative bacteria.
Penicillin measured by IU =0.6µg , 1667 IU = 1mg.
Classes of penicillins:
According to the antibacterial spectra penicillin classified into:
1-
Narrow-spectrum β-lactamase sensitive penicillins- include: Penicillin
G (benzylpenicillin) from Penicillium chrysogenum
anarrow spectrum
bshort half life
cpenicillinase sensitive
dacid liable
It is effective against number of gram-positive and gram negative cocci, gram
positive bacilli and spirochetes.It is used by injection.
2Narrow-spectrum, Acid-resistant penicillins: Peniciilin V
similar in spectrum to penicilline G but not used for treatment of bacteremia
and less active against gram-negative bacteria. It is more acid-stable than
penicillin G so given orally, it is effective against some anaerobic organisms.
3β-lactamase
resistant
penicillins
(antistaphylococcal
penicillin): Methicillin, cloxacillin, dicloxacillin, floxacillin and oxacillin.
4Broad-spectrum
penicillins:
Ampicillin,
amoxicillin,
Carbenicillin and ticarcillin. They have an antibacterial spectrum similar to
penicillin G but more effective against gram-negative bacilli. They are given
orally and parentrally.
5Antipseudomonal penicillin: piperacillin and carbenicillin they
are effective against P.aeruginosa.
6Potentiated penicillins: Amoxicillin-clavulinic acid(4:1)
(Clavamox). Clavulinic acid is beta-lactamase inhibitor, combine with βlactamase and preventing it from attacking β-lactam ring of amoxicillin.
Clavamox is a broad-spectrum antibiotic that is used in tratment of skin
infection, urinary tract infection, wound infection and respiratory infection.
Probenecid: inhibits tbular secretion of penicillin and prolongs blood levels of
penicillins that have very short plasma half-lives.
Procain: slows absorption of intramuscular injected penicillin which result in
prolongation of of drug action.
Adverse effects:
Allergic reactions vomiting and diarrhea, or enteritis may occur in cattle and
horses when used orally. Respiratory distress may occurs.
Resistance:
It is the ability of microorganisms to remain available and multiply in
present of certain concentration of antibacterial drug that kill or inhibit
another microorganisms.
Resistance to antimicrobial drugs may result from mutation, and mutant
strains may developed from the missuse of antimicrombial drugs.
1- Natural resistance to penicillin occurs in organisms that lack a peptidoglycan
cell wall like mycoplasma or have cell walls that are impermeable to the drug.
2- Acquired resistance to the penicillin by plasmid transfer has a signifiant
clinical problem.
Mechanisms underlying microbial resistance to cell wall synthesis
inhibitors include the production of antibiotic-inactivating enzyme, changes
in the structure of target receptors, increased efflux via drug transporters,
and decrease in the permeability of microbes cellular membrane to
antibiotics
Cephalosporins:
They have the same mode of action as the penicillins. All kinds of
cephalosporins are semisynthetic.
Most of them administered parentrally because they lack the ability to be
well absorbed by GIT. Once absorbed they are distributed to tissues and
fluids, with the exception of the CNS. Some cephalosporins are absorbed into
the CSF but this absorption is limited.metabolism occurs in the liver with
elemination occurring in the kidneys by glomerular filtration and tubular
secretion into urine. Most cephalosporins are excreted through the feces via
the biliary system.
Antibacterial spectrum:
1-first generation: cephalothin, cephapirin are acid labile. Cephalexin(keflex)
orally acid is stable. They are active against gram positive aerobes and
anaerobes, also it is active against proteus mirabilis, E colli and klebsiella.
2-Second generation: cefamandole given parentrally. It is acid labile. They are
generally active against both gram positive and gram negative bacteria.
3-thirdgeneration: cefotaxim and moxalactam. They are broad spectrum
effective against Pseudomonus spp.
4-fourth geneation: cefeprime broad spectrum, more resistant to betalactamase.
Adverse effects:
Cephalosporins are usually safe for use in animals. However allergic reaction
can occur. Rare bleeding disorders have been reporte with some
cephalosporins. Others have rarely caused seizures, vomiting and diarrhea
have been reported in some individuals.
Tetracyclines:
Mechanism of action: are bacteriostatic antibiotics that bind reversibly to the
30S ribosome, also they prevent access of the aminoacyl tRNA to the
receptor site on ribosomal complex, so resulted in inhibition of protein
synthesis.
Tetracyclines classes:
Tetracyclines can be clafied according to the differences in the duration of
action into:
1- short-acting tetracyclines
chlortetracycline, oxytetracycline and tetracycline- dosage interval 6hours.
2- intermediate acting tetracyclines
demclocycline and methacycline – dosage interval 12 hours.
3- long acting tetracyclines
4- doxycyclin and minocycline – dosage interval 24 hours.
Antibacteria activity of tetracycline: broad spectrum gram positive and gram
negative aerobic bacteria except Pseudomonus and Proteus, also effective
against Rickettsiae and Chlamydia and some protozoa like theleria and
anaplasma.
Side effects:
1-Tetracyclines have chelating activity (binding with Ca, Mg, Al) so resulted in
teeth discoloration in young animals and children, decalcification of bone in
developing fetus and pregnant animals.
2-Rapid IV injection of tetracycline can produce hypotension and sudden
collapse. This effect can be avoided by slow infusion of the drug (>min).
3- irritation at the side of injection.
4-GIT disturbances.
5-hepatotoxicity, nephrotoxicity and photosensetivit
Aminoglycosides
These are water soluble, bactericidal broad spectrum antidiotics include
amikacin (semisynthetic), gentamicin, kanamycin and neomycin (natural).
Mechanism of action:
They inhibit protein synthesis by irreversible binding to 30S which lead to
misread the genetic code and production of false protein.
Activity: They are effective against aerobic organim, since anaerobes lack the
oxygen-requiring transport system which is necessory to transport antibiotics
across the cell membrane.They are effective against most gram-negative and
many gram-positive bacteria.
Side effects:
Include serious side effects, such as nephrotoxicity, ototoxicity and
neuromuscular synaptic dysfunction. Diarrhea may occur due to distruption
of bacterial flora.
Clinical uses:
Aminoglycosides are used to treat pneumonia, endometritis, urinary tract
infection, bacterial enteritis, conjunctivitis, skin and soft tissue infections.
Chloramphenicol
It is a broad spectrum antibiotic that acts against gram-negative and grampositive bacteria, Reckettsia and Chlymedia. Its use is restricted to lifethreatening infections in which there are no alternative because of its
toxicity. It is used in treatment of Salomnella spp. and the resistant strains of
Pseudomonas aeroginosa.
Mechanism of action:
Chloramphenicol binds to the bacteria 50S ribosomal subuint and inhibits
protein synthesis by impairing the peptidyl transferase activity.
Chloramphenicol metabolized primarily by glucoronide conjugation. In
cats a charecterstic genetic defeciency in glucuronyl transferase actvity leads
to plasma half-lives that are often considerably longer than those in other
species like equine (cat t ½ 5.1hr., horse 0.9 hr.)
Side effects:
1- Aplastic anemia (dose independent).
2- Bone marrow depression leads to anemia (dose dependent).
3- GIT disturbance (diarrhea).
4- Hepatotoxicity.
Clinical uses:
It is used to treat bacterial respiratory tract infection, enteritis and bacterial
conjunctivitis.
Macrolides
They are effective against gram-negative and gram positive bacteria,
Mycoplasma and some Reckettsiae.
Erythromycin is very irritant when given parentraly. It is given orally.
Tylosin, Spiromycine are used for treatment of Mycoplasma in poultry.
Oleandomycin also used in vet. Medicine.
Mechanism of action:
They are binding irreversibly to a site on the 50S subunit of the bacterial
ribosome, thus inhibiting the translocation steps of protein synthesis.
Side effects:
1- GIT disturbance.
2- Hepatotoxicity.
3- Bone marrow depression.
Lincosamides
These are include lincomycin and Clindamycin which are used to treat upper
respiratory tract infection and skin infection in dogs, cats and swine as well as
mastitis in cattle. Clindamycin is approved for use in dogs and cats to treat
deep pyoderma, wound infection, abscess, dental infection and
osteomyelitis.
Side effects: include occasional vomiting and diarrhea.
Vancomycin
It is not commonly used in vet.medicine. it is administered orally to
control Clostridum difficile, and to treat resistant Staphylococcal and
streptococcal infections. Side effects: include thrombophlebitis and febrile
reactions. Ototoxicity, nephrotoxicity and hypersensitivity are other possible
side effects.
Spectinomycin
It is effective against gram-negative and some gram-positive bacteria and
some Mycoplasma. It acts by inhibition of protein synthesis in bacteria. It is
not effective against anaerbic bacteria. It is used to control air sacculitis and
chronic respiratory disease in poultry. In pigs used to control and treat
infectious diarrhea caused by E.colli. In cattle is indicated for treatment of
bovine respiratory disease associated with Pasturella. Spectinomycine may
cause milde swelling at the site of injection.
Polymyxins
They include polymyxin B and polymyxin E (colistin) are most commonly used
topically and orally. Mechanism of action: they are interact strongly with
phospholipids in bacteral cell membrane and distrupt their permeability and
function. Side effects of polymyxin include nephrotoxicity and neurotoxicity if
given parentrally. Bacitracin is limited to topical application because of
nephrotoxicity.
Sulfonamides and Trimethoprim
Sulfa drugs are broad spectrum antibacterials classified into:
1- Absorbable sulfonamides which also subdevided acording to the
duration of action into:
a- Short acting highly absorbed and highly excreted sulfonamides: with
dosing interval (4-6hrs). these include suladiazine, sulfamerazine
sulfamethazin, they are cauld triple sulfa, used together to decrease
side effects.
b- Intermediate acting sulfa: dosing interval (12hrs) such as
sulfamethoxazole.
c- Long acting sulfa: dosing interval (24hrs) such as
sulfamethoxpyridazine
d- Extra-long acting sulfa: dosing interval(4-7days) such as sulfadoxin.
2- poorly absorbable sulfonamide (intestinal sulfa, gut active sulfa) include
sulfaguanidine,
succinylsulfathiazole,
phthaylsulfathiazole
and
phthylsulfacetamide.
3- Topical sulfonamides used as ear drops, dusting powder or ointment.
Sulfacetamide used as eye drops to treat opthalmic infections.
Sulfathiazole is commonly incloded in wound powders.
Mechanism of action:
Sulfonamides are bactriostatic inhibitors of folic acid synthesis, they are
competitive inhibitors of dihydropteroate synthase. Trimethoprim is a
selective inhibitor of bacterial dihydrofolate reductase that prevents
formation of the active tetrahydro form of folic acid.
p-aminobenzoic acid (PABA)
purines
DNA
dihydrofolic acid
dihydrpteroate synthae
sulfonamides
tetrahydrofolic acid
dihydrofolate reductase
trimethoprim
Note; sulfonamides must not be used in case of presence of pus because
pus contains large amounts of para-amino-benzoic acid (PABA) which
antagonize the action of sulfonamides.
Clinical uses:
Sulfonamides used to treat acute urinary tract infection, respiratory tract
infection wound infection, coccidiosis and foot rot.
Side effects:
1- sulfonamides:
These include urticaria, vomiting, diarrhea, anorexia, fever and crystal
formation within the kidneys, which can result in hematuria, proteinuria and
tubular damage. Keratoconjunctivitis sicca has been reported in dogs. The
use of these drugs has been limited in food-producing animals because of
residues of the drugs in meat, milk and eggs.
2-trimethoprim:
May cause predictable adverse effects of an antifolate drugs including
megaloplastic anemia, leukopenia and granulocytopeia.
A combination of trimethoprim with sulfathiazole (1:5) in human and with
sulfadiazine (1:5) in veterinary medicine have a synergistic effect.
Fluoroquinolones
They are bactericidal broad spectrum antibacterial that act by targeting
DNA-gyrase which resulte in inhibition of DNA-synthesis. This group include
enrofloxacin,difloxacin and orbifloxacin.
Clinical uses:
In dogs and cats include the treatment of bacterial skin and soft tissue
infection, respiratory infection and cystitis. In cattle for the treatment of
bovine respiratory disease. In chickens used to control the mortality
associated with E. colli. In turkeys used to control the mortality with E.colli
and Pasteurella multocida.
Side effects:
Include the formation of lesions in the joint articular cartilige during rapid
growth phas4es of dogs. They also associated with CNS simulation.
Nitrofurans
Include nitrofurazone, nitrofurantoin and furazolidone which are reduced by
sensitive bactria to an active agent that inhibits various enzymes and cause
DNA damage. Uses: necrotic enteritis cocidiosis.
Rifampin: inhibits DNA-dependent RNA polymerase. It is mainly used to treat
tuberculosis.
Metronidazole
Bacteriocidal used for treatment of Tricimoniasis, Giardiasis and amoebiasis
and obligate anaerobic bacteria. The drug bind to DNA and disrupt cell
function.
Antimycobacterial drugs
The chemotherapy of inections caused by Mycobacterium tuberculosis, M.
leprae, and M. avium is complicated by numerous factors, including:
1- Limited information about the mechanisms of antimycobacterial drug
actions.
2- The development of resistance.
3- The intracellular location of mycobacteria.
4- The chronic nature of mycobacterial disease, which requires protected
drug treatment and is associated with drug toxicties.
5- Patient compliance.
Chemotherapy of mycobacterial infections almost always involves the use
of drug combinations to delay the emergence of resistance and to
enhance antimycobacterial efficacy.
The major drugs used in tuberculosis are: isoniazid (INH), rifampin,
ethambutol, pyrazinamide and streptomycin.
Mechanism of action:
Izoniazid (INH): its mechanism of action involves inhibition of mycolic acids,
characterstic components of mycobacterial cell walls.
Rifampin:inhibits DNA-dependent RNA polymerase.
Ethambutol: inhibits arabinosyl transferases involved in the synthesis of
arabinogalactan, a component of mycobacterial cell walls.
Pyrazinamide: its mechanism of action is unknown; however, its
bacteriostatic action appears to require metabolic conversion via
pyrazinamidases present in M. tuberculosis.
Streptomycin:is mentioned before.
\Drugs for leprosy
Including dapsone, acedapsone alone or with rifampin or clofazimine.
Antiviral drugs
The use of these drugs in vet medicine is still limited. Because no antiviral
agents are veterinary-approved, human-approved antiviral agents are used.
They are used in treatment of optic viral infection and nonneoplastic feline
leukemia virus associated disease. Topical and systemic antiviral are
available. Amantidine, ganciclovir, idoxurdine and azidothymidine may be
beneficial in vet medicine.
Amantidine inhibit ifluenza virus replication. Ganciclovir inhibits DNA
polymerases of cytomegalovirus and HSV (herpes simplex virus).
Antifungal drugs
Fungal infections(mycoses) are classified into two types: topical (superficial),
which affect the skin and mucous membranes, and systemic, which affect
blood, lungs or CNS. A topical fungal infection may be diagnosed by direct
microscopic examination for the presence of delicate hyphae in skin cells or
the presence of spores on the surface of an infected hair. Systemic mycoses
usually is diagnosed through serologic tests. There are oral, topical and
parentral antifungal drugs. Antifungal or antimycotic drugs are devided into
four classes:
(1)
(2)
polyene antifungal agents including Amphotericin B, Nystatin.
Imidazole antifungal agents including ketoconazole, miconazole and
itraconazole.
(3) Antimetabolic antifungal agents including flucytosine.
(4) Superficial agents including griseofulvin
Drugs for systemic fungal infections:
1- Amphotericin B:
It is poorly absorbed from GIT, so it is usually administered by slow
intravenous infusion. It is widely distributed to all tissues except CNS.
Mechanism of action: the fungicidal action of amphotericin B is due to its
effects on the permeability and transport properties of fungal membranes by
binding to ergosterol, a sterol spesific to fungal cell membranes result in
formation of artificial pores. It is used in tratment of systemic mycoses in
dogs and cats.
Side effects: including anorexia, vomiting, seizures, anemia, and cardiac
disturbance. Nephrotoxicity occurs in most patients.
2- Flucytosine:
Is fungistatic oral antifungal agent acts as antimetabolite. It is used in
treatment of cryptococcal infection.
3-Azole antifungal agents: the azoles used for systemic mycoses include
ketoconazole, fluconazole and itraconazole. They act by interfering with
fungal cell membrane permeability by inhibiting the synthesis of ergosterol.
Ketoconazole and miconazole are two of the most commonly used drugs in
this class. Ketoconazole is available in oral and topical preparations, and
miconazole in parenteral and topical preparations. Itraconazole is used to
treat dogs and cats with systemic mycotic infection.
Systemic drugs for superficial fungal infections:
Griseofulvin:
Is interferes with microtubule function in dermatophytes and may inhibit
the synthesis of nucleic acids. It is administered orally in the form of tablet or
powder. It is used in tratment of dermatophytosis.
Topical drugs for superficial fungal infections:
Nystatine:
Is polene antibiotic. Mechanism of action similar to amphotericin B. it is
commonly used topically to suppress local Candida infections and orally to
eradicate GIT fungi in patients with impaired defense mechanism.
Other topical antifungal agents that are widley used include the azole
compounds miconazole and clotrimazole
.