Penicillins antibiotics

The penicillins are beta-lactam antibiotics which treat bacterial infections, usually for Gram-positive organisms. They inhibit the formation of cross-links in the bacterial cell wall, weakening the wall and causing cell death when the bacterium tries to divide.

Resistance is usually a result of β-lactamases produced by bacteria, where the β-lactamase destroys the β-lactam ring.

Penicillins are poorly lipid soluble and therefore penetration into the cerebrospinal fluid is poor. The exception is when the meninges are inflamed, which is why penicillins are used in treating meningitis.

The penicillins each consist of a thiazolidine ring attached to a β-lactam ring that is itself modified by a variable side chain. Whereas the thiazolidine–β-lactam ring is required for antibacterial activity, the side chain has been manipulated to yield many penicillin derivatives that have altered pharmacologic properties and antibacterial spectra of activity.

As a result of modifi cations to the R side chain, penicillins come in several classes: the natural penicillins, the antistaphylococcal penicillins, the aminopenicillins, and the extended-spectrum penicillins. In addition, some of the penicillins have been combined with _-lactamase inhibitors, which markedly expand the number of bacterial species that are susceptible to these compounds. The members of each class share similar pharmacokinetic properties and spectra of activity but may be quite distinct from members of other classes.

NATURAL PENICILLINS

The natural penicillins, penicillin G and penicillin V, are the great grandparents of the penicillin antibiotic family but still have much to say about the treatment of antibacterial infections. They are called natural penicillins because they can be purified directly from cultures of Penicillium mold.

Since nearly all bacteria have cell walls composed of peptidoglycan, it is not surprising that the natural penicillins are active against some species of gram- positive, gram-negative, and anaerobic bacteria, as well as some spirochetes. Despite this broad range of activity, most bacteria are either intrinsically resistant or have now acquired resistance to the natural penicillins. Understanding the reasons for this can help one remember which species remain susceptible. In turn, the bacterial spectra of the natural penicillins can be used as a foundation for remembering the spectra of the other classes of penicillins.

Mechanism of Resistance

The six Ps explain resistance to the natural penicillins:

Penetration—natural penicillins, like most β-lactams, penetrate poorly into the intracellular compartment of human cells, so bacteria that for the most part reside in this compartment, such as Rickettsia and Legionella, are protected from them.

Porins—Some gram-negative bacteria, such as E. coli, Proteus mirabilis, Salmonella enterica, and Shigella spp., have porins in their outer membranes that do not allow passage of the hydrophobic natural penicillins to the periplasmic space.

Pumps—some gram-negative bacteria, such as P. aeruginosa, have effl ux pumps that prevent the accumulation of penicillins within the periplasm. Although these pumps by themselves may only cause a marginal change in susceptibility, they can work together with penicillinases and porins to have a dramatic effect.

Penicillinases—many bacteria, both gram-positive (staphylococci) and gram-negative (some Neisseria and Haemophilus strains, many of the enteric species, and some anaerobes, such as Bacteroides fragilis), make penicillinases that degrade the natural penicillins.

PBPs—some bacteria produce PBPs that do not bind natural penicillins with a high affi nity (e.g., some strains of Streptococcus pneumoniae).

Peptidoglycan—some bacteria, such as Mycoplasma and Chlamydia spp., do not make peptidoglycan and therefore are not affected bythe natural penicillins.

ANTISTAPHYLOCOCCAL PENICILLINS

The antistaphylococcal penicillins (also called the “penicillinase-resistant penicillins”) have bulky residues on their variable side chains that prevent binding by the staphylococcal β-lactamases. As a result, these penicillins are useful in treating infections caused by S. aureus and Staphylococcus epidermidis. However, they are unable to bind the PBPs of two special groups of staphylococci called methicillin- resistant S. aureus (MRSA) and methicillin-resistant S. epidermidis (MRSE).

AMINOPENICILLINS

The aminopenicillins, ampicillin and amoxicillin, have spectra of activity similar to the natural penicillins with one exception: An additional amino group in their side chain increases their hydrophilicity and allows them to pass through the porins in the outer membranes of some enteric gram-negative rods, such E. coli, P. mirabilis, S. enterica, and Shigella spp. This extends the spectra of the aminopenicillins to include these bacteria. Aminopenicillins, however, share the natural penicillins’ vulnerability to β-lactamases, and many of the gram-negative bacteria that were initially susceptible to the aminopenicillins are now resistant due to the acquisition of β-lactamase encoding genes.

Antimicrobial Activity of Aminopenicillins

Gram-positive bacteria:

Streptococcus pyogenes
Viridans streptococci
Some Streptococcus pneumoniae
Some enterococci
Listeria monocytogenes

Gram-negative bacteria

Neisseria meningitidis
Some Haemophilus infl uenzae
Some Enterobacteriaceae

Anaerobic bacteria

Clostridia spp. (except C. diffi cile)
Actinomyces israelii

Spirochetes

Borrelia burgdorferi

AMINOPENICILLIN/β-LACTAMASE INHIBITOR COMBINATIONS

Compounds have been developed to inhibit the β-lactamases of many gram-positive and gram-negative bacteria. These inhibitors are structurally similar to penicillin and therefore bind β-lactamases, which results in the inactivation of the β-lactamases. Two of these inhibitors, clavulanate and sulbactam, are used in conjunction with the aminopenicillins to greatly expand their spectra of activity. Ampicillin-sulbactam is the parenteral formulation and amoxicillin-clavulanate is the oral formulation of these combinations. Sulbactam and clavulanate inactivate the β-lactamases of many grampositive, gram-negative, and anaerobic bacteria. As a result, they dramatically broaden the antimicrobial spectrum of the aminopenicillins.

Antimicrobial Activity of Aminopenicillin/β-Lactamase Inhibitor Combinations

Gram-positive bacteria

Some Staphylococcus aureus
Streptococcus pyogenes
Viridans streptococci
Some Streptococcus pneumoniae
Some enterococci
Listeria monocytogenes

Gram-negative bacteria

Neisseria spp.
Haemophilus infl uenzae
Many Enterobacteriaceae

Anaerobic bacteria

Clostridia spp. (except C. diffi cile)
Actinomyces israelii
Bacteroides spp.

Spirochetes

Borrelia burgdorferi

EXTENDED-SPECTRUM PENICILLINS

The extended-spectrum penicillins consist of piperacillin and ticarcillin. The side chains of these agents allow for even greater penetration into gram-negative bacteria than is seen with the aminopenicillins. For example, the side chain of piperacillin is polar, which increases its ability to pass through the outer membrane porins of some gram-negative bacteria. (Incidentally, piperacillin got its name from its side chain, which contains a piperazine derivative.) In addition, the extended-spectrum penicillins are in general more resistant to cleavage by gram-negative β-lactamases than are aminopenicillins, although they remain susceptible to some of these enzymes.

Thus, compared to the aminopenicillins, the extended-spectrum penicillins are more active against gram-negative bacilli, including many strains of P. aeruginosa. They maintain some of the gram-positive activity of the natural penicillins but, like the natural penicillins, are susceptible to the β-lactamases of staphylococci. They have modest activity against anaerobes. Piperacillin has broader activity than ticarcillin.

Antimicrobial Activity of Extended-Spectrum Penicillin + β-Lactamase Inhibitor Combinations

Gram-positive bacteria

Some Staphylococcus aureus
Streptococcus pyogenes
Viridans streptococci
Some Streptococcus pneumoniae
Some enterococci
Listeria monocytogenes

Gram-negative bacteria

Neisseria spp.
Haemophilus infl uenzae
Most Enterobacteriaceae
Pseudomonas aeruginosa

Anaerobic bacteria

Clostridia spp. (except C. diffi cile)
Bacteroides spp.

EXTENDED-SPECTRUM PENICILLIN/ β-LACTAMASE INHIBITOR COMBINATIONS

The fullest antimicrobial potential of the penicillins has been achieved by combining extended-spectrum penicillins with β-lactamase inhibitors. The two available combinations are piperacillin-tazobactam and ticarcillin-clavulanate. The β- lactamase inhibitors neutralize many of the β-lactamases that otherwise inactivate the extended-spectrum penicillins, resulting in a marked enhancement of their activity.

Thus, piperacillin-tazobactam and ticarcillin-clavulanate are the decathletes of the penicillins, with activity against most aerobic gram-positive bacteria, including many β-lactamase–producing staphylococci, most aerobic gram-negative bacteria, and nearly all anaerobic bacteria except Clostridium diffi cile. As would be expected based on the activity of their penicillin components, piperacillin-tazobactam has a broader spectrum than ticarcillin-clavulanate. Its excellent activity against grampositive, gram-negative, and anaerobic bacteria makes piperacillin-tazobactam one of the most powerful antibiotics available today.

KEY POINTS

Benzylpenicillin is active against staphylococci (may produce beta-lactamase),
streptococci and Neisseria spp. It is given by injection as it is inactivated by gastric
acid and absorption from the gut is low.
Phenoxymethylpenicillin has a similar spectrum of activity to benzylpenicillin, but
it is gastric acid-stable and can therefore be given orally.
Amoxicillin and ampicillin have a similar spectrum of activity. They are active
against Gram-positive and Gram-negative organisms but they are inactivated by
beta-lactamase. Amoxicillin can also be given in combination with the beta-
lactamase inhibitor clavulanic acid, which extends the spectrum of activity of
amoxicillin (co-amoxiclav).
Flucloxacillin is not inactivated by beta-lactamase and is therefore effective against
beta-lactamase producing staphylococci.
The antipseudomonal penicillins, piperacillin and ticarcillin, are only available in
combination with beta-lactamase inhibitors. They have important activity against
Pseudomonas aeruginosa and are administered with an aminoglycoside in
Pseudomonas septicaemias.
Temocillin is the most recently introduced beta-lactamase resistant penicillin. It is
used to treat multi-drug resistant Gram-negative bacteria.

KEYWORDS

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Gafacom

Penicillin class of antibiotics

Penicillins antibiotics