18.01.3.1 β-Lactams

Probably, the best known examples of antibiotics are the penicillins.  The penicillins are from the β-lactams group of inhibitors of bacterial cell wall synthesis.  The β-lactams are a group of chemically related agents that also includes the cephalosporins and the carbapenams. All of the β-lactams inhibit the synthesis of the bacterial cell wall.  In particular, the β-lactams inhibit enzymes (transpeptidases) involved in cross-linking the peptidoglycans.Their action weakens the cell wall so that the bacteria lyses (ruptures).  The β-lactams are bactericidal, which means they kill susceptible bacteria.  Unfortunately, resistance to the β-lactams has developed.  This resistance is due to induction of β-lactamases in microbials, and these β-lactamases can breakdown some β-lactams, which makes them ineffective. The spectrum of activity of the different β-lactams is determined by the transpeptidase enzymes they target and their susceptibility to breakdown by the β-lactamases. 

Penicillins are considered the drugs of choice for many infections.  The first penicillins were the naturally occurring penicillins such as benzylpenicillin (also known as penicillin G).  Benzylpenicillin is bactericidal and has a narrow spectrum of activity.  Benzylpenicillin is more effective against Gram-positive than Gram-negative microbials.  The main disadvantage of benzylpenicillin is that it is destroyed by the acid in the stomach, and cannot be used orally.  Benzylpenicillin is used intravenously or intramuscularly in serious infections.  For instance, benzylpenicillin is used to treat bacterial endocarditis (which is inflammation of inner heart with streptococci), meningitis, pneumonia, and syphilis.

Further development of the penicillins was undertaken to provide an orally active compound.  An example of an orally active penicillin is amoxycillin.  Amoxycillin is semisynthetic and has a moderate spectrum of activity.  However, amoxycillin is broken down by β-lactamases.  Thus, microbials that have induction of β-lactamases, are not susceptible to amoxicillin. 

One way to overcome this is to use amoxycillin in combination with the irreversible β-lactamase inhibitor clavulanic acid.  The clavulanic acid inhibits the β-lactamase, so that the β-lactamase cannot destroy the amoxycillin, and amoxycillin remains available to inhibit the synthesis of the bacterial cell wall.  Clavulanic acid therefore increases the spectrum of activity of amoxycillin.  The combination of amoxycillin and clavulanic acid is known as co-amoxiclav. 

Amoxycillin alone is used orally or intravenously in the treatment of a number of bacterial infections including chronic bronchitis, pneumonia, ear infections, sinusitis and gonococcal infection (“the clap”). Amoxycillin in combination with clavulanic acid is used in ear and sinus infections unresponsive to amoxycillin alone i.e. when the amoxycillin is broken down by the β-lactamases.  The combination treatment is also used orally in severe pneumonia, and epididymo-orchitis (infection of epididymis/testis).

Another approach when microbes have developed resistance to amoxycillin is to use a penicillin that is resistant to β-lactamases.  Flucloxacillin is not susceptible to β-lactamases, and this is a major advantage over amoxycillin.  Flucloxacillin is active against the β-lactamase producing Staphylcocci responsible for a number of skin infections (e.g. boils, carbuncles, mastitis, and infected scabies) and are used in the treatment of these infections.  However, a disadvantage of flucloxacillin is that it is narrow spectrum, and is only effective against a small spectrum of microbes.  Flucloxacillin is also used in the treatment, of infections in bones and joints.

One problem with the penicillins is that 10% of people are allergic to penicillins.  As penicillin allergy can be very severe on a second exposure, this should be avoided.  People who are allergic to penicillin have to take alternative antibiotics.

The second group of β-lactams are the cephalosporins.  The cephalosporins are broad spectrum and bacteriocidal.  Like the penicillins, the cephalosporins weaken the bacterial cell wall. However, the cephalosporins are rarely first choice antibiotic therapy as they commonly cause gastrointestinal adverse effects.  They are often used to treat infections in patients allergic to penicillins.

Cephalexin was one of the first cephalosporins synthesised, and is known as a first generation cephalosporin.  Cephalexin is one of the few cephalosporins active after oral administration.  Cephalexin is a moderate spectrum antibacterial and is more effective against Gram-positive than Gram-negative bacteria, Despite this, cephalexin is used to treat infections of the urinary tract caused by Gram-negative bacteria.  The main use of cephalexin is in the treatment of Straphylococcal and Streptococcal infections in subjects allergic to penicillin.

From the structure of the first generation of cephalosporins, such as cephalexin, the scientists tried to change the structure to improve effectiveness against Gram-negative bacteria.  An example of a second generation cephalosporin is cefuroxime.  Cefuroxime is active after oral or intravenous administration.  Cefuroxime is a very important antibiotic as it is more effective against Gram-negative than Gram-positive bacteria, which provides us with an antibiotic that can be used in serious Gram-negative bacterial infections including those caused by Haemophillus influenza (e.g. hospital and community acquired pneumonia), meningitis and septicaemia.

Further cephalosporins were developed to exploit this ability to inhibit Gram-negative bacteria.  An example of a third generation cephalosporin is cefotaxime.  Cefotaxime is not active after oral administration, which is a disadvantage.  It is used intravenously.  Like cefuroxime, cefotaxime is more effective against Gram-negative than Gram-positive bacteria.  Cefotaxime is used intravenously in the treatment of severe infections such as pneumonia, orbital cellulitis (eye infection), bacterial meningitis and septicaemia.

An example of fourth generation cephalosporin is cefepime. It has the greatest action against Gram-negative bacteria and minimal action against Gram-positive bacteria among all the four generations of cephalosporins. It is used intravenously or intramuscularly in the treatment of Pseudomonas aeruginosa infections and in the empirical treatment of sepsis in neutropenic or immunosuppressed people.

Other b-lactams antibacterials have been developed to be resistant to breakdown by the b-lactamases.  These are the carbapenams and monobactams.  The carbapenams are considered to have the broadest spectrum of all antibacterials.  Imipenem is a carbapenams and is effective against Gram-positive and Gram-negative organisms.  It was originally resistant to all β-lactamases, which made it a very effective antibiotic.  However, this resistance has not lasted, and new β-lactamases have been induced by the bacteria to breakdown imipenem and reduce its effectiveness.  Imipenem is used in the treatment of life-threatening infections, particularly hospital-acquired infections, when other antibacterials are not considered appropriate.

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