Chapter 13 - أں-Lactam antibiotics: cephalosporins than against penicillins, but cephamycins and...

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Transcript of Chapter 13 - أں-Lactam antibiotics: cephalosporins than against penicillins, but cephamycins and...

  • Chapter

    13 David Greenwood

    β-Lactam antibiotics: cephalosporins

    All cephalosporins are based on cephalosporin C, which was discov- ered by Edward Abraham and his colleagues in Oxford as a minor component of the antibiotic complex produced by Cephalosporium acremonium, a mold cultivated from a Sardinian sewage outfall by Giuseppe Brotzu in 1948. Interest in cephalosporin C was fuelled by its stability to staphylococcal β-lactamase (shared by all subse- quent cephalosporins), which was causing concern at the time, and they probably owe their continued development to this property. Over 100 semisynthetic cephalosporins have since been marketed, although not all have survived into present-day use.

    In all cephalosporins the β-lactam ring is fused to a six-membered dihydrothiazine ring in place of the five-membered thiazolidine ring of penicillins (see pp. 226–227). The basic 7-aminocephalosporanic acid skeleton can be modified at a number of positions. • Alterations at the C-3 position tend to affect the pharmacokinetic

    and metabolic properties. • Introduction of a methoxy group at C-7 yields a cephamycin

    with enhanced stability to β-lactamases, including the cephalosporinases of certain Bacteroides spp.

    • Changes at the 7-amino position alter, in general, the antibacterial activity or β-lactamase stability or both.

    Other compounds conveniently considered alongside the cepha- losporins, since their properties are very similar, include: • the oxacephems, in which the sulfur of the dihydrothiazine ring

    is replaced by oxygen • the carbacephems, in which the sulfur is replaced by carbon.


    As new cephalosporins have become available they have been loosely classified into ‘generations’, but these descriptions are too simplistic, and are to be discouraged. The following grouping is adopted here:

    • Group 1: Parenteral compounds of moderate antimicrobial activity and susceptible to hydrolysis by a wide variety of enterobacterial β-lactamases.

    • Group 2: Oral compounds of moderate antimicrobial activity and moderately resistant to some enterobacterial β-lactamases.

    • Group 3: Parenteral compounds of moderate antimicrobial activity resistant to a wide range of β-lactamases. Some are available as esters for oral administration.

    • Group 4: Parenteral compounds with potent antimicrobial activity and resistance to a wide range of β-lactamases.

    • Group 5: Oral compounds (often achieved by esterification) resistant to a wide range of β-lactamases. Most exhibit potent activity against enterobacteria; activity against Gram-positive cocci is variable.

    • Group 6: Parenteral compounds with activity against Pseudomonas aeruginosa. They vary widely in their spectrum of activity against other bacterial species.

    • Group 7: Compounds characterized by activity against methicillin-resistant staphylococci.

    Although the ‘generation’ categories often used are impre- cise, ‘first-generation’ compounds roughly correspond to Groups 1 and 2; ‘second-generation’ to group 3; ‘third- generation’ to groups 4–6. Certain group 6 and 7 com- pounds are sometimes allocated to so-called ‘fourth and fifth generations’.

    Some cephalosporins, including cefalonium and cefaloram (group 1) and cefquinone and ceftiofur (group 4) are used only in veterinary medicine and are not discussed further here.

  • pharmacokinetics 171

    Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 Group 7

    Cefacetrile Cefaclor Cefbuperazone* Cefmenoxime Cefcapene Cefepime Ceftaroline

    Cefaloridine Cefadroxil Cefmetazole* Cefodizime Cefdinir Cefoperazone Ceftobiprole

    Cefalotin Cefalexin Cefminox* Cefotaxime Cefditoren Cefozopran

    Cefamandole Cefatrizine Cefotetan* Ceftizoxime Cefetamet Cefpimizole

    Cefapirin Cefprozil Cefotiam Ceftriaxone Cefixime Cefpiramide

    Cefazolin Cefradine Cefoxitin* Flomoxef† Cefpodoxime Cefpirome

    Cefonicid Cefroxadine Cefuroxime Latamoxef† Cefteram Cefsulodin

    Ceforanide Loracarbef‡ Ceftibuten Ceftazidime

    *7-Methoxycephalosporin (cephamycin). †7-Methoxyoxacephem. ‡1-Carbacephem.


    Most cephalosporins are active against staphylococci other than methicillin-resistant strains, including those producing β-lactamase. The degree of activity varies among different members of the group. Streptococci, including pneumococci, are susceptible but Enterococcus faecalis, Ent. faecium and L. monocytogenes are virtually completely resistant. Streptococcus pneumoniae strains with reduced susceptibility to penicillins are also less susceptible to the cephalosporins. Many Gram- negative species including neisseriae, Haemophilus influenzae, Escherichia coli, salmonellae, some klebsiellae and Proteus mira- bilis are sensitive to varying degrees. Inoculum-related effects are common, particularly when compounds of groups 1 and 2 are tested against Gram-negative bacilli. Ps. aeruginosa is sen- sitive only to group 6 compounds. Except for cephamycins, activity against many anaerobes is unreliable. Mycobacteria, mycoplasmas, chlamydiae and fungi are resistant.

    Cephalosporins are usually bactericidal at concentrations above the minimum inhibitory concentration (MIC) and bac- tericidal synergy is commonly demonstrable with aminogly- cosides and a number of other agents.


    The most important form of resistance is that due to the elab- oration of β-lactamases (pp. 228–231). All cephalosporins are relatively stable to staphylococcal β-lactamase, but resis- tance among Gram-negative genera is a good deal more com- plicated. The chromosomal β-lactamase of Esch. coli, which has virtually no hydrolytic activity against ampicillin, slowly degrades some group 1 cephalosporins and is responsible for the inoculum effect observed with Esch. coli. Chromosomal β-lactamases of Bacteroides fragilis are also more active against cephalosporins than against penicillins, but cephamycins and

    oxacephems are unusual in their stability to these enzymes. Cephalosporins exhibit considerable variation in stability to the enzymes of genera with an inducible, or derepressible, chromosomal β-lactamase and to plasmid-mediated enzymes of Gram-negative bacilli (pp. 230–231).

    The resistance of Gram-negative bacilli does not depend solely on β-lactamase formation. It varies also with the extent to which the antibiotic can penetrate the outer cell membrane and reach the site of enzyme formation. This property, known as crypticity, can be measured by comparing the enzyme activ- ity of intact and disrupted cells. Resistance may also result from a change in the biochemical target of the antibiotic (i.e. the penicillin-binding proteins).


    Group 2 agents are well absorbed, with bioavailability often exceeding 85%. The bioavailability of some of the agents in other groups is enhanced by prodrug formulation. These agents tend to have improved absorption following food, whereas food has little or a deleterious effect on the absorp- tion of group 2 compounds.

    Cephalosporins are usually well distributed, achieving high concentrations in the interstitial fluid of tissues and in serous cavities. Penetration into the eye and the cerebrospinal fluid (CSF) is poor, though some cephalosporins achieve adequate levels in the CSF in the presence of meningeal inflammation. They cross the placenta.

    Compounds that carry an acetoxymethyl group at C-3, such as cefalotin and cefotaxime, are susceptible to mamma- lian esterases that remove the acetyl group to form the corre- sponding hydroxymethyl derivative with reduced antibacterial activity. The relevance (if any) of deacetylation to therapy has not been established.

    Cephalosporins are generally excreted into urine by glomer- ular filtration and tubular secretion; elimination is depressed by

  • 172 chapter 13 β-Lactam antibiotics: cephaLosporins

    probenecid and renal failure. Most are rapidly eliminated with plasma half-lives of 1–2 h but some are more persistent. The less active metabolites resulting from removal of acetoxymethyl groups at C-3 are also excreted in the urine. Some excretion is via the bile, and certain compounds, notably cefoperazone and cefpiramide, are preferentially excreted by this route.



    Hypersensitivity occurs in 0.5–10% of patients, mostly in the form of rashes, eosinophilia, drug fever and serum sickness. In addition to immediate reactions, a maculopapular rash with or without fever, lymphadenopathy and eosinophilia may appear after several days’ treatment. As with penicillins, allergy to cephalosporins is probably based on major and minor anti- genic determinants, but they are less well characterized than with penicillins. Clinical reactions to cephalosporins in peni- cillin-allergic patients are uncommon and severe reactions are very rare. About 10% of such reactions are said to occur, gen- erally in patients who react to a variety of drugs. Nonetheless, the generally accepted advice is that cephalosporins should not be given to patients who have previously suffered a well- documented severe reaction to penicillins. Specific allergy to cephalosporins also occurs, but there is no evidence that the compounds differ markedly in allergenicity.


    Rare reversible abnormalities of platelet function and coagu- lation resulting from several different mechanisms have been described. Thrombocytopenia and neutropenia are occasion