Cephalosporines
Cephalosporines
made their debut in 1948 when Brotzu isolated an antibacterial agent
from the cultures of a fungus Cephalosporium
acremonium . Since then, there has been agradual growing of interest in the
production of these drugs, culminating over the last decade in frenetic
activity on the part of scientists to develop newer cephalosporines, so much so
that a systematic classification has become necessary.
·
First generation cephalosporines—cephalothin, cefazolin,cephalexin,
cephapirin, cephradine, and cefadroxil. These drugs are active mainly against
gram-positive bacteria, and are less effective against gram-negative
micro-organisms.
·
Second generation cephalosporines—cefamandole, cefoxitin,cefaclor,
cefuroxime, cefuroxime axetil, loracarbef, cefonicid, cefmetazole, cefotiam,
cefprozil, and cefotetan. These drugs have better efficacy against
gram-negative bacteria.
·
Third
generation cephalosporines—cefotaxime, cefpo-doxime proxetil, ceftizoxime, ceftriaxone,
cefopera-zone, cefdinir, cefditoren, cefixime, ceftibuten, and ceftazidime.
These drugs are highly active against the Enterobacteriaceae
(includingb-lactamase
producingstrains), but are less effective against gram-positive cocci as
compared to the first generation cephalosporines.
·
Fourth generation cephalosporines—cefepime is theprominent example of
this group, which is very useful in the treatment of infections due to aerobic
gram-negative bacilli resistant to third generation cephalosporines.
·
Oxacephalosporines—flomoxef, latamoxef.
The following cephalosporines are
well absorbed orally: cephalexin, cefaclor, cefadroxil, loracarbef, cefprozil,
cefixime, cefpodoxime proxetil, ceftibuten, and cefuroxime axetil. The
remaining cephalosporines are administered intramuscularly or intravenously.
Excretion is mainly renal. Many
cephalosporines are concentrated in the bile and can also penetrate into CSF
easily.
Cephalosporines
inhibit bacterial cell wall synthesis in the same way as penicillins (vide supra).
·
The most important adverse effects arise out of hypersen-
sitivity in the same manner as penicillins. The similarity is because of the
shared beta-lactam structure of the two groups of antibiotics, which also
accounts for the cross- reactivity that is not uncommonly observed.
Manifestations of allergy include skin rashes, bronchospasm, fever, and
anaphylaxis. However, the incidence of anaphylactic reactions to
cephalosporines is said to be less than 0.02%, (0.04% in those patients with
previous penicillin allergy).
·
Seizures have been reported following therapeutic admin-
istration.
·
Vomiting, diarrhoea and pancreatitis may occur.
·
Pseudocholelithiasis may follow intravenous administration
of ceftriaxone.
·
A disulfiram-like reaction can develop following the use of
cefoperazone, moxalactam, cefotetan, or cefamandole followed by ethanol
ingestion.
·
Blurred vision, deviation of the eyes, rapid eye movements,
and bilateral mydriasis have been reported in patients who developed CNS
toxicity (seizures, encephalopathy) following parenteral administration of
cefazolin and ceftazidime.
·
Rare effects reported with cephalosporin administration
include renal failure, interstitial nephritis, nephrolithiasis and
crystalluria.
·
Coagulopathies may occur following IV moxalactam, cefazolin,
cefoperazone, cefmetazole and cefamandole.
·
Leukopenia, thrombocytopenia, anaemia, and agranulocy- tosis
may occur following cephalosporin therapy.
·
Skin rashes may occur with cephalosporin administration.
·
Stevens-Johnson syndrome has been reported withcephalexin
ingestion, and toxic epidermal necrolysis occurred following cefazolin
administration.
·
Acute overdose produces manifestations similar to those seen
with penicillin, including the possibility of convul-sions. Treatment is
supportive.
·
Cephalosporines containing an n-methylthiotetrazole (nMTT) side chain, such as cefamandole,
cefazolin, cefmetazole, cefotetan, cefperazone, and moxalactam, can dissociate
in the body after administration and release free nMTT which results in acute
toxicity. Further, nMTT inhibits the enzyme aldehyde dehydrogenase (in the same
manner as disulfiram), and in conjunction with alcohol can cause a
disulfiram-like reaction. It is also postulated that the nMTT side chain is
responsible for producing hypopro-thrombinaemia, since it depletes vitamin
K-dependant clot-ting factors by inhibition of vitamin K epoxide reductase. If
this occurs, fresh frozen plasma and vitamin K1 should be
administered.
·
Chronic effects of cephalosporine therapy include serum
sickness, interstitial nephritis, hepatitis, and immune-mediated haemolytic
crisis.
·
Urinalysis should be monitored following very large doses of
cephalosporines, or when such drugs are used in large doses for prolonged
periods of time.
·
Activated charcoal may be indicated in patients with under-lying
renal insufficiency, following an extremely large over-dose (greater than 15
times the usual single therapeutic dose).
·
Treament of allergic reactions in the usual manner.
·
The coagulopathies associated with intravenous
cephalo-sporine therapy can be corrected with the administration of exogenous
vitamin K and fresh frozen plasma.
·
Supportive measures.
·
In severe overdosage where increased absorption may have
occurred and there exists severe renal impairment, dialysis may be considered.
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