Cephalosporin

HI Inlluenzae type b produces J3 lactamases and therefore are resistant to ampicillin. These 3 lactamase producing strains remain sensitive to the extended spectrum cephalosporins
• Ceftriaxone or cefotaxime IV are used as a single agents
• Infections caused by ampicillin – resistant strains can be treated with
1. Trimethoprim – sulfamethoxazole
2. Amoxicillin I clavulanic acid
3. Extended spectrum cephalosporins
4. Azithromycin and clarithromycin
• F’loraquin lones are highly active against H. influenzae but are not currently recommended for the treatment of children or pregnailt women because of possible effects on articular cartilage

Cefuroxime REF: Goodman and Gillman 11th edition page 746-747, KDT 5^TH edition page 663

See APPENDIX-36 for classification of “Cephalosporins”

Cefoxitine has got no activity against anaerobes[Ref: KM’ W^hIe p.703-710]

Caphalosporins

Antibacterial activity of cephalosporins

First generation cephalosporins : –

• These are active against gram positive cocci including staphylococci.

Second generation cephalosporins : ?

• More active against gram negative organism, Also has some activity against gram positive organisms.
• Some members also have activity against anaerobes e.g., cefotetan, Cefnzetazole and cefoxitin.
• Among the second generation cephalosporins, cefuroxime attains higher C.S.F. concentration.

Third generation cephalosporins : –

• Have highly augumented activity against gram negative enterobacteriacea.
• Less active against gram (+ve) cocci and anaerobes.
• Highly resistant to [3 lactamases from negative bacteria.
• Some third generation cephalosporins have antipseudomonal activity : – e.g., Ceftazidime and cefoperazone.
• Ceftazidime + aminoglycoside is the treatment of choice for pseudomonas infections.

Fourth generation cephalosporins : ?

• These drug possess activity against gram negative organisms (including pseudomonas) resistant to 3rd generation cephalosporins.
• Their efficacy against gram positive cocci is similar to 3rd generation compounds but an important point to remember is that they are not active against anaerobes.

General features of Cephalosporins :- (Some important points to remember)

• Cephalosporin like other lactam antibiotics exert their action by inhibiting cell wall synthesis.
• Cephalosporins are excreted primarily by the kidney therefore they require dose reduction in renal failure.
• Probenecid slows the tubular secretion of most of the cephalosporins. Cefpiranzide, ceftriaxone and cefperazone are exceptions because they are excreted predominantly in the bile.
• Cefotaxime is deacetylated in vivo. The metabolite has less antimicrobial activity than the parent compound and is excreted by the kidneys. None qf the other cephalosporins appears to undergo appreciable metabolism.
• Several cephalosporins penetrate into C.S.F. in sufficient concentrations to be useful for the treatment of meningitis.

These include: ?

• Cefotaxime
• Ceftriaxone
• Cefepime
• Cephalosporins also cross the placenta and they are found in high concentrations in synovial and pericardial fluids.
• Penetration into the aqueous humour of the eye is relatively good after systemic administration of the third generation agents but penetration into the vitreous humour is poor.
• No cephalosporins is active against enterococcus fecalis, MRSA and listeria monocytogens.
• Concentrations in bile usually are high with those achieved after administration of cefoperazone and cefpiranzide being the highest.

Adverse reactions

• Most common side effect of cephalosporin is hypersensitivity reaction. Immediate reactions such as anaphylaxis, bronchosposam and urticaria are observed.
• Cephalosporins have been implicated as potentially nephrotoxic agents (cephaloridine is considered the most nephrotoxic cephalosporin. It is no longer available in the united states). Cephalothin is another cephalosporin that produces renal toxicity, it causes acute tubular necrosis.
• Cephalosporins cause disulfiram like reaction (e.g., cefamandole, cefotetan, cefoperazone). These are caused by drugs which have rnethylthiotetrazole group.
• Cephalosporins have been associated with diarrhoea (is more frequent with cefoperazone because of its greater biliary excretion).

Cefoperazone [Ref: Goodman Gilman 17thie 1147, 1148; Katzung 10                                           p. 7371

Remember: ?

• Most cephalosporins are excreted mainly by tubular secretion.
• But ceftriaxone and cefoperazone are excreted mainly in bile and no dose adjustment is required in renal insufficiecy.
• The other unique feature of cefriaxone is its long half life.
• Thus it can be injected O.D. or B.D. in serious infections.

According to Goodman and Gilman

“All cephalosporins are excreted through kidney except celPiramide and cefoperazone which are excreted predominantly in the bile”.

About ceftriaxone Goodman Gilman mentions.

“50% of this drug is excreted through urine while 50% of it is excreted through bile”.

But Katzung differs from Goodman Gilman

“All cephalosporins are excreted through kidney except _.for cefoperazone and ceftriaxone which are excreted mainly through the bilian’ tract”.

Cefoperazone does not require dose adjustment when used in a patient with reduced GFR, as this drug is primarily excreted through the bile.

Ref: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th Edition, Page 1210; Essentials of Medical Pharmacology By K D Tripathi, 5th Edition, Pages 664-6; KDT 6th Edition, Page 706

Except option Cefipime all the rest are 3rd generation cephalosporin.

Fourth generation cephalosporins are extended spectrum agents with similar activity against gram-positive organisms as first generation cephalosporins.

They also have a greater resistance to beta-lactamases than the third generation cephalosporins.

• Cefepime
• Cefluprenam
• Cefozopran
• Cefpirome
• Cefquinome

If isolate is resisatnt to ampicillin, extended spectrum cephalosporins such as cefotaxime or ceftriaxone are used.

Ref: Harrison’s Principles of Internal Medicine, 17th Edition, Page 923 ; Text Book of Pediatrics By Nelson, 17th Edition, Pages 2042, 7905

Ans. is ‘d’ i.e., Cephalosporin 

Treatment of meningococcal infection

• A third generation cephalosporin, such as ceftriaxone or ceftazidime is DOC for the treatment of meningococcal infections.
• In penicillin allergic patients chloramphenicol is DOC.
• Rifampicin is DOC for chemoprophylaxis. Alternative drugs are :
• Ciprofloxacin                          • Ceftriaxone
• Ofloxacin                               • Azithromycin

Ans. is ‘d’ i.e., Cephalosporins 

.  Ureoplasma ureolyticum (a mycoplasma) lacks cell wall. Their lack of cell wall is associated with resistance to cell-wall active antimicrobial agents, such as penicillins and cephalosporins ((3-lactam drugs).

Ans. is ‘b’ i.e., Carbapenems; ‘c’ i.e., Cephalosporins

Allergic reaction to penicillin

o The main hazard with the penicillin is allergic reactions.

o These include itching, rashes (eczematous or urticaria), fever and angioedema.

o Anaphylactic shock can occur though rarely (1 in 10,000).

o Allergies are least when penicillins are given orally and most likely with local application.

o Penicillin G is the most common drug implicated in drug allergy —› Procaine penicillin preparation of PnG has the highest incidence (procaine is itself allergic).

o There is cross-allergy between all the various forms of penicillin, probably due to in part to their common structure, and in part to the degradation products common to them all.

o There is partial cross-allergy between penicillins and cephalosporins (5-10%).

         Carbapenems also have some cross-allergy with penicillins, but less than cephalosporins.

o Monobactoms (aztreonam) do not have cross reactivity.

o So, Pt with penicillin ‘G’ allergy should not receive any penicillin, cephalosporins and carbapenems (Imipenem. meropenem). Monobactams (Aztreonam) are safe

“Order of cross reactivity with penicillin G :- Other penicillins (maximum) > Cephalosporins > Carbapenems

> Monobactams (no cross reactivity)”.

Ans. is ‘a’ i.e., Cephalosporins-III generation

ESBL are lactamases that mediate resistance (by hydrolyzing) to extended spectrum (third generation) cephalosporins, penicillins and monobactams (e.g. aztreonam).

Ans. is ‘c’ i.e., Cefepime

o Cefepime and cefepirome aree generation cephalosporins.

Ans. is ‘c’ i.e., Cefpirome

Ans. is ‘d’ i.e., Cefuroxime

o Cefuroxime is 2^nd generation cephalosporin.

Ans. is ‘b’ i.e., Active against olny gram negative bacteria

Cephalosporins are active against gram positive as well as gram negative bacteria, and are bactericidal.

o Ceftriaxone is a parentral cephalosporin.

o Third generation cephalosporins are highly resistant to beta-lactamases from gram negative bacteria.

Ans. is ‘c’ i.e., Cefoxitin has got no activity against anaerobes

Ans. is ‘b’ i.e., Cefamendole

o Disulfiram like reaction – cefamandole, cefoperazone, moxalactam and cefotetan can cause disulfiram like reaction with alcohol.

Ans. is ‘b’ i.e., Cefoperazone

o Cefoperazone is primarily exreted in bile in contrast to other cephalosporins that are usually excreted by the kidney –> safe in renal failure.

o Cephalosporins that can be used in presence of renal failure :- i) Cefoperozone, ii) Ceftriaxone, iii) Cefoperamide

Ans. is ‘a’ i.e., Cephadroxil

o Cephalosporins with antipseudomonal activity :- Ceftazidime, Cefoperazone, Cefepime

Ans. is ‘c’ i.e., Third generation cephalosporins

DOC for H. influenzae meningitis Cs –> Third generation cephalosporin.

Ans. A i.e. Cephadroxil

Ans. is ‘b’ i.e., Ceftazidime

Adverse effects of cephalosporins

• Hypersensitivity reaction – It is the most usual side effect. There is cross allergy between penicillins and cephalosporine in 5-10% of cases.
• Diarrhea – due to alteration of gut flora, maximum with oral cephradine and parentral cefperazone (cefperazone is significantly excreted in bile) → May cause pseudomembranous colitis caused by Cl. difficle.
• Superinfection – Most common organisms are candida and pseudomonas, less common are staphylococci, proteus.
• Ceftriaxone achieves high concentration in bile and, as the calcium salt, may precipitate to cause symptoms resembling cholelithiasis (Biliary pseudolithiasis).
• Nephrotoxicity – highest with cephaloridine.
• Bleeding – ceftriaxone, cefoperazone, moxalactam & cefamandole can cause hypoprothrmbinemia and bleeding.
• Disulfiram like reaction – cefamandole, cefoperazone, moxalactam and cefotetan can cause disulfiram like reaction with alcohol.
• Neutropenia and thrombocytopenia can be caused by ceftazidim.

Ans. is ‘a’ i.e., Cephadroxil

Cephalosporins with antipseudomonal activity :- Ceftazidime, Cefoperazone, Cefepime

H.Influenzae type.B produces J3 lactamases and therefore are resistant to ampicillin. These 3 lactamase producing strains remain sensitive to the extended-spectrum cephalosporins 

• Ceftriaxone or cefotaxime IV are used as single agents 

• Infections caused by ampicillin-resistant strains can be treated with 

1. Trimethoprim-sulfamethoxazole 

2. Amoxicillin I clavulanic acid 

3. Extended-spectrum cephalosporins 

4. Azithromycin and clarithromycin 

• Fluoroquinolones are highly active against H. influenzae but are not currently recommended for the treatment of children or pregnant women because of possible effects on articular cartilage

Ans. b. Ceftobiprole

Ans. is ‘b’ i.e., Gram positive bacteria 

Ans. is ‘b’ i.e., Cefoperazone

Drugs acting against Pseudomonas.

• Penicillins – Piperacillin, Carbenicillin, Ticarcillin, Mezlocillin.
• Cephalosporins – Ceftazidime, Cefoperazone, Cefepime.
• Carbapenems – Imipenem, meropenem
• Monobactams – Aztreonam.
• Aminoglycosides – Tobramycin, Gentamycin, Amikacin.
• Fluroquinolones – Ciprofloxacin, Levofloxacin, Norfloxacin.. 
• Other – Polymixin B, Colistin.