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.