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Principles of antibiotic therapy
Antibiotics aim to kill organisms while causing no harm to the
patient - this concept is known as selective toxicity. It is best
achieved by inhibiting bacterial functions that are not present in
human cells, for example the peptidoglycan of bacterial cells is
inhibited by penicillin. The difference between the dose necessary
for treatment and that which causes harm is usually large and is
known as the therapeutic index. The aminoglycosides are exceptions
to this because doses just above the therapeutic level can be
toxic. While all antimicrobials have potential unwanted effects,
fortunately serious unwanted effects are not frequent.
Choice of therapy
Antibiotic choice depends on the:
- infection site: sufficient concentrations of antimicrobial may be
difficult to achieve in some sites such as abscesses, bone, the CSF
or areas with poor blood supply and some sites with low pH inhibit
certain antibiotics (e.g. aminoglycosides);
- organism: identification of the organism predicts the natural
history of the infection, thereby allowing treatment optimization;
- susceptibility pattern: Streptococcus pyogenes is invariably susceptible
to penicillin, but other organisms such as Acinetobacter
and Pseudomonas are resistant, so antibiotics should be chosen to
cover the resistance pattern of all the potential pathogens;
- severity of infection: severe infections require antibiotics to be
given by the parenteral route;
- history of allergy: a previous allergic response may limit the
choice of antibiotic;
- likelihood of unwanted effects: for example, aminoglycosides
should be used with care in patients with pre-existing renal disease.
Routes of administration
Antibiotics are usually taken orally in mild infections, but intravenous
therapy is usually required in severe infections, such as
septicaemia, to ensure adequate antibiotic concentrations are
achieved. Intravenous therapy may also be chosen for patients
unable to tolerate oral therapy. Topical administration is suitable
for skin infections. More rarely, antibiotics are given per rectum
(e.g. metronidazole for surgical prophylaxis) or intravaginally as
pessaries. Children require palatable liquid formulations to maximize
adherence.
Monitoring therapy
It is possible to measure the concentration of an antibiotic in the
serum or at the site of infection (e.g. in the CSF for meningitis).
This may be necessary to:
- ensure that there are adequate therapeutic concentrations at the
site of infection;
- reduce the risk of toxicity, which is important where the therapeutic
index is low (serum levels of aminoglycosides should be
measured in serum taken just before and 1 h after intravenous or
intramuscular dosage, which allows the dose to be adjusted according
to normograms and careful adherence to guidelines, e.g. for a
high peak the dosage may be reduced or for a high trough level
the medication is given less frequently);
- assist in the management of an infection with intermediate
susceptibility (if inhibition of an organism occurs only at high
antibiotic concentrations, it is important to ensure sufficient concentrations
are found at the site of infection, e.g. in Pseudomonas
meningitis, antibiotic concentrations should be measured in the
CSF);
- study the pharmacokinetics of the drug (treatment plans are
based on knowing the absorption, distribution and protein binding
of drugs). In the development of new antibiotics the way in which
the new agent is absorbed and distributed throughout the body is
studied by careful sampling.
Adverse events
Mild gastrointestinal upset is probably the most frequent side
effect of antibiotic therapy. Rarely, severe allergic reactions may
lead to acute anaphylactic shock or serum sickness syndromes.
Gastrointestinal tract
Antibiotic activity can upset the balance of the normal flora within
the gut (�-lactams are especially likely to do this) resulting in
overgrowth of commensal organisms such as Candida spp. Alternatively,
antibiotic therapy may provoke diarrhoea or, more seriously,
pseudomembranous colitis (see
Clostridium
).
Skin
Cutaneous manifestations range from mild urticaria or maculopapular,
erythematous eruptions to erythema multiforme and the
life-threatening Stevens-Johnson syndrome. Most cutaneous reactions
are mild and resolve after discontinuation of therapy.
Haemopoietic system
Patients receiving chloramphenicol or antifolate antibiotics may
exhibit dose-dependent bone marrow suppression. More seriously,
aplastic anaemia may rarely complicate chloramphenicol therapy.
High doses of β-lactam antibiotics may induce granulocytopenia.
Antibiotics are a rare cause of haemolytic anaemia. Many antibiotics
cause a mild reversible thrombocytopenia or bone marrow
depression.
Renal system
Aminoglycosides may cause renal toxicity by damaging the cells
of the proximal convoluted tubule. Patients who are elderly, have
pre-existing renal disease or are also receiving other drugs with
renal toxicity are at higher risk. Tetracyclines may also be toxic to
the kidneys.
Liver
Isoniazid and rifampicin may cause hepatitis; this is more common
in patients with pre-existing liver disease. Other agents associated
with hepatitis are tetracycline, erythromycin, pyrazinamide,
ethionamide and, very rarely, ampicillin or fluoroquinolones.
Cholestatic jaundice may follow tetracycline or high-dose fusidic
acid therapy.
