Transcript 23-8. Antibacterials

•Amphenicols
•Macrolides
•Lincosamides
•Polymyxins
•Streptogramins
•Oxazolidinones
Sulfonamides
Quinolones
Metronidazole
Oxiquinolones
Nitrofurans
Others
Assoc. Prof. Ivan Lambev (www.medpharm-sofia.eu)
AMPHENICOLS
•Chloramphenicol
•Thiamphenicol (with SH_group instead of nitro
functional group (–N02): less ADRs but less
antibacterial activity
•Florfenicol (analog of thiamphenicol)
CHLORAMPHENICOL
Originally isolated from Streptomyces venezuelae,
chloramphenicol was the first broad-spectrum
antibacterial developed (1947). It is now produced
synthetically because has a very simple structure.
Mechanism of action
It is a nonionized, highly lipophilic compound that
enters bacterial cells by passive diffusion
and binds primarily to the 50S ribosomal
subunit. Bacterial protein synthesis is inhibited.
Chloramphenicol can also bind to the
mammalian ribosome (70S) that resembles
bacterial ribosomes and interfere with
mitochondrial protein synthesis. This is
particularly relevant in erythropoietic cells.
It is bacteriostatic for most Gram-positive
and many Gram-negative aerobic bacteria.
Resistance is commonly plasmid-mediated and
occurs as a result of enzymatic inactivation by
several types of chloramphenicol transacetylase.
Chlorampenicol
p.o., i.v., i.m., s.c.
•Dogs: 50 mg/kg/8 h
•Cats: 50 mg/kg/12 h
Pharmacokinetics
●Well distributed, incl. CNS and eye.
●Attains higher concentrations for a long time
in CSF than other antibacterials (30–50% of plasma
concentrations in the absence of meningitis).
●Eliminated by hepatic glucuronide conjugation
in the dog: only 5–10% is excreted in the urine.
●In the cat, more than 25% is excreted in the urine
because of reduced ability to glucuronidate drugs.
●Chloramphenicol should not be given to young
animals (ill-equipped with metabolizing enzymes)
and avoided in adults with liver disease.
ADRs
●Reversible, dose-related anemia can
occur in dogs and cats. Cats may be more
susceptible.
●Idiosyncratic fatal aplastic anemia has
not been reported in small animals.
●Chloramphenicol inhibits hepatic microsomal
enzymes and prolongs effects of drugs
such as barbiturates and phenytoin. The
inhibition is irreversible and long lasting.
Gray baby syndrome in human
Advantage:
good penetration
including
in brain and eyes
Disadvantage:
bone marrow
toxicity
Florfenicol is a structural analog of thiamphenicol
with greater activity against pathogenic bacteria than
chloramphenicol and thiamphenicol. It is also active
against enteric bacteria, resistant to chloramphenicol.
Florfenicol can cause dose-related bone marrow
suppression but has not been reported to cause
fatal aplastic anemia in humans.
Currently it is approved for use only in cattle,
aquaculture and pigs. In cattle it is used to treat
infectious conjunctivitis and respiratory disease
caused by Pasteurella and Haemophilus.
Florfeniciol
®
(Norfenicol )
Florfeniciol (Norfenicol®)
Withdrawal Period
Cattle
Meat and offal:
By intramuscular injection (at 20 mg/kg, twice): 39 days
By subcutaneous injection (at 40 mg/kg, once): 44 days
Milk:
Not permitted for use in lactating animals producing milk
for human consumption.
Swine
Meat and offal:
By intramuscular injection (at 15 mg/kg, twice): 22 days
MACROLIDES and KETOLIDES
•Azithromycin (t1/2 40–68 h, tab. 500 mg)
•Erythromycin
•Clarithromycin (antihelicobacter activity)
•Josamycin (saliva excretion)
•Midecamycin
•Oleandomycin (saliva excretion)
•Roxithromycin
•Spiramycin (saliva excretion)
•Tylosin
•Ketolides: Telithromycin
Inhibition of bacterial protein synthesis by macrolides
Antibacterial spectrum of macrolides
●Active against Gram-positive aerobic bacteria,
Mycoplasma and Bartonella henselae (cat scratch
disease) with good intracellular distributions.
Erythromycin
●Erythromycin is the drug of choice for treatment of
Campylobacter jejuni infections.
●It is one of the drugs of choice for treatment of
Mycoplasma infections.
●Erythromycin has greater activity against
Staphylococcus than lincomycin but not clindamycin.
Resistance to erythromycin is plasmid encoded.
Bartonella
henselae
Cat scratch disease
Tylosin
●Tylosin is less active against bacteria
but more active against many Mycoplasma.
●Tylosin is often prescribed for feline respiratory
tract infections, caused by Mycoplasma, Chlamydia
and Gram-positive bacteria.
●Tylosin is used to treat bacterial overgrowth of the
small intestine and antibiotic-responsive diarrhea
(other common choices are tetracyclines and
metronidazole).
●Tylosin should not be used in horses.
Spiramycin
●It excretes mainly with saliva and is marketed
in combination with metronidazole, for treatment
of oral infections in dogs and cats.
•Rodogyl® (spiramycin/metronidazole)
Azithromycin and clarithromycin –
derivatives of erythromycin with greater potency
and a wider spectrum of activity, particularly against
Gram-negative aerobes: Mycobacteria, Bartonella,
Borrelia, Brucella, Leptospira, Campylobacter,
Helicobacter, Chlamydia and Toxoplasma.
●They are suitable for p.o. administration once daily.
●Both drugs are concentrated in phagocytes and
phagolysosomes. They are
expensive but may
be affordable for small
animals such as cats.
Azitrhromycin penetrates into phagocytes so that
it is effective against intracellular tubercle bacilli.
Many macrolide-resistant
strains are susceptible
to ketolides.
Telithromycin is active against S. pyogenes,
S. pneumoniae, S. aureus, H. influenzae, Moraxella
catarrhalis, Mycoplasmas, Legionella, Chlamydia,
H. pylori, N. gonorrhoeae, B. fragilis, and T. gondii.
Azithromycin
•Dogs: 10 mg/kg/24 h
•Cats: 5 mg/kg q.24–48 h
Erythromycin
10–20 mg/kg q.8–12 h p.o.
Clarithromycin
2.5–10 mg/kg/12 h p.o.
Tylosin
10 mg/kg/8 h p.o.
LINCOSAMIDES
Clindamycin
is a chlorine-substituted derivative
of Lincomycin, an antibiotic that is elaborated
by Streptomyces lincolnensis.
●Clindamycin and Lincomycin penetrate well into all
tissues, incl. bone, and have been popular for treating
osteomyelitis. Clindamycin is more potent than lincomycin
especially against obligate anaerobes.
●Clindamycin is indicated for Toxoplasma and Neospora
infections although in human medicine sulfadiazine and
pyrimethamine remain the drugs
of choice for toxoplasmosis.
●Clindamycin is one of
several suitable drugs for
treating chronic
rhinosinusitis in cats.
Clindamycin
10 – 20 mg/kg
q. 12 h
Lincomycin
–
p.o., i.m., i.v., s.c.
12.5 – 25 mg/kg
q. 12 h
p.o., i.m., i.v., s.c.
10 – 20 mg/kg p.o.
q. 8 – 12 h
●Clindamycin is commonly combined with an
aminoside in human medicine to treat or prevent
mixed aerobic-anaerobic bacterial infections such
as those associated with intestinal perforation.
●Clindamycin reportedly has synergistic effects
with metronidazole against Bacteroides fragilis.
●Combinations of clindamycin with macrolides or
chloramphenicol are antagonistic in vitro.
●Common ADRs are diarrhea and colitis due to
C. difficile; nausea, skin rashes; impaired liver
function and neutropenia.
STREPTOGRAMINS
Synercid® are combination of two antibiotics:
quinupristin and dalfopristin in a 30:70 ratio.
It is rapidly bactericidal for most microorganisms.
Synercid® is approved for treatment of infections
caused by staphylococci or by vancomycinresistant strains of Enerococus faecium,
but not Enterococcus faecalis, which is resistant.
The principal toxicities are infusion-related events,
such as pain at the infusion site, and
an arthralgia-myalgia syndrome.
POLYMYXINS (B and E)
They are mainly toxic antibiotics derived from
strains of the soil bacterium Bacillus polymyxa.
Colistin (Polymyxin E) alters bacterial membrane
permeability. It is highly active against many
Gram-negative bacteria, incl. P. aeruginosa but
not Proteus. Polymyxins have nephro- and
neurotoxicity in small animal. Therefore they are
generally only used in topical or ophthalmic
medications, often in combination with
bacitracin and neomycin or tetracycline.
OXAZOLIDINONES
Linezolid is a synthetic antimicrobials, active against
Gram-positive organisms including staphylococci,
streptococci, enterococci, Gram-positive anaerobic
cocci, and Gram-positive rods such as Corynebacteria
and L. monocytogenes. It is primarily a bacteriostatic
agent except for streptococci, for which it is bactericidal.
Linezolid inhibits protein synthesis by preventing
formation of the ribosome complex that initiates
protein synthesis. Its unique binding site, located on
23S ribosomal RNA of the 50S subunit, results in
no cross-resistance with other drug classes.
SULFONAMIDES
G. Domagk
(1895–1964),
bacteriologist and
pathologist discovered
the first sulfonamide
in 1935. Nobel prize for
Physiology and Medicine
in 1939.
Mechanism of action
•Unlike man, most bacteria cannot
utilize external folic acid, a nutrient
which is essential for growth, and they have
to synthesize it from para-aminobenzoic acid
(PABA). Sulfonamides are structurally similar
to PABA and inhibit the dihydrofolate synthetase
in the biosynthetic pathway for folic acid.
•High concentrations of PABA antagonize
the effectiveness of sulfonamides.
Folic acid is required for purine and pyrimidine synthesis
and hence nucleic acid synthesis. Sulfonamides not only
block formation of folic acid – they are incorporated into the
precursors, forming a pseudometabolite that is reactive
and antibacterial. Mammalian cells are not susceptible
to sulfonamides. The combination of sulfonamides
with trimethoprim potentiates their activity.
Trimethoprim enters bacteria and inhibits bacterial dihydrofolic
acid reductase, thus acting on the same metabolic pathway as
sulfonamides. Therefore the combination has synergistic
activity. The binding affinity of trimethoprim is 50 000 times
greater for the bacterial enzyme than for mammalian enzyme.
DHF synthetase
PABA
DHF reductase
DHFA
()
Sulfonamides
THFA
Purines
()
Trimethoprim
Dietary folate
in man
DNA
Proteins
Synergism between trimethoprim and the sulfonamide
results in up to 40% of bacteria that are resistant to
one component being susceptible to the combination.
Clinical applications
●Toxoplasma infection (combined with pyrimethamine).
●Chlamydia infection.
●Nocardia infection (with or without trimethoprim).
●Bordetella bronchiseptica infection
(kennel cough).
●Prostatic infections (concentrations
in prostatic tissue are 10-fold
greater than in plasma).
Co-trimoxazolе (BAN)
30 mg/kg q.12–24 h
p.o., i.v., i.m., s.c
●Poorly absorbed sulfonamides can be used to treat
GI infections, including coccidiosis (sulfaguanidine),
or ulcerative colitis (sulfasalazine).
●Topical sulfonamides are used in ophthalmic and
skin preparations.
●Trimethoprim-sulfonamide may be the treatment of
choice for Pneumocystis pneumonia.
Sulfacetamidе
•collyrium 20% 10 ml
For local treatment of bacterial conjunctivitis
Resistance is common and due to the
production of dihydrofolate synthetase
with reduced affinity for binding of
sulfonamides, and is transmitted in
Gram-negative bacteria by plasmids.
•Resistant strains of Staphylococcus
aureus can synthesize more PABA
than normal.
Pharmacokinetics
•Most sulfonamides are well absorbed
orally. They are widely distributed in
the body and cross the BBB and placenta.
•Sulfonamides are metabolized in the liver,
initially by acetylation which shows
genetic polymorphism. The acetylated
product has no antimicrobial actions but
retains toxic potential.
Distribution of sulfonamides in
tissue is good. A large number
of parent drugs and N-acetyl
metabolites are excreted by
the kidney.
ADRs of sulfonamides
Hypersensitivity reactions to sulfonamides include
polyarthritis and fever, cutaneous eruptions,
thrombocytopenia, leukopenia and hepatitis. The
sulfonamide molecule is too small to be
immunogenic. It is thought that hypersensitivity
reactions occurs of the hydroxylamine metabolites
that forms from oxidation of the para-amino group.
They are cytotoxic and capable of binding
to protein. Doberman and pinschers are
predisposed to sulfonamide hypersensitivity.
This may be because of a reduced ability to detoxify
hydroxylamine groups compared with mixed-breed dogs. Also,
dobermans and other breeds of dogs commonly affected with
von Willebrand’s disease (Scottish terriers, German shepherds)
may not tolerate sulfonamides well. These drugs probably
should be avoided in dobermans.
Keratoconjunctivitis sicca (KCS) may occur with prolonged use
of some sulfonamides. It is probably most often associated
with sulfasalazine, as this drug is used for long-term treatment
of ulcerative colitis. KCS has also been reported within
the first week of treatment in a small proportion of dogs treated
with trimethoprim-sulfadiazine.
●Crystalluria, hematuria and urinary tract obstruction can
occur as a result of concentration of sulfonamides in renal
tubules and acid pH. Ensure that animals receiving
sulfonamides are well hydrated.
Excessive salivation: Cats foam at the mouth if given oral
sulfonamide drugs, if enteric-coated tablets are broken.
●Trimethoprim-sulfonamides have been reported to cause
idiosyncratic severe hepatic necrosis on rare occasions.
●Aplastic anemia and thrombocytopenia may occur rare.
●It has been postulated but not proven that Co-Trimoxazole
is a risk factor for acute pancreatitis.
●Sulfonamides at high doses (30 mg/kg twice daily) may
decrease iodinization of colloid and decrease concentrations
of thyroxine and triiodthyronine.
QUINOLONES
(inhibitors of DNA gyrase, resp.
inhibitors of topoisomerases)
•Nalidixic acid and its derivatives
•Fluoroquinolones
Nalidixic acid has been available
for over 60 years but low activity
poor tissue distribution, and
adverse effects limited its use
to being a second- and thirdline oral treatment for
Gram (–) low
urinary tract infections.
Gr (—):
 E.
coli
 Salmonella
 Shigella
 P. aeruginosa
•Nalidixic acid
®
(Nelidix )
®
•Gramurin
Changes to the basic quinolone
structure such as the addition
of fluorine and piperazine ring
have dramatically increased
antibacterial potency, particularly
against P. aeruginosa. The new
compounds are called
4-fluoroquinolones
(or fluoroquinolones)
Bactericidal effect
•Gr (+): topoisomerase IV
•Gr (–):
topoisomerase II
(DNA gyrase)
Ciprofloxacin
Bacterial DNA
topoisomerase II and IV)
( )
Fluoroquinolones
•Bactericidal effect; very broad antibacterial spectrum
•High activity against
P. aeruginosa, Salmonella,
Shigella, Neisseria,
Campylobacter,
and Chlamydia
•Beta-lactamase
stability
•Limited and
variable
activity
against
streptococci
●Active against 90–100% of bacterial isolates from
urine (where concentrations are 10–20-fold higher
than in plasma) including methicillin-resistant
Staphylococcus (MRSA).
●Active against Brucella, Mycobacterium,
and Mycoplasma.
●Penetrate intracellularly, thus potentially effective
against intracellular bacteria.
●Concentrate in phagolysosomes, enhancing
intracellular killing.
Clinical applications of fluoroqinolones
in animals
●Urinary tract infections caused by Pseudomonas
●Bacterial prostatitis in dogs
●Serious Gram-negative systemic infections
●Osteomyelitis caused by Gram-negative aerobes
●Saprophytic Mycobacterium infection in cats
●Deep granulomatous pyoderma
●Serious bacterial respiratory tract infections
●Neutropenic, febrile patients with cancer
●Otitis externa due to Gram-negative infections
Indications (infections) in humans:
•urinary
•respiratory
•GIT
•genital
(incl. gonorrhoea)
•septicemia
•ophthalmic (topically)
Moxifloxacin
Tabl. 400 mg
400 mg once daily
in humans
•Enrofloxacin
•Gatifloxacin
•Levofloxacin (Tavanic®) –
S-isomer of ofloxacin
500 mg/24 h p.o. 10 days
•Norfloxacin
•Lomefloxacin
•Ofloxacin
•Pefloxacin etc.
>70% F (p.o.)
DD/2 applications
Good intracellular distribution
50–80%/24 h
urinary excretion
ADRs
●Vomiting, inappetence or diarrhea may occur
occasionally. Facial erythema and edema have
been reported rarely, as have tremors and ataxia.
●Seizures have been reported rarely in animals with
CNS disorders, with high doses and with concurrent
use of NSAIDs.
●An apparent species-specific toxicity is acute retinal
degeneration in cats treated with enrofloxacin. Blindness often results but some cats may regain vision.
It has been postulated that the relatively open
BBB of cats combined with the lipophilic properties
of enrofloxacin predispose cats to accumulating high
concentrations of the drug in the CNS. The risk may
be higher in cats with urinary tract infections and
concomitant renal failure and care should be taken
with dosage in geriatric cats or those with liver or
renal impairment. It is not clear whether other
fluoroquinolones can also cause blindness.
●Fluoroquinolones should not be used in young
animals as they cause erosion of articular cartilage
(in dogs more than cats and large dogs especially).
The mechanism of cartilage damage may be related
to chelation of magnesium in joints. Lesions have
been documented in dogs given five times the recommended dose and occur within 1–2 days of beginning
administration. It is recommended that fluoroquinolones be avoided in large breed dogs up to 18 months
of age (12 months for medium breeds, 9 months for
small breeds). If a fluoroquinolone must be used
because there is no suitable alternative, strict
restriction (especially for large breed dogs) and use
of chondroprotectives are advised.
•Co-administration of ciprofloxacin
and theophylline causes
eleveted plasma theophylline
concentrations due to inhibition
of cytochrome P450.
•Both drugs are epileptogenic.
Fluoroquinolones
Adapted from Bennett and Brown (2003)
METRONIDAZOLE
10–20 mg/kg q.12–24 h p.o.
Metronidazole is bactericidal to anaerobic bacteria,
probably in a concentration-dependent manner. After
entry into the cell it undergoes reduction to produce
metabolites, some of which have antibacterial activity.
These cause extensive breakage of DNA strands and
inhibit the DNA repair enzyme. This reduction reaction
occurs under anaerobic conditions. It is also
active against many protozoa but the mechanisms
involved are incompletely understood. Resistance is
rare among susceptible bacteria and involves reduced
intracellular drug activation.
Metronidazole is bactericidal for many Gram (+)
and most Gram (–) obligate anaerobes. It has
no effect on aerobic bacteria. It is active against
Balantidium coli, E. histolytica, Giardia and
Trichomonas. Campylobacter are moderately
susceptible. Helicobacter pylori are commonly
susceptible but the susceptibility of animalderived Helicobacter spp has not been
established.
Clinical applications
●GI infections with Balantidium coli, Entamoeba
histolytica, Giardia, Trichomonas or anaerobic bacteria.
●Mouth infections, periodontal disease, ulcerative
gingivitis in combination with spiramycin (e.g. Rodogyl®).
●Bacterial overgrowth of the small intestine and
antibiotic-responsive diarrhea.
●Anaerobic soft tissue infections, especially where
good tissue penetration is important.
●In combination with a fluoroquinolone for sepsis.
ADRs
●Vomiting, nausea.
●Dose-related neurotoxicity has been reported
in dogs. Signs included severe ataxia, positional
nystagmus (involuntary eye movement),
seizures and head tilt.
●Cats often salivate
profusely.
●Inappetence
has been noted
in horses.
●A marginal and contentious carcinogenic effect
has been observed in some laboratory studies.
As a result metronidazole and other nitroimidazoles are no longer used in food-producing
animals in some countries.
●Metronidazole may be teratogenic and therefore
should not be used during pregnancy, especially
in the first 3 weeks, unless the benefits to the
mother outweigh potential risks to the fetus.
OXIQUINOLONES
They block RNA polymerase.
TILBROQUINOL
– enteroantiseptic with
antiamoebic activity
NITROXOLIN
– broad
spectrum
uroantiseptic (p.o.)
NITROFURANS
– broad spectrum antibacterial agents
FURAZOLIDONE, NIFUROXAZIDE
– enteroantiseptics (Salmonella etc.)
NITROFURANTOIN (p.o.)
– uroantiseptic: E. coli,
Proteus mirabilis, Staph. aureus,
Klebsiella, Serratia, Pseudomonas.
It blocks carbohydrate metabolism
by inhibiting its acetyl CoA synthesis.
Furazolidone: 2.2–20 mg/kg q.8–24 h p.o.
●Nitrofurantoin has broad antibacterial activity but
its use in small animals is limited to treatment
of lower urinary tract infections.
●Nitrofurantoin is rapidly absorbed from the gut.
It is rapidly eliminated (drug appears in the urine
within 30 min of administration) and therapeutic
blood concentrations cannot be maintained.
Approximately 40–50% of the drug is eliminated
unchanged in the urine.
●ADRs in small animals include GI disturbances
and hepatopathy.
Nitrofurantoin
®
(Furadantin ):
4 mg/kg q.6–8 h
RIFAMPICIN (RIFAMPIN – USAN)
This semisynthetically modified antibiotic product of
Streptomyces mediterranei has been an important
component of the treatment of tuberculosis in humans.
Rifampicin acts by inhibiting RNA polymerase, which
catalyzes the transcription of DNA to RNA.
It is bactericidal and has a wide spectrum:
●Brucella, Staphiloccocus spp. (incl. MRSA)
●Gram (+) and (–) anaerobic bacteria, incl. B. fragilis.
●Chlamydia and Rickettsia
●Mycobacterium tuberculosis and leprae
Clinical applications
●Rifampicin is primarily used in small animal practice
to treat chronic granulomatous skin infections in dogs.
●It is used in combination with erythromycin to treat
Rhodococcus equi neumonia in foals.
Pharmacokinetics
Absorption after oral administration is good. Rifampicin
is effective against intracellular bacteria. Penetration
into CSF is poor but enhanced by inflammation.
Penetration into phagocytic cells is excellent. Its
t1/2 in dogs is 8 h. Rifampicin is acetylated in the liver
to a bioactive metabolite which is excreted in bile.
Rodococcus
equi is a
Gram (+)
coccobacillus.
It is found in dry
and dusty soil.
Rifampicin
(Rifampin)
10–20 mg/kg/12 h
Rifampicin can induce hepatic microsomal enzymes,
which may result in increased elimination rate with
time. The metabolism of other drugs (barbiturates,
ketoconazole, theophylline, hormonal contraceptives,
and GCS), may be increased. Urine, feces, sweat
and tears may be colored red-orange.
Adverse effects
Approximately 20% of dogs develop increases in
hepatic serum enzyme concentrations and may
progress to clinical hepatitis. This may be fatal in
dogs with a history of liver disease.
Clofazimine
Clofazimine binds to DNA and may inhibIts
function as a template. It is used in humans as
part of multidrug protocols to treat leprosy.
It is used in cats to treat Mycobacterium
lepraemurium and other nontuberculous
mycobacterial infections. Hepatoxicity
has been reported in dogs.
Cofazimine – p.o.
•Dogs: 4–8 mg/kg/8 h
•Cats: 4–8 mg/kg/8 h
PRINCIPLES OF RATIONAL
ANTIBACTERIAL
THERAPY
(Adapted from Laurence et al., 1997 & others)
The following principles, many of which
apply to drug therapy in general, are a
guide to good clinical practice
with antimicrobial agents.
(1) Make a diagnosis precisely:
– defining the site of action;
– defining the microorganism(s) responsible
and their sensitivity to drugs;
– biological samples for laboratory must be
taken before treatment is begun.
(2) Aims of therapy
The goal of antibacterial therapy is to help the body
eliminate infectious organisms without toxicity to the
host. It is important to recognize that the natural defense
mechanisms of a patient are of primary importance in
preventing and controlling infection. Examples of
natural defenses against bacterial invasion are:
●the mucociliary escalator in the respiratory tract
●the flushing effect of urination
●the normal flora in the GIT.
All such mechanisms can be affected by disease or
therapeutic interventions.
Once microbial invasion occurs, various host
responses serve to combat the invading
organisms, including:
●the inflammatory response
●cellular migration and phagocytosis
●the complement system
●antibody production.
The difficulty of controlling infections in immunocompromised patients emphasizes that antibacterial therapy
is most effective when it supplements endogenous
defense mechanisms rather than when acting as the
sole means of control.
(3) Consider factors affecting the success
of antibacterial therapy
•Bacterial susceptibility
Various factors need to be considered in susceptibility
testing. The minimum inhibitory concentration (MIC) is
the concentration of drug that must be attained at the
infection site. In general, if bacteria are not susceptible
to a drug in vitro they will be resistant in vivo.
•Distribution to the site of infection
To be effective, an antibacterial agent must be
distributed to the site of infection and come into contact
with the infecting organism in adequate concentrations.
Bacteria that locate intracellularly (Bartonella,
Brucella, Chlamydia, Mycobacterium, Rickettsia)
will not be affected by antibacterial agents that remain
in the extracellular space. Staphylococcus is
facultatively intracellular and may sometimes
resist treatment because of intracellular survival.
Drugs that accumulate in leukocytes and other
cells include fluoroquinolones, lincosamides,
sulfonamides and macrolides but
aminoglycosides and β-lactams do not achieve
effective intracellular concentrations.
An infectious process often adversely affects the
distribution of a drug in vivo. An exception
is inflammation of the meninges (meningitis), which
reduces the normal barrier between blood and CSF,
so that antibacterial agents may cross this barrier.
This breakdown of barriers by inflammation does not
occur to an appreciable extent with the blood–prostate
and blood–bronchial barrier.
Effective antibacterial concentrations may not be
achieved in poorly vascularized tissues, e.g.
the extremities during shock, sequestered bone
fragments or heart valves.
(4) Remove barriers to cure (e.g. lack of free
drainage of abscesses, obstruction in the
urinary or respiratory tracts).
(5) Decide whether therapy is necessary.
As a general rule, acute infections require
therapy whilst chronic infections
may not. Chronic abscess or empyema
respond poorly. Even some acute infections
such as gastroenteritis are better managed
symptomatically than by antimicrobials.
(6) Choose the most suitable route of
administration of antibacterial drug(s)
● Topical administration is valuable for disorders of
eye and ear and some skin or gut infections. High
drug concentration may be achieved locally in this
way and some drugs too toxic for routine systemic
administration (bacitracin, neomycin, polymyxins)
can be useful topically.
● Oral administration is adequate in most infections
and is usually preferable for home treatment. Some
owners find it easier to administer drugs orally with
food.
If in doubt, administration on an empty stomach
(no food for 1–2 h before and after dosing)
is recommended, as the most common outcome
of drug–ingesta interactions is impaired systemic
drug availability.
●Parenteral administration is not routinely
advantageous but can be useful for fractious,
unconscious or vomiting patients, or those with
oral/pharyngeal/esophageal pain or dysfunction.
(7) Select the best drugs. This involves
consideration of:
– specificity (the antimicrobial activity of a
drug must cover the infecting organisms);
– pharmacokinetic factors (the chosen drug
must reach the site of infection (e.g. by
crossing BBB);
– the patients (who may previously had
allergic reactions to antimicrobials or
whose routes of drug elimination may be
impaired, e.g. by renal disease).
8. Client consent and compliance
As with all drug therapy, antibacterials will not
be effective unless administered correctly to
the patient. It is important to maximize the
likelihood that a client will administer
drugs at the right dose and dosing interval.
(9) Indications for combination therapy:
– to avoid the development of resistance
in chronic infections (e.g. FIV, tuberculosis).
– to broaden the antibacterial spectrum:
a) in a unknown mixed infection;
b) unusual pathogens, including Mycobacterium,
Rhodococcus and fungi.
c) if the microorganism cannot be predicted
(septicemia complicating neutropenia);
– to obtain potentation (e.g. penicillin plus
gentamicin for enterococcal endocarditis)
(10) Antimicrobial therapy in pregnancy
or lactation
PRC B have:
•Azithromycine
•Erythromycine
•Penicillins
•Most
cephalosporines
PRCs
LRCs
A: controlled studies
show no risk (Vit. B9)
B: no evidence of risk in
humans (Penicillins)
C: risk cannot be ruled
out (Bisoprolol)
D: positive evidence of
risk (Diazepam)
X: contraindicated in
pregnancy (Estrogens)
L1: safest (Ibuprofen,
Paracetamol)
L2: safer (Cephalosporins,
Omeprazole)
L3: moderately safe
(Acarbose, Aspirin)
L4: possibly hazardous
(Diazepam)
L5: contraindicated
(ACE inhibitors)
(11) Administer the drug in optimum dose
and frequency
– Inadequate dose may encourage the
development of microbial resistance.
– Intermittent dosing is preffered to
continual infusion.
– Plasma concentration monitoring can be
applied to optimize therapy with aminosides,
fluoroquinolones, co-trimoxazole, and
cephalosporins, in patients with kidney disease.
(12) Continue therapy until apparent
cure has been achieved.
– Most acute infections are treated for
5 to 10 days. There are many exceptions
to this, such as typhoid fever, tuberculosis, and infective endocarditis, in which
relapse is possible long after apparent
clinical cure and so the drugs are
continued for a long time, determined
by clinical experience.
(13) Test for cure. In some infections,
microbiological proof of cure is desirable because
disappearance of symptoms and signs
occurs before the microorganisms are
eradicated, e.g. urinary tract infections
(examinations must be done after
withdrawal of drug therapy).
(14) Prophylactic therapy for surgical
and dental procedures should be of very limited
duration. It should be started at the time of
surgery to reduce the risk of producing
resistant microorganisms.
(15) Remember that the most important carriers
of cross infections are your 10 fingers.