Clinical Pharmacology and Therapeutics

COMMONLY PRESCRIBED ANTIBACTERIAL DRUGS 327
Pharmacokinetics
Absorption of these drugs from the gut is inadequate in the
life-threatening infections for which they are mainly indicated.
They are given intravenously every 4–6 hours. Their half-lives
range from 1 to 1.5 hours and they are renally excreted.
CEPHALOSPORINS
FIRST-GENERATION CEPHALOSPORINS
So-called first-generation cephalosporins (e.g. cephalexin,
cefaclor, cefadroxil) are effective against Streptococcus pyogenes
and Streptococcus pneumoniae, E. coli and some staphylococci.
They have few absolute (i.e. uniquely advantageous)
indications. Their pharmacology is similar to that of the penicillins
and they are principally renally eliminated.
SECOND- AND THIRD-GENERATION
CEPHALOSPORINS
Second- and third-generation cephalosporins are active
against H. influenzae and in some instances Pseudomonas and
anaerobes, at the expense of reduced efficacy against Grampositive
organisms. β-Lactamase stability has been increased.
Arguably the most generally useful member of the group is
cefuroxime, which combines lactamase stability with activity
against streptococci, staphylococci, H. influenzae and E. coli. It
is given by injection eight-hourly (an oral preparation is also
available, as cefuroxime axetil). It is expensive, although
when used against Gram-negative organisms that would otherwise
necessitate use of an aminoglycoside, this cost is partly
offset by savings from the lack of need for plasma concentration
determinations.
Of the third-generation cephalosporins, ceftazidime, ceftriaxone
and cefotaxime are useful in severe sepsis, especially
because (unlike earlier cephalosporins) they penetrate the
blood–brain barrier well and are effective in meningitis.
Adverse effects
About 10% of patients who are allergic to penicillins are also
allergic to cephalosporins. Some first-generation cephalosporins
are nephrotoxic, particularly if used with furosemide, aminoglycosides
or other nephrotoxic agents. Some of the thirdgeneration
drugs are associated with bleeding due to increased
prothrombin times, which is reversible with vitamin K.
MONOBACTAMS
Monobactams (e.g. aztreonam) contain a 5-monobactam ring
and are resistant to β-lactamase degradation.
AZTREONAM
Uses
Aztreonam is primarily active against aerobic Gram-negative
organisms and is an alternative to an aminoglycoside. It is used
in severe sepsis, often hospital acquired, especially infections of
the respiratory, urinary, biliary, gastro-intestinal and female
genital tracts. It has a narrow spectrum of activity and cannot be
used alone unless the organism’s sensitivity to aztreonam is
known.
Mechanism of action
The 5-monobactam ring binds to bacterial wall transpeptidases
and inhibits bacterial cell wall synthesis in a similar way
to the penicillins.
Adverse effects
Rashes occur, but there appears to be no cross-allergenicity
with penicillins.
Pharmacokinetics
Aztreonam is poorly absorbed after oral administration, so it
is given parenterally. It is widely distributed to all body compartments,
including the cerebrospinal fluid. Excretion is
renal and the usual half-life (one to two hours) is increased in
renal failure.
IMIPENEM–CILASTATIN AND MEROPENEM
Uses
Imipenem, a carbapenem, is combined with cilastatin, which
is an inhibitor of the enzyme dehydropeptidase I found in the
brush border of the proximal renal tubule. This enzyme breaks
down imipenem in the kidney. Imipenem has a very broad
spectrum of activity against Gram-positive, Gram-negative and
anaerobic organisms. It is β-lactamase stable and is used for treating
severe infections of the lung and abdomen, and in patients
with septicaemia, where the source of the organism is unknown.
Meropenem is similar to imipenem, but is stable to renal dehydropeptidase
I and therefore can be given without cilastatin.
Adverse effects
Imipenem is generally well tolerated, but seizures, myoclonus,
confusion, nausea and vomiting, hypersensitivity, positive
Coombs’ test, taste disturbances and thrombophlebitis have all
been reported. Meropenem has less seizure-inducing potential
and can be used to treat central nervous system infection.
Pharmacokinetics
Imipenem is filtered and metabolized in the kidney by dehydropeptidase
I. This is inhibited by cilastatin in the combination.
Imipenem is given intravenously as an infusion in three
or four divided daily doses.
AMINOGLYCOSIDES
Uses
Aminoglycosides are highly polar, sugar-containing derivatives.
They are powerful bactericidal agents that are active
against many Gram-negative organisms and some Grampositive
organisms, with activity against staphylococci and