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.
CEPHALOSPORINSFIRST-GENERATION CEPHALOSPORINS
So-called first-generation cephalosporins (e.g. cephalexin,
cefaclor,cefadroxil) are effective against Streptococcus pyo-
genesandStreptococcus pneumoniae,E. coliand some staphylo-
cocci. They have few absolute (i.e. uniquely advantageous)
indications. Their pharmacology is similar to that of the peni-
cillins and they are principally renally eliminated.
SECOND- AND THIRD-GENERATION
CEPHALOSPORINS
Second- and third-generation cephalosporins are active
againstH. influenzaeand in some instances Pseudomonasand
anaerobes, at the expense of reduced efficacy against Gram-
positive 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. influenzaeandE. 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 other-
wise necessitate use of an aminoglycoside, this cost is partly
offset by savings from the lack of need for plasma concentra-
tion determinations.
Of the third-generation cephalosporins, ceftazidime,cef-
triaxoneandcefotaximeare 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, amino-
glycosides or other nephrotoxic agents. Some of the third-
generation drugs are associated with bleeding due to increased
prothrombin times, which is reversible with vitamin K.
MONOBACTAMSMonobactams (e.g. aztreonam) contain a 5-monobactam ring
and are resistant to β-lactamase degradation.
AZTREONAM
Uses
Aztreonamis 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 aztreonamis
known.Mechanism of action
The 5-monobactam ring binds to bacterial wall transpepti-
dases 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
Aztreonamis poorly absorbed after oral administration, so it
is given parenterally. It is widely distributed to all body com-
partments, 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
downimipenemin the kidney. Imipenemhas a very broad
spectrum of activity against Gram-positive, Gram-negative and
anaerobic organisms. It is β-lactamase stable and is used for treat-
ing severe infections of the lung and abdomen, and in patients
with septicaemia, where the source of the organism is unknown.
Meropenemis similar to imipenem, but is stable to renal dehy-
dropeptidase I and therefore can be given without cilastatin.Adverse effects
Imipenemis generally well tolerated, but seizures, myoclonus,
confusion, nausea and vomiting, hypersensitivity, positive
Coombs’ test, taste disturbances and thrombophlebitis have all
been reported. Meropenemhas less seizure-inducing potential
and can be used to treat central nervous system infection.Pharmacokinetics
Imipenemis filtered and metabolized in the kidney by dehy-
dropeptidase I. This is inhibited by cilastatinin the combina-
tion.Imipenemis given intravenously as an infusion in three
or four divided daily doses.AMINOGLYCOSIDESUses
Aminoglycosides are highly polar, sugar-containing deriva-
tives. They are powerful bactericidal agents that are active
against many Gram-negative organisms and some Gram-
positive organisms, with activity against staphylococci andCOMMONLYPRESCRIBEDANTIBACTERIALDRUGS 327