Cephalosporins

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Chapter: Essential pharmacology : Betalactam Antibiotics

These are a group of semisynthetic antibiotics derived from ‘cephalosporin-C’ obtained from a fungus Cephalosporium. They are chemically related to penicillins; the nucleus consists of a βlactam ring fused to a dihydrothiazine ring.


CEPHALOSPORINS

 

These are a group of semisynthetic antibiotics derived from ‘cephalosporin-C’ obtained from a fungus Cephalosporium. They are chemically related to penicillins; the nucleus consists of a βlactam ring fused to a dihydrothiazine ring, (7-aminocephalosporanic acid). By addition of different side chains at position 7 of βlactam ring (altering spectrum of activity) and at position 3 of dihydrothiazine ring (affecting pharmacokinetics), a large number of semisynthetic compounds have been produced. These have been conventionally divided into 4 generations. This division has a chronological sequence of development, but more importantly, takes into consideration the overall antibacterial spectrum as well as potency.

 


 

All cephalosporins are bactericidal and have the same mechanism of action as penicillin, i.e. inhibition of bacterial cell wall synthesis. However, they bind to different proteins than those which bind penicillins. This may explain differences in spectrum, potency and lack of cross resistance.

 

Acquired resistance to cephalosporins could have the same basis as for penicillins, i.e.:

 

a)         alteration in target proteins (PBPs) reducing affinity for the antibiotic.

b)        impermeability to the antibiotic or its efflux so that it does not reach its site of action.

c)         elaboration of βlactamases which destroy specific cephalosporins (cephalosporinases).

 

Though the incidence is low, resistance has been developed by some organisms, even against the third generation compounds. Individual cephalosporins differ in their:

 

a)      Antibacterial spectrum and relative potency against specific organisms.

b)      Susceptibility to βlactamases elaborated by different organisms.

c)       Pharmacokinetic properties—many have to be injected, some are oral; majority are not metabolized, and are excreted rapidly by the kidney; have short t½s, probenecid inhibits their tubular secretion.

d)      Local irritancy on i.m. injection; few cannot be injected i.m.

 

FIRST GENERATION CEPHALOSPORINS

 

These were developed in the 1960s, have high activity against gram-positive but weaker against gram-negative bacteria.

 

Cefazolin

 

This prototype first generation cephalosporin is active against most PnG sensitive organisms, i.e. Streptococci (pyogenes as well as viridans), gonococci, meningococci, C. diphtheriae, H. influenzae, clostridia and Actinomyces. Activity against Klebsiella and E. coli is relatively high, but it is quite susceptible to staphylococcal βlactamase. It can be given i.m. (less painful) as well as i.v. and has a longer t½ (2 hours) due to slower tubular secretion; attains higher concentration in plasma and in bile. It is the preferred parenteral first generation cephalosporin, especially for surgical prophylaxis.

 

Dose: 0.25 g 8 hourly (mild cases), 1 g 6 hourly (severe cases) i.m. or i.v.

 

ALCIZON, ORIZOLIN 0.25 g, 0.5 g, 1 g per vial inj.

 

Cephalexin

 

It is an orally effective first generation cephalosporin, similar in spectrum to cefazolin, but less active against penicillinase producing Staphylococci and H. influenzae. It is little bound to plasma proteins, attains high concentration in bile and is excreted unchanged in urine; t½ ~60 min. It is one of the most commonly used cephalosporins.

 

Dose: 0.25–1 g 6–8 hourly (children 25–100 mg/kg/day). CEPHACILLIN 250, 500 mg cap; SPORIDEX, ALCEPHIN, CEPHAXIN 250, 500 mg cap, 125 mg/5 ml dry syr., 100 mg/ml pediatric drops.

 

ALCEPHINLA: Cephalexin + probenecid (250 + 250 mg and 500 + 500 mg) tabs.

 

Cephradine

 

Another orally active drug, almost identical to cephalexin, but less active against some organisms. Oral administration has caused diarrhoea as side effect. It is available for parenteral use also.

 

Dose: 0.25–1 g 6–12 hourly oral/i.m/i.v.

 

CEFLAD 0.25, 0.5, 1 g per vial inj.

 

Cefadroxil

 

A close congener of cephalexin; has good tissue penetration—exerts more sustained action at the site of infection; can be given 12 hourly despite a t½ of 1 hr. It is excreted unchanged in urine, but dose need be reduced only if creatinine clearance is < 50 ml/min. The antibacterial activity of cefadroxil and indications are similar to those of cephalexin.

 

Dose: 0.5–1 g BD. DROXYL 0.5, 1 g tab, 250 mg/5 ml syr; CEFADROX 0.5 g cap, 125 mg/5 ml syr and 250 mg kid tab; KEFLOXIN 0.5 g cap, 0.25 g Distab, 125 mg/5 ml susp.

 

 

SECOND GENERATION CEPHALOSPORINS

 

These were developed subsequent to the first generation compounds and are more active against gram-negative organisms, with some members active against anaerobes, but none inhibits P. aeruginosa. Clinically, they have been largely replaced by the 3rd generation agents that are more active.

 

Cefuroxime

 

It is resistant to gram-negative βlactamases: has high activity against organisms producing these enzymes including PPNG and ampicillin-resistant H. influenzae, while retaining significant activity on gram-positive cocci and certain anaerobes. It is well tolerated by i.m. route and attains relatively higher CSF levels, but has been superseded by 3rd generation cephalosporins in the treatment of meningitis. It has been employed for single dose i.m. therapy of gonorrhoea due to PPNG.

 

CEFOGEN, SUPACEF, FUROXIL 250 mg and 750 mg/ vial inj; 0.75–1.5 g i.m. or i.v. 8 hourly, children 30–100 mg/kg/day.

 

Cefuroxime axetil

 

This ester of cefuroxime is effective orally, though absorption is incomplete. The activity depends on in vivo hydrolysis and release of cefuroxime.

 

Dose: 250–500 mg BD, children half dose; CEFTUM, SPIZEF 125, 250, 500 mg captab and 125 mg/5 ml susp.

 

Cefaclor

 

It retains significant activity by the oral route and is more active than the first generation compounds against H. influenzae, E. coli and Pr. mirabilis.

 

Dose: 0.25–1.0 g 8 hourly

 

KEFLOR, VERCEF, DISTACLOR 250 mg cap, 125 and 250 mg distab, 125 mg/5 ml dry syr, 50 mg/ml ped. drops.

 

THIRD GENERATION CEPHALOSPORINS

 

These compounds introduced in the 1980s have highly augmented activity against gram-negative Enterobacteriaceae; some inhibit Pseudomonas as well. All are highly resistant to βlactamases from gram-negative bacteria. However, they are less active on gram-positive cocci and anaerobes.

 

Cefotaxime

 

It is the prototype of the third generation cephalosporins; exerts potent action on aerobic gram-negative as well as some gram-positive bacteria, but is not active on anaerobes (particularly Bact. fragilis), Staph. aureus and Ps. aeruginosa. Prominent indications are meningitis caused by gram-negative bacilli (attains relatively high CSF levels), life-threatening resistant/ hospital-acquired infections, septicaemias and infections in immunocompromised patients. It is also utilized for single dose therapy (1 g i.m. + 1 g probenecid oral) of PPNG urethritis, but is not dependable for Pseudomonas infections.

 

Cefotaxime is deacetylated in the body; the metabolite exerts weaker but synergistic action with the parent drug. The plasma t½ of cefotaxime is 1 hr, but is longer for the deacetylated metabolite—permitting 12 hourly doses in many situations.

 

Dose: 1–2 g i.m./i.v. 8–12 hourly, children 50–100 mg/kg/day.

 

OMNATAX, ORITAXIM, CLAFORAN 0.25, 0.5, 1.0 g per vial inj.

 

Ceftizoxime

 

It is similar in antibacterial activity and indications to cefotaxime, but inhibits B. fragilis also. It is not metabolized—excreted by the kidney at a slower rate; t½ 1.5–2 hr.

 

Dose: 0.5–2.0 g i.m./i.v. 8 or 12 hourly.

 

CEFIZOX, EPOCELIN 0.5 and 1 g per vial inj.

 

Ceftriaxone

 

The distinguishing feature of this cephalosporin is its longer duration of action (t½ 8 hr), permitting once, or at the most twice daily dosing. Penetration into CSF is good and elimination occurs equally in urine and bile.

 

Ceftriaxone has shown high efficacy in a wide range of serious infections including bacterial meningitis (especially in children), multi-resistant typhoid fever, complicated urinary tract infections, abdominal sepsis and septicaemias. A single dose of 250 mg i.m. has proven curative in gonorrhoea including PPNG, and in chancroid.

 

Hypo-prothrombinaemia and bleeding are specific adverse effects. Haemolysis is reported.

 

OFRAMAX, MONOCEF, MONOTAX 0.25, 0.5, 1.0 g per vial inj.

 

For skin/soft tissue/urinary infections: 1–2 g i.v. or i.m./ day.

 

Meningitis: 4 g followed by 2 g i.v. (children 75–100 mg/ kg) once daily for 7–10 days.

 

Typhoid: 4 g i.v. daily × 2 days followed by 2 g/day (children 75 mg/kg) till 2 days after fever subsides.

 

Ceftazidime

 

The most prominent feature of this third generation cephalosporin is its high activity against Pseudomonas. It has been specifically used in febrile neutropenic patients with haematological malignancies, burn, etc. Its activity against Enterobacteriaceae is similar to that of cefotaxime, but it is less active on Staph. aureus, other gram positive cocci and anaerobes like Bact. fragilis. Its plasma t½ is 1.5–1.8 hr.

 

Neutropenia, thrombocytopenia, rise in plasma transaminases and blood urea have been reported.

 

Dose: 0.5–2 g i.m. or i.v. every 8 hr, children 30 mg/kg/ day. Resistant typhoid 30 mg/kg/day.

 

FORTUM, CEFAZID, ORZID 0.25, 0.5 and 1 g per vial inj.

 

Cefoperazone

 

Like ceftazidime, it differs from other third generation compounds in having stronger activity on Pseudomonas and weaker activity on other organisms. It is good for S. typhi and B. fragilis also, but more susceptible to βlactamases. The indications are—severe urinary, biliary, respiratory, skinsoft tissue infections, meningitis and septicaemias. It is primarily excreted in bile; t½ is 2 hr. It has hypoprothrombinaemic action but does not affect platelet function. A disulfiramlike reaction with alcohol has been reported.

 

Dose: 1–3 g i.m./i.v. 8–12 hourly.

 

MAGNAMYCIN 0.25 g, 1, 2 g inj; CEFOMYCIN, NEGAPLUS 1 g inj.

 

Cefixime

 

It is an orally active third generation cephalosporin highly active against Enterobacteriaceae, H. influenzae and is resistant to many βlactamases. However, it is not active on Staph. aureus, most pneumococci and Pseudomonas. It is longer acting (t½ 3 hr) and has been used in a dose of 200–400 mg BD for respiratory, urinary and biliary infections. Stool changes and diarrhoea are the most prominent side effects.

 

TOPCEF, ORFIX 100, 200 mg tab/cap, CEFSPAN 100 mg cap, 100 mg/5 ml syr.

 

Cefpodoxime Proxetil

 

It is the orally active ester prodrug of 3rd generation cephalosporin cefpodoxime. In addition to being highly active against Enterobacteriaceae and streptococci, it inhibits Staph. aureus. It is used mainly for respiratory, urinary, skin and soft tissue infections.

 

Dose: 200 mg BD (max 800 mg/day)

 

CEFOPROX 100, 200 mg tab, 100 mg/5 ml dry syr; CEPODEM 100, 200 mg tab, 50 mg/5 ml susp.

 

Cefdinir

 

This orally active 3rd generation cephalosporin has good activity against many β lactamase producing organisms. Most respiratory pathogens including gram-positive cocci are susceptible. Its indications are pneumonia, acute exacerbations of chronic bronchitis, ENT and skin infections.

 

Dose: 300 mg BD

 

SEFDIN, ADCEF 300 mg cap, 125 mg/5 ml susp.

 

Ceftibuten

 

Another oral 3rd generation cephalosporin, active against both gram-positive

and gram-negative bacteria, but not pneumococci and Staph. aureus and stable to βlactamases. It is indicated in respiratory, urinary and gastrointestinal infections; t½ 2–3 hours.

 

Dose: 200 mg BD or 400 mg OD.

 

PROCADAX 400 mg cap, 90 mg/5 ml powder for oral suspension.

 

Ceftamet Pivoxil

 

This ester prodrug of ceftamet, a 3rd generation cephalosporin has high activity against gram-negative bacteria, especially Enterobacteriaceae and N. gonorrhoea; used in respiratory, skinsoft tissue infections, etc.

 

Dose: 500 mg BD–TDS.

 

ALTAMET 250 tab; CEPIMEO 500 mg tab.

 

FOURTH GENERATION CEPHALOSPORINS

 

Cefepime

 

Developed in 1990s, this 4th generation cephalosporin has antibacterial spectrum similar to that of 3rd generation compounds, but is highly resistant to βlactamases, hence active against many bacteria resistant to the earlier drugs. Ps. aeruginosa and Staph. aureus are also inhibited. Due to high potency and extended spectrum, it is effective in many serious infections like hospital-acquired pneumonia, febrile neutropenia, bacteraemia, septicaemia, etc.

 

Dose: 1–2 g (50 mg/kg) i.v. 8–12 hourly.

 

KEFAGE, CEFICAD, CEPIME 0.5, 1.0 g inj.

 

Cefpirome

 

This 4th generation cephalosporin is indicated for the treatment of serious and resistant hospital-acquired infections including septicaemias, lower respiratory tract infections, etc. Its zwitterion character permits better penetration through porin channels of gram-negative bacteria. It is resistant to many βlactamases; inhibits type 1 β lactamase producing Enterobacteriaceae and it is more potent against gram-positive and some gram-negative bacteria than the 3rd generation compounds.

 

Dose: 1–2 g i.m./i.v. 12 hourly;

 

CEFROM, CEFORTH 1 g inj; BACIROM, CEFOR 0.25, 0.5, 1.0 g inj.

 

Adverse Effects

 

·      Pain after i.m. injection occurs with many. This is so severe with cephalothin as to interdict i.m. route, but many others can be injected i.m. (see individual compounds). Thrombophlebitis of injected vein can occur.

 

·       Diarrhoea due to alteration of gut ecology or irritative effect is more common with oral cephradine and parenteral cefoperazone (it is significantly excreted in bile).

 

·   Hypersensitivity Reactions caused by cephalosporins are similar to penicillin, but incidence is lower. Rashes are the most frequent manifestation, but anaphylaxis, angioedema, asthma and urticaria have also occurred. About 10% patients allergic to penicillin show cross reactivity with cephalosporins. Those with a history of immediate type of reactions to penicillin should better not be given a cephalosporin. Skin tests for sensitivity to cephalosporins are unreliable. A positive Coombs’ test occurs in many, but haemolysis is rare.

 

·      Nephrotoxicity is highest with cephaloridine, which consequently has been withdrawn. Cephalothin and a few others have lowgrade nephrotoxicity which may be accentuated by preexisting renal disease, concurrent administration of an aminoglycoside or loop diuretic.

 

·  Bleeding occurs with cephalosporins having a methyl-thiotetrazole or similar substitution at position 3 (cefoperazone, ceftriaxone). This is due to hypo-prothrombinaemia caused by the same mechanism as warfarin and is more common in patients with cancer, intraabdominal infection or renal failure.

 

·      Neutropenia and thrombocytopenia are rare adverse effects reported with ceftazidime and some others.

 

·      A disulfiramlike interaction with alcohol has been reported with cefoperazone.

 

Uses

 

Cephalosporins are now extensively used antibiotics. Their indications are:

·      As alternatives to PnG; particularly in allergic patients (but not who had anaphylactic reaction); one of the first generation compounds may be used.

 

·   Respiratory, urinary and soft tissue infections caused by gram-negative organisms, especially Klebsiella, Proteus, Enterobacter, Serratia. Cephalosporins preferred for these infections are cefuroxime, cefotaxime, ceftriaxone.

 

·       Penicillinase producing staphylococcal infections.

 

·     Septicaemias caused by gram-negative organisms: an aminoglycoside may be combined with a cephalosporin.

 

·        Surgical Prophylaxis: the first generation cephalosporins are popular drugs. Cefazolin (i.m. or i.v.) is employed for most types of surgeries including those with surgical prosthesis such as artificial heart valves, artificial joints, etc.

 

·      Meningitis: Optimal therapy of pyogenic meningitis requires bactericidal activity in the CSF, preferably with antibiotic concentrations several times higher than the MBC for the infecting organism. For empirical therapy before bacterial diagnosis, i.v. cefotaxime/ceftriaxone is generally combined with ampicillin or vancomycin. Ceftazidime + gentamicin is the most effective therapy for Pseudomonas meningitis.

 

·       Gonorrhoea caused by penicillinase producing organisms: ceftriaxone is a first choice drug for single dose therapy of gonorrhoea if the penicillinase producing status of the organism is not known. Cefuroxime and cefotaxime have also been used for this purpose. For chancroid also, a single dose is as effective as erythromycin given for 7 days.

 

·      Typhoid: Currently, ceftriaxone and cefoperazone injected i.v. are the fastest acting and most reliable drugs for enteric fever. They are an alternative to fluoroquinolones (especially in children) for empirical therapy, since many S. typhi strains are resistant to chloramphenicol, ampicillin and cotrimoxazole.

 

·   Mixed aerobicanaerobic infections in cancer patients, those undergoing colorectal surgery, obstetric complications: cefuroxime, cefaclor or one of the third generation compounds is used.

 

·  Hospital acquired infections resistant to commonly used antibiotics: cefotaxime, ceftizoxime or a fourth generation drug may work.

 

·      Prophylaxis and treatment of infections in neutropenic patients: ceftazidime or another third generation compound, alone or in combination with an aminoglycoside.

 

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