Transcript 22-7. Antibacterials

• BETA-LACTAM
ANTIBIOTICS
• GLYCOPEPTIDES
• AMINOGLYCOSIDES
(aminosides)
• TETRACYCLINES
Assoc. Prof. I. Lambev (www.medpharm-sofia.eu)
Antiinfective agents are among the most dramatic
examples of the advances of modern medicine.
Many infectious diseases once considered incurable
and lethal now can be treated. The remarkably powerful
and specific activity of antimicrobial drugs is due to their
selective toxicity for targets that are either unique
to microorganisms or much more important in them
than in animals or humans. Among these targets are
bacterial and fungal cell wall-synthesizing enzymes, the
bacterial ribosome, the enzymes required for nucleotide
synthesis and DNA replication, the mechanism of viral
replication, etc. The much older and less selective
cytotoxic drugs are the antiseptics and disinfectants.
Antiinfective agents may be classified
according to their antimicrobial activity:
1. Antibacterial drugs (antibiotics
and synthetic drugs)
2. Antiviral drugs
3. Antifungal drugs
4. Antiprotozoal drugs
5. Anthelmintic drugs
6. Insecticides for ectoparasites
7. Antiseptics and Disenfectant (Not are drugs)
8. Prepartaions for Disinsection (Not are drugs)
9. Prepartaions for Deratisation (Not are drugs)
10. Vaccines, Serums, and Immunoglobulins
ANTIBIOTICS – mechanism of action
β-lactams, Glycopeptides
30S: Aminoglycosides
30S: Tetracyclines
50S: Chloramphenicol
50S: Macrolides, Lincosamides
50S: Linezolide, Streptogramins
Polymyxins
Rifampicin
Adverse Drug Reactions (ADRs)
Antibacterial agents may cause:
●direct host toxicity (aminoglycosides)
●toxic interactions with other drugs
●interference with protective effects of normal host
microflora (by suppressing obligate anaerobes,
e.g selection or promotion of drug resistance)
●tissue lesions at injection sites (tetracyclines)
●impairment of host immune system
(chloramphenicol)
●reduced phagocytosis (tetracyclines)
●inhibition of phagocytosis (aminoglycosides)
●hypersensitivity reactions (penicillins, aminosides,
sulfonamides)
●hepatic microsomal enzyme induction (rifampicin)
or inhibition (chloramphenicol, metronidazole)
that interferes with their own metabolism
as well as that of concurrent medications
●residues in animal products for human
consumption (all antibacterials).
NB: withdrawal periods…
Because of the potential for some
antibacterials to reduce protein
production, incl. antibodies
(e.g. aminoglycosides,
amphenicols, lincosamides, macrolides,
tetracyclines), concurrent antibacterial
medications need to be selected carefully
when immunizing animals, especially
with killed vaccines.
Selection or promotion of resistance
Antibacterial agents do not cause bacteria to
become resistant but their use preferentially
selects resistant populations of bacteria.
Some genes that code for resistance have been
identified in bacterial cultures. The most clinically
important for resistance are plasmids. They carry
genes that may benefit survival of the
organism (e.g. antibacterial resistance)
transmitted from one bacterium to another.
Plasmids are cytoplasmic
genetic elements which transfer drug
resistance to previously susceptible bacteria.
Acquired resistance is not a problem in all bacteria.
For example, Gram-positive bacteria (with
some exceptions, incl. Staphylococcus spp) are
often unable to acquire resistance plasmids
(and thus acquire resistance through mutation,
a slower process), whereas resistance is an
increasing problem in many Gram-negative
pathogens such as the Enterobacteriaceae.
Enterobacteriaceae:
• E. coli, Salmonella, Schigella
• Yersinia pestis (plugue!)
• Klebsiella
• Enterobacter
• Serratia
• Citrobacter
The intestine is a major site of transfer of
antibacterial resistance. This is important when
antibacterial agents are used in animals
in contact with fecal material, an
enormous reservoir of intestinal bacteria.
Nosocomial infections
In veterinary hospitals, nosocomial infection
(infection acquired during hospitalization) by
resistant bacteria is an emerging problem. Bacteria
most frequently implicated in veterinary hospitals are
Klebsiella, Escherichia, Proteus and
Pseudomonas spp.
Factors predisposing to nosocomial infections include
age extremes (young or old), severity of disease,
duration of hospitalization, use of invasive support
systems, surgical implants, defective immune
responses and prior antibacterial drug use.
The drugs with greatest potential to suppress
endogenous flora are those most active against
obligate anaerobic bacteria (amphenicols,
lincosamides, beta-lactams) and those
undergoing extensive enterohepatic recycling
(chloramphenicol, lincosamides, tetracyclines).
Cephalosporins are a major risk factor in humans.
Hypersensitivity
Hypersensitivity reactions to antibacterial agents are
reported less frequently in VM than in
human patients, where they constitute 6–10% of all
drug reactions. To induce an allergic response, drug
molecules must be able to form covalent bonds with
macromolecules such as proteins. Bonding with the
protein carrier enables reaction with T lymphocytes
and macrophages. The reactive moiety is usually a
drug metabolite, e.g. the penicilloyl moiety
of penicillins.
●Hypersensitivity reactions depend on the
combination of antigen and antibody and are not
dose related. The first episode cannot be anticipated,
although atopic individuals have a greater
tendency to develop drug allergies.
●Hypersensitivity reactions have been reported most
frequently in veterinary patients with cephalosporins,
penicillins and sulfonamides.
●Doberman pinschers have an increased
risk of sulfonamide hypersensitivity, possibly due to
delayed sulfonamide metabolism.
●The probability of an anaphylactoid reaction (i.e.
direct histamine release that is not immunologically
mediated) is increased with penicillin preparations
containing methylcellulose as a stabilizer.
Drug hypersensitivity may manifest in different ways.
●Acute anaphylaxis is associated with IgE-triggered
mast cell degranulation and characterized by one
or more of the following signs: hypotension,
bronchospasm, angioedema, urticaria, erythema,
pruritus, pharyngeal and/or laryngeal edema,
vomiting and colic.
BETA-LACTAM ANTIBIOTICS
(inhibitors of cell wall synthesis)
Their structure contains a beta-lactam ring.
The major subdivisions are:
(a) penicillins whose official names
usually include or end in “cillin”
(b) cephalosporins which are
recognized by the inclusion
of “cef” or “ceph” in their
official names.
(c) carbapenems (e.g. meropenem,
imipenem)
(d) monobactams (e.g. aztreonam)
(e) beta-lactamase inhibitors (e.g.
clavulanic acid, sulbactam).
A. FLEMING
(1881–1955)
•Penicillin G
- P. notatum
I. PENICILLINS
(1929)
The fugus Penicillium chrysogenum
The cell wall completely surrounds the cytoplasmic
membrane, maintains cell shape and integrity, and
prevents cell lysis from high osmotic pressure. The
cell wall is composed of a complex cross-linked
polymer of polysaccharides and polypeptides,
peptidoglycan (murein, mucopeptide). The
polysaccharide contains alternating amino sugars,
N-acetylglucosamine, and N-acetylmuramic acid.
A five-amino-acid peptide is linked to the
N-acetylmuramic acid sugar. This peptide
terminates in D-alanyl-D-alanine.
Penicillin-binding protein (PBP, an enzyme)
removes the terminal alanine in the process of
forming a cross-link with a nearby peptide.
Cross-links give the cell wall its structural rigidity.
Beta-lactam antibiotics covalently bind to
the active site of PBPs. This inhibits the
transpeptidation reaction, halting
peptidoglycan synthesis, and the cell dies.
Beta-lactams kill bacterial cells only
when they are actively growing and
synthesizing cell wall.
NARROW SPECTRUM PENICILLINS
• Biosynthetic (natural) penicillins
• Antistaphylococcal penicillins
BROAD SPECTRUM PENICILLINS
• Aminopenicillins
• Antipseudomonal penicillins
- Carboxypenicillins
- Ureidopenicillins
1. NARROW SPECTRUM PENICILLINS
a) Biosynthetic (natural) penicillins
Benzylpenicillin (Penicillin G® Na or K) – i.m.
Phenoxymethylpenicillin (Penicillin-VK®) – p.o.
Benzathine benzylpenicillin (effect 2 to 4 weeks)
b) Antistaphylococcal penicillins
Isoxazolyl penicillins
- Cloxacillin, Dicloxacillin
- Flucloxacillin, Oxacillin
Others: Methicillin, Nafcillin (crosses BBB)
Antibacterial spectrum of narrow-spectrum
biosynthetic penicillins:
●Narrow-spectrum penicillins are active against
Gram-positive aerobes and obligate anaerobes.
●They are ineffective against most Gram-negative
aerobes and Penicillase-producing
Staphylococcus.
Antibacterial spectrum of
antistaphylococcal penicillins:
● Staphylococcus spp (without MRSA)
Clinical applications
Narrow-spectrum biosynthetic penicillins:
are still the drugs of choice in small animals include
clostridial diseases, listeriosis, actinomycosis,
anaerobic infections (abscess, fight wound,
pyothorax) and β-hemolytic streptococcal
infections.
Antistaphylococcal penicillins:
●Staphylococcal skin infections in dogs
●Surgical prophylaxis, especially for orthopedic
procedures
●Treatment of osteomyelitis, discospondylitis
Penicilline G Sodium®:
20 000 – 40 000 /IU/kg/BW
q.6–8 h i.v., i.m., s.c.
Penicillin-VK® (Potassium):
10 mg/kg/BW q.8 h p.o.
Cloxacillin,
Dicloxacillin,
Flucloxacillin:
10 – 40 mg/kg
q.8 h p.o.
500 mg
Flucloxacillin
2. BROAD-SPECTRUM PENICILLINS
a) Aminopenicillins
The aminopenicillins have identical spectrum
and activity, but amoxicillin is better absorbed
orally (70–90%). They are effective against
streptococci, enterococci, and some
Gram-negative organisms (incl. H. pylori)
but have variable activity against staphylococci
and are ineffective against P. aeruginosa.
Amoxicillin and Ampicillin
J. Robin Warren (2005)
Barry J. Marshall (2005)
Clinical applications of aminopenicillins
●Soft tissue non-staphylococcal infections
in dogs and cats.
●Cat abscesses.
●Uncomplicated urinary tract infections, but
amoxicillin-clavulanate might be a better choice.
●Some enteric infections.
●Amoxicillin in combination with metronidazole
and omeprazole has been used for treatment
of Helicobacter gastritis.
Cat abscesses
Amoxicillin:
10 – 20 mg/kg/BW
q. 8–12 h
i.v., i.m., s.c. p.o.
AMOXICILLIN
b) Antipseudomonal penicillins
These drugs retain activity against streptococci and
possess additional effects against Gram-negative
organisms, including various Enterobacteriaceae
(E. coli, Salmonella, Schigella, Proteus)
and Pseudomonas.
•Carboxypenicillins
- Carbenicillin (out…)
- Ticarcillin
•Ureidopenicillins
- Azlocillin
- Mezlocillin
- Piperacillin
Clinical applications in VM
●For topical treatment of otitis externa due to P.
aeruginosa resistant to other drugs.
●For systemic treatment infections
by Pseudomonas spp, usually in combination
with an aminosides to delay the emergence
of resistance.
●When combined with clavulanate, ticarcillin is
effective against many β-lactamase producing
strains of otherwise resistant Gram-negative
bacteria and Staphylococcus.
Known drug interactions
●Penicillins are often said to be synergistic with
aminoglycosides against many Gram-positive
microorganisms, incl. Staphylococcus aureus.
●Narrow-spectrum penicillins such as penicillin G
are synergistic with drugs that bind β-lactamase
enzymes, including cloxacillin, clavulanate and
some cephalosporins.
Antibacterial drugs have been
classified broadly into:
1. Bacteriostatic, i.e. those that act primarily
by arresting bacterial multiplication, such as
tetracyclines, amphenicols, macrolides,
lincosamides, sulfonamides, trimetrhoprime.
2. Bactericidal, i.e. those which act primarily
by killing bacteria, such as beta-lactams,
glycopeptides, aminoglycosides, isoniazid,
rifampicin, fluoroquinolones, metronidazole.
Adverse effects
The main hazard with the penicillins is allergic reaction.
These include itching, rashes (eczematous or urticarial),
fever, and angioedema. Rarely (about 1 in 10 000) there
is anaphylactic shock which can be fatal (about 1 in
100 000 treatment courses). Allergies are
least likely when penicillins are given orally and most
likely with local application. Metabolic opening of the
β-lactam ring creates a highly reactive penicilloyl group
which polymerizes and binds with tissue proteins to form
the major antigenic determinant. The anaphylactic
reaction involves specific IgE antibodies which can be
detected in the plasma of susceptible patients.
Amoxicillin:
rash 11 hours after
administration
There is cross-allergy between all the various
forms of penicillin, probably due in part to their
common structure, and in part to the degradation
products common to them all.
Partial cross-allergy exists between penicillins
and cephalosporins (a maximum of 10%) which
is of particular concern when the reaction to either
group of antimicrobials has been angioedema or
anaphylactic shock.
Carbapenems and the monobactams
have a much lower risk of cross-reactivity.
When the history of allergy is not clear and it is
necessary to prescribe a penicillin,
the presence of IgE antibodies in serum
is a useful indicator of reactions mediated by
these antibodies, i.e. immediate (type 1) reactions.
Additionally, an intradermal test for allergy may
be performed; appearance of wheal reaction
indicates a positive response.
Only about 10% of patients with a history
of “penicillin allergy” respond positively.
Other (nonallergic) ADRs include diarrhoea due to
alteration in normal intestinal flora which may progress to
Clostridium difficile-associated diarrhoea. Neutropenia
is a risk if penicillins or other β-lactam antibiotics are
used in high dose and usually for a period of longer than
10 days. Rarely penicillins cause anaemia, sometimes
hemolytic, and thrombocytopenia or interstitial
nephritis. Penicillins are presented as their sodium
or potassium salts. Extremely high plasma penicillin
concentrations cause convulsions. Co-amoxiclav,
flucloxacillin, or oxacillin given in high doses for
prolonged periods in the elderly may cause
hepatic toxicity.
Antibacterial drugs have been
classified broadly into:
1. Bacteriostatic, i.e. those that act primarily
by arresting bacterial multiplication, such as
tetracyclines, amphenicols, macrolides,
lincosamides, sulfonamides, trimetrhoprime.
2. Bactericidal, i.e. those which act primarily
by killing bacteria, such as beta-lactams,
glycopeptides, aminoglycosides, isoniazid,
rifampicin, fluoroquinolones, metronidazole.
Adverse effects
The main hazard with the penicillins is allergic reaction.
These include itching, rashes (eczematous or urticarial),
fever, and angioedema. Rarely (about 1 in 10 000) there
is anaphylactic shock which can be fatal (about 1 in
100 000 treatment courses). Allergies are
least likely when penicillins are given orally and most
likely with local application. Metabolic opening of the
β-lactam ring creates a highly reactive penicilloyl group
which polymerizes and binds with tissue proteins to form
the major antigenic determinant. The anaphylactic
reaction involves specific IgE antibodies which can be
detected in the plasma of susceptible patients.
Amoxicillin:
rash 11 hours after
administration
There is cross-allergy between all the various
forms of penicillin, probably due in part to their
common structure, and in part to the degradation
products common to them all.
Partial cross-allergy exists between penicillins
and cephalosporins (a maximum of 10%) which
is of particular concern when the reaction to either
group of antimicrobials has been angioedema or
anaphylactic shock.
Carbapenems and the monobactams
have a much lower risk of cross-reactivity.
When the history of allergy is not clear and it is
necessary to prescribe a penicillin,
the presence of of IgE antibodies in serum
is a useful indicator of reactions mediated by
these antibodies, i.e. immediate (type 1) reactions.
Additionally, an intradermal test for allergy may
be performed; appearance of wheal reaction
indicates a positive response.
Only about 10% of patients with a history
of “penicillin allergy” respond positively.
Other (nonallergic) ADRs include diarrhoea due to
alteration in normal intestinal flora which may progress to
Clostridium difficile-associated diarrhoea. Neutropenia
is a risk if penicillins or other β-lactam antibiotics are
used in high dose and usually for a period of longer than
10 days. Rarely penicillins cause anaemia, sometimes
hemolytic, and thrombocytopenia or interstitial
nephritis. Penicillins are presented as their sodium
or potassium salts. Extremely high plasma penicillin
concentrations cause convulsions. Co-amoxiclav,
flucloxacillin, or oxacillin given in high doses for
prolonged periods in the elderly may cause
hepatic toxicity.
II. CEPHALOSPORINS
The nucleus of the cephalosporins, 7-aminocephalosporanic acid, bears a close resemblance to 6-aminopenicillanic acid. The intrinsic antimicrobial activity
of natural cephalosporins is low, but the attachment
of various R1 and R2 groups has yielded hundreds
of potent compounds of low toxicity. Cephalosporins
can be classified into four major generations,
depending mainly on the their antibacterial spectrum
and some pharmacokinetic properties.
7-Aminocephalosporanic acid nucleus
Ceftriaxon
Cephalosporins are similar to penicillins, but more
stable to many bacterial beta-lactamases and
therefore have a broader spectrum of activity.
However, strains of E. coli and Klebsiella species
expressing extended-spectrum beta-lactamases
that can hydrolyze most cephalosporins are
becoming a problem!
Klebsiella pneumoniae
1. First-generation cephalosporins
●cefadroxil, cefalonium, cefazolin,
●cefalotin, cefapirin, cefradine
These drugs are very active against Gram-positive
cocci (pneumococci, streptococci, and
Staphylococci). Cephalosporins are not active
against MRSA. E. coli, K. pneumoniae, and
P. mirabilis are often sensitive. Anaerobic cocci
are usually sensitive except Bacteroides fragilis.
They do not cross BBB.
Clinical applications
First-generation
●Osteomyelitis
●Skin infections caused by Staphylococcus
(but not MRSA)
●Soft tissue infections due to susceptible organisms
●Urinary tract infections (but not prostatis)
●Discospondylitis
●Bacterial conjunctivitis (cefalonium)
Cefalonium (Cepravin™): 250 mg
Carton – 8 cows: 32 syringes)
• Long-acting cephalosporin
• Cure existing infections at dry off
• Protect against mastitis and reduce
new infections at calving
Cefalonium (Cepravin™): 250 mg in spray
syringes (jeringas – spanish): intrammary
Indications:
In conjunction with teat spraying and proper management of the
cow during the drying off period, the careful administration of
Cepravin Dry Cow at drying off reduces new infections in the
dry period and treats subclinical mastitis.
Dosage
1 syringe per quarter (3 monts) immediately after final milking
Withholding Period
Milk: Treatment to be at least 49 days before calving.
Milk from the first 8 milkings after calving must be discarded.
Meat: 30 days
2. Second-generation cephalosporins
•cefalexin, cefamandole,
•cefuroxime, cefoxitin
They are active against organisms inhibited by first-generation drugs, but in addition they have extended Gramnegative coverage. Klebsiellae (incl. those resistant to
cefalotin) are usually sensitive. Cefamandole,
cefuroxime, and cefaclor are active against H. influenzae
but not against serratia or B. fragilis. In contrast, cefoxitin,
and cefotetan are active against B. fragilis and some
serratia strains but are less active against H. influenzae.
Cefalexin p.o.
•Cats: 22 – 50 mg/kg q.8–12 h
•Dogs: 20 – 40 mg/kg q.8–12 h
Clinical applications
Second-generation
●Orally active cephalosporins in dogs and cats.
●In veterinary institutions the human-approved
formulation cefuroxime is used for surgical
prophylaxis for orthopedic surgery.
Cefuroxime
Zinacef™:
20–50 mg/kg/BW
q.8–12 h
i.v., i.m., s.c.
Cefoxitin
10–30 mg/kg
q.6–8 h
i.v., i.m., s.c.
3. Third-generation cephalosporins
•cefoperazone, cefpodoxime, cefotaxime,
•cefovecin, ceftriaxone
Compared with second-generation agents, these
drugs have extanded Gram-negative coverage,
and some are able to cross the BBB. Thirdgeneration drugs are active against Citrobacter,
Serratia marcescens, and Providencia. They are
also effective against β-lactamase-producing
strains of Haemophilus and Neisseria.
Clinical applications
●Third-generation cephalosporins should be
reserved in small animal practice for serious
infections caused by Gram-negative aerobic
and facultatively anaerobic bacteria, especially
Enterobactericaceae.
●They may also be indicated for the treatment
of urinary tract infections.
Ceftriaxone
15 – 50 mg/kg
q.12–24 h i.v.
Cefpodoxime
5 – 10 mg/kg
q.12–24 h
●Ceftriaxone and
cefotaxime
are approved for the
treatment of meningitis,
including meningitis
caused by pneumococci,
meningococci,
H. influenzae,
and susceptible enteric
Gram-negative rods,
but not by L.
monocytogenes.
Neisseria meningitidis
●Ceftazidime and
cefoperazone are
the only two drugs
with useful activity
against P. aeruginosa.
●Cefovecin is registered in some markets
for use in canine skin and soft tissue infections
associated with Staph. intermedius, β-hemolytic
streptococci, Escherichia and Pasteurella multocida;
canine urinary tract infections associated with
Escherichia and Proteus spp; feline skin and soft
tissue infections associated with Pasteurella multocida, Fusobacterium spp, Bacteroides spp, Prevotella
oralis, β-hemolytic streptococci and
Staphylococcus intermedius; and feline
urinary tract infections associated with
Escherichia.
4. Fourth-generation cephalosporins
•cefepime, cefpirome
●Are used in human medicine for treatment of
nosocomial or community-acquired lower
respiratory tract infections, bacterial meningitis
and urinary tract infections.
III. CARBAPENEMS
•Doripenem
•Ertapenem
•Meropenem
•Tienam (imipenem/cilastatin)
Imipenem has a wide spectrum with good
activity against many Gram-negative rods,
including P. aeruginosa, Gram-positive
organisms, and anaerobes.
It is resistant to most β-lactamases.
Imipenem is inactivated by dehydropeptidases
in renal tubules, resulting in low urinary
concentrations. It is administered together
with an inhibitor of renal dehydropeptidase
(Cilastatin) for clinical use.
● The most common ADRs of carbapenems
are nausea, vomiting, diarrhea, skin rashes,
and reactions at the infusion sites. Excessive
levels of imipenem in patients with renal
failure may lead to seizures.
● Meropenem and ertapenem are less likely to
cause seizures than imipenem. Patients allergic
to penicillins may be allergic to carbapenems.
Clinical applications of carabapenems in VM
●For serious and multiresistant bacterial infections.
Known drug interactions
●Additive or synergistic antibacterial effects may occur
against some bacteria when imipenem is used with an
aminoglycoside.
●Antagonism of antibacterial effects may occur if used
with other β-lactams.
●Synergy may occur against Nocardia when used in
combination with Co-Trimoxazole.
●Chloramphenicol may antagonize the antibacterial
efficacy of imipenem.
IV. MONOBACTAMS
•Aztreonam
Monobactams are drugs with a monocyclic β-lactam
ring. They are relatively resistant to beta-lactamases
and active against Gram-negative rods (including
Pseudomonas and Serratia). They have no activity
against Gram-positive bacteria or anaerobes.
Aztreonam is given i.v.
Penicillin-allergic patients tolerate aztreonam.
V. BETA-LACTAMASE INHIBITORS
(̶)
•Clavulanic acid
•Sulbactam
•Tazobactam
Ampicillin, amoxicillin, ticarcillin, and
piperacillin are also available in combination
with one of several beta-lactamase inhibitors:
clavulanic acid, sulbactam, or tazobactam.
The addition of a beta-lactamase inhibitor
extends the activity of these penicillins to include
beta-lactamase-producing strains of S. aureus,
(without MRSA), E. coli, K. pneumoniae,
P. aeruginosa, Proteus, H. influenzae).
•CO-AMOXICLAV
(amoxicillin + clavulanic acid)
Augmentin
•SULTAMICILLIN
(ampicillin + sulbactam)
•PIPERACILLIN + TAZOBACTAM
Tazocin
•CEFOPERAZONE + SULBACTAM
Sulperazon
●Amoxicillin-clavulanate has many applications in
small animal practice because of its broad spectrum
and excellent activity against Staphylococcus. It is
often the drug of first choice for infections in skin, soft
tissue and urinary tract and for surgical prophylaxis.
●A combination of ampicillin and sulbactam (another
β-lactamase inhibitor) is available in some countries
and has similar uses.
●The indication for ticarcillin-clavulanate is usually
for systemic treatment of susceptible P. aeruginosa
infections resistant to other antibacterials.
Co-Amoxiclave (BAN):
Amoxicillin & Clavulanate
• Augmentin®
• Clavulox®
Antibacterial spectrum
for amoxicillinclavulanate
* MRSA
Amoxicillin & Clavulanate
(Augmentin®, Clavulox®)
12.5–25 mg/kg q.8–12 h
p.o., i.m., s.c.
Antibacterial spectrum for ticarcillin-clavulanate
* MRSA are resistant
GLYCOPEPTIDES
Glycopeptides inhibit synthesis of cell wall
peptidoglycan and inhibit bacterial cell membrane
permeability: Teicoplanin, Vancomycin,
Aviparcin and Bacitracin.
Bacitracin has activity against Gram-positive
organisms but is markedly nephrotoxic. It is
restricted to topical and ophthalmic use in
combination with polymyxin and/or neomycin
(e.g. Bivacin®, Topocin®, etc.).
●The most common indication of Vancomycin
would be MRSA infections or multidrug-resistant
Enterococcus.
●Teicoplanin is administered IM but can also be
given by rapid IV injection.
●Vancomycin and Teicoplanin are not absorbed
orally. They are drug of choice for the oral treatment
of bowel inflammations occurring as a complication of
antibiotic therapy (pseudomembranous enterocolitis
caused by Clostridium difficile) in human.
AMINOGLYCOSIDES
Aminoglycosides have a hexose ring, either
streptidine (in streptomycin) or 2-deoxystreptamine
(in other aminoglycosides), to which various amino
sugars are attached by glycosidic linkages.
They are water-soluble, stable in solution, and
more active at alkaline than at acid pH.
Aminoglycosides have polar groups in their
molecules and do not absorb in GIT.
Streptomycin
Streptomycin. Its antibacterial activity
is due to its binding to the 30S subunit of the
bacterial ribosome and inhibiting of protein
synthesis. It has a wide spectrum of
antibacterial activity but is primarily used to
treat mycobacterial infections (i.m.).
•The main problems are eighth nerve
toxicity (vestibulotoxicity more than
deafness), nephrotoxicity, allergic reactions.
Gentamicin
Tobramycin
Mechanisms of action
Inside the cell, aminoglycosides bind to specific
30S-subunit ribosomal proteins and inhibit
protein synthesis in at least three ways:
(1) interference with the initiation complex
of peptide formation;
(2) misreading of mRNA, which causes incorporation
of incorrect amino acids into the peptide, resulting
in a nonfunctional or toxic protein;
(3) breakup of polysomes into nonfunctional
monosomes.
Aminoglycosides act bactericidal
on dividing and non-dividing
extracelular microorganisms.
They are in general active
against staphylococci
and aerobic Gram-negative
organisms including P. aeruginosa
and almost all the Enterobacteriaceae.
Aminoglycosides are mostly used against Gramnegative enteric bacteria almost always used in
combination with a β-lactams to extend coverage
to include potential Gram-positive pathogens and
to take advantage of the synergism between
these two classes of drugs.
Penicillin-aminoglycoside combinations also are
used to achieve bactericidal activity in the treatment
of enterococcal endocarditis and to shorten duration
of therapy for viridans streptococcal and
staphylococcal endocarditis.
Amikacin
Gentamicin
– sol. 80 mg/2 ml (80 mg/8 h i.m.)
Kanamycin
Neomycin
- Bivacin – spray derm. fl 150 ml
(neomycin/bacitracin), Nemybacin®
- Topocin – pulvis adspersorius
(neomycin/bacitracin)
Netilmicin
Streptomycin
Tobramycin. Inhaled Tobramycin (Tobi®)
is used to treat mucoviscidosis in humans.
Gentamicin (Spelt with an “i”)
●Probably now the most commonly used aminoside
for severe infections caused by Gram (–) aerobic
bacteria in dogs with oft-treated ear infections
Tobramycin: More active against
Pseudomonas than gentamicin.
Amikacin is particularly important in
treating serious Pseudomonas and other Gram (–)
infections in immunosuppressed patients. It can be
administered for 2–3 weeks at recommended doses
with less risk of nephrotoxicity than with gentamicin.
Gentamicin:
6 mg/kg q.24 h
i.m., i.v., s.c.
Tobramycin:
1–2 mg/kg q. 8 h
i.m., i.v., s.c.
ADRs:
Ototoxicity and nephrotoxicity are more likely to
be encountered when therapy is continued for more
than 5 days, at higher doses, in the elderly, and
in the setting of renal insufficiency. Concurrent
use with loop diuretics (e.g. furosemide, ethacrynic
acid) or other nephrotoxic antimicrobial agents
(vancomycin, amphotericin) can potentiate nephrotoxicity. Ototoxicity can manifest as auditory
damage, resulting in tinnitus and high-frequency
hearing loss initially, or as vestibular damage,
evident by vertigo, ataxia, and loss of balance.
•Streptomycin and gentamicin are the most
vestibulotoxic agents.
•Neomycin, kanamycin, and amikacin are
the most cochlear toxic agents.
•Neomycin, tobramycin, and gentamicin
are the most nephrotoxic agents.
•In very high doses, aminoglycosides can produce
a curare-like effect with neuromuscular
blockade that results in respiratory paralysis. This
paralysis is usually reversible by calcium gluconate
(given promptly i.v.) or neostigmine.
•Hypersensitivity occurs infrequently.
Mechanisms of resistance
●mutation of the organisms, resulting in altered
ribosomes that no longer bind the drug
●reduced permeability of the bacteria to the drug
●inactivation of the drug by bacterial enzymes.
Pharmacokinetics
●Aminoglycosides are not significantly absorbed
from the gut, so must be given parenterally to
treat systemic infections.
●All have poor tissue penetration (including CNS
and eye) as they are highly hydrophilic.
●They are eliminated almost exclusively by
glomerular filtration.
●Half-lives are short in plasma (40–60 min) but
much longer (>30 h) for tissue-bound drug.
●Aminosides have a prolonged postantibiotic
effect. Once-daily dosing is now recommended to reduce toxicity.
●The bactericidal action of aminosides is enhanced
in an alkaline medium and may be reduced
by acidity secondary to tissue damage.
●All aminoside bind to and are inactivated by pus.
Spectinomycin is structurally
related to aminoglycosides.
●Has limited clinical application because
resistance develops readily.
●Is marketed in combination with lincomycin,
which marginally enhances activity
against Mycoplasma.
TETRACYCLINES
Tetracyclines enter microorganisms in part by passive
diffusion and in part by an energy-dependent process
of active transport. Susceptible cells concentrate the
drug intracellularly. Once inside the cell, tetracyclines
bind reversibly to the 30S subunit of the bacterial
ribosome, blocking the binding of aminoacyl-tRNA
to the acceptor site on the mRNA-ribosome complex.
This prevents addition of amino acids to the growing
peptide. Tetracyclines are
broad-spectrum bacteriostatic
antibiotics that inhibit
protein synthesis.
●Tetracyclines have activity against many
Gram (+) and Gram (–) aerobic bacteria but
acquired resistance limits their activity against
many species, such as Staphylococcus,
Enterococcus, Enterobacteriaceae (including
Enterobacter, Escherichia,
Proteus and Salmonella, Shigella).
●Atypical bacterial species (Rickettsia, Borrelia,
Chlamydia and Mycoplasma) are generally
susceptible, though some Mycoplasma
(M. bovis) are resistant.
●In VM tetracyclines are used most frequently
for atypical bacterial diseases due to Chlamydia
(in cats), Borrelia, Rickettsia and Mycoplasma.
●Tetracyclines are the drugs of choice for
Ehrlichia canis and Rickettsia infections.
●Brucellosis is commonly treated with tetracyclines
in combination with rifampicin or streptomycin.
●Tetracyclines have antiinflammatory properties
that are independent of their antibacterial
action, particularly in the case of doxycycline and
minocycline.
tick
Ehrlichia canis
is a bacterial infections
that is transmitted
through tick bite and
causes high fever, rash
and bleeding disorders.
In humans
also against :
- Plasmodium
falciparum
- Yersinia
pestis
(plague!)
Doxycycline: 5–10 mg/kg/12 h p.o. or i.v.
Minocycline: 5–15 mg/kg/12 h p.o.
Oxytetracycline: 20 mg/kg/8 h p.o.
Pharmacokinetics
Absorption after oral administration is approximately
60–70% for tetracycline, oxytetracycline, and
methacycline; and 95–100% for doxycycline and
minocycline. A portion of an orally administered dose
of tetracycline remains in the gut lumen, modifies
intestinal flora, and is excreted in the feces.
Absorption occurs mainly in the upper small intestine
and is impaired by food and same cations (Ca2+, Mg2+,
Fe2+, Fe3+ or Al3+), by dairy products, antacids and by
alkaline pH.
Tetracyclines are 40–80% bound by serum proteins.
They are distributed widely to tissues and body fluids
except for CSF. Minocycline reaches very high
concentrations in tears and saliva, which makes it
useful for eradication of the meningococcal carrier
state. Tetracyclines cross the placenta to reach
the fetus and are also excreted in milk. As a result of
chelation with calcium, tetracyclines are bound to and
damage – growing bones and teeth. Carbamazepine,
phenytoin, barbiturates, and chronic alcohol ingestion
may shorten the half-life of doxycycline by 50% by
induction of hepatic enzymes that metabolize the drug.
Tetracyclines are excreted mainly in bile and urine.
Concentrations in bile exceed those in serum tenfold.
From 10 to 50% of various tetracyclines is
excreted into the urine, mainly by glomerular
filtration. From 10% to 40% of the drug is excreted
in feces. Doxycycline, in contrast to other
tetracyclines, is eliminated by nonrenal
mechanisms, do not accumulate significantly
and require no dosage adjustment in renal failure.
Tetracyclines and macrolides have a good
intracellular distribution.
A newly approved tetracycline analog, tigecycline,
is a semisynthetic derivative of minocycline.
It is poorly absorbed orally and must be administered
intravenously (t1/2 36 h).
ADRs
of tetracyclines
Brown staining of the teeth
Nausea, vomiting, and diarrhea are the most common
reasons for tetracycline medication.
Nausea, anorexia, and diarrhea can usually be
controlled by administering the drug with food
or carboxymethylcellulose, reducing drug
dosage, or discontinuing the drug.
Tetracyclines modify the normal flora and overgrowth
of pseudomonas, proteus, staphylococci, resistant
coliforms, clostridia, and candida. This can result in
intestinal disturbances, anal pruritus, vaginal or oral
candidiasis, or enterocolitis with shock and death.
Tetracyclines are readily bound to calcium deposited
in newly formed bone or teeth.
When a tetracycline is given during pregnancy, it can
be deposited in the fetal teeth, leading to fluorescence,
discoloration, and enamel dysplasia; it can be deposited
in bone, where it may cause deformity or growth
inhibition.
The main mechanisms of resistance
to tetracyclines and its analogs are:
(1) impaired influx or increased efflux by an
active transport protein pump;
(2) ribosome protection due to production
of proteins that interfere with tetracycline
binding to the ribosome;
(3) enzymatic inactivation.