Penicillins

01Drug classification

Every penicillin is the same core, 6-aminopenicillanic acid, with a different side chain. The side chain decides whether the drug survives stomach acid, resists penicillinase or passes the outer membrane of gram-negatives, and so which group it falls in.

From mould to medicine

1. 1928

   Fleming's plate

   In his London laboratory, Alexander Fleming notices that a Penicillium mould contaminating a plate of staphylococci has killed the bacteria around it.

2. 1940

   The Oxford team

   Howard Florey, Ernst Chain and Norman Heatley purify enough penicillin to protect animals infected with streptococci, staphylococci and clostridia.

3. 1941

   The first patient

   An Oxford policeman with abscesses all over his body is the first person treated. He improves within a day, but the supply runs out and he dies a few weeks later.

4. 1941 to 1944

   Made in bulk

   In Peoria, Illinois, a broth made with corn steep liquor and a strain of Penicillium chrysogenum from a mouldy cantaloupe, making six times more penicillin than Fleming's, and then the drug companies' deep-tank fermentation bring mass production.

5. 1945

   The Nobel Prize

   Fleming, Chain and Florey share the Nobel Prize in Physiology or Medicine.

6. 1959 to 1961

   Semisynthetic penicillins, and MRSA

   Methicillin, the first semisynthetic penicillin to resist staphylococcal penicillinase, comes into use in 1959. Strains of S. aureus resistant to it are reported in the UK in 1961: MRSA.

02Pharmacokinetics

Penicillin G is broken down by stomach acid, so it is given intravenously or intramuscularly, and its short half-life means doses every four hours or so in serious infections. Penicillin V survives acid and is the oral form, taken on an empty stomach.

Made into a poorly soluble salt with procaine or benzathine and injected into muscle, penicillin G becomes a depot that leaks into the blood slowly:

• procaine penicillin G lasts about a day, so it is given once daily;
• benzathine penicillin G lasts weeks: one injection of 2.4 million units treats early syphilis, one injection can treat streptococcal sore throat, and an injection every three to four weeks, kept up for years, stops rheumatic fever from coming back.

Both depots go into muscle only, never into a vein (Contraindications, below).

Amoxicillin is absorbed better from the gut than ampicillin, so it reaches higher levels by mouth and causes less diarrhoea; ampicillin is mostly given by injection. Co-amoxiclav is given by mouth or, in much of Europe, intravenously; ampicillin–sulbactam is the injected combination used elsewhere. Piperacillin–tazobactam is given by infusion.

Most penicillins leave in the urine, amoxicillin and ampicillin with half-lives of about an hour. Nafcillin is cleared mainly in bile and oxacillin partly, so their doses aren't cut in kidney failure. Flucloxacillin leaves mainly in the urine, but its dose is cut only in severe kidney failure.

03Pharmacodynamics

Like every β-lactam, a penicillin binds the PBPs and stops the wall's cross-links, so it kills most bacteria that are growing; enterococci it only holds back (the β-lactam overview has more). Its killing depends on the time the free drug stays above the MIC, which with half-lives this short is why penicillins are given so often. Each group's side chain sets what it reaches.

Narrow-spectrum penicillins

Penicillin G reaches streptococci, penicillin-susceptible pneumococci, meningococci, Treponema pallidum and clostridia. Most S. aureus, though, make a penicillinase, so penicillin G rarely works against them.

Penicillinase-resistant penicillins

The penicillinase-resistant, or antistaphylococcal, penicillins carry a bulky side chain that keeps staphylococcal penicillinase off the ring. They are the drugs of choice for methicillin-susceptible S. aureus (MSSA), but MRSA, with its PBP2a, resists them, as it resists nearly every β-lactam. They do nothing for enterococci or gram-negatives.

Extended-spectrum penicillins

An amino group on the side chain lets the aminopenicillins, ampicillin and amoxicillin, reach some gram-negatives that penicillin G misses. They are the drugs of choice for Listeria and Enterococcus faecalis, neither of which any cephalosporin treats on its own.

Piperacillin, an antipseudomonal penicillin, passes the outer membrane of Pseudomonas aeruginosa and binds its PBPs. Ticarcillin, an older one, is now little used.

Two narrower penicillins have come back in parts of Europe because they survive many ESBLs: pivmecillinam, taken by mouth, which binds only PBP2 of enteric bacteria, and temocillin, given by injection, which has lost activity against gram-positives and anaerobes.

With a β-lactamase inhibitor

The aminopenicillins and piperacillin are broken by staphylococcal penicillinase and by the β-lactamases of many gram-negatives, so they are often given with an inhibitor that takes the enzyme's blow (the β-lactam overview has which inhibitor blocks which enzyme).

• Co-amoxiclav (amoxicillin with clavulanate) also reaches β-lactamase-producing S. aureus (but not MRSA), H. influenzae, Moraxella, many E. coli and anaerobes such as Bacteroides.
• Piperacillin–tazobactam covers a broad range of gram-positives, gram-negatives and anaerobes, Pseudomonas among them. It does not reach MRSA.

04Clinical indications

Pivmecillinam and temocillin are used for gram-negative urinary infections.

of benzathine penicillin G, one dose into muscle, for early syphilis

2.4million unitsof benzathine penicillin G, one dose into muscle, for early syphilis

between injections of benzathine penicillin G, kept up for years, to stop rheumatic fever coming back

3 to 4weeksbetween injections of benzathine penicillin G, kept up for years, to stop rheumatic fever coming back

by mouth, 30 to 60 minutes before a dental procedure, to prevent endocarditis in patients at high risk

2g of amoxicillinby mouth, 30 to 60 minutes before a dental procedure, to prevent endocarditis in patients at high risk

05Adverse drug reactions

β-Lactams, penicillins above all, are the antibiotics most often reported to cause allergy; the β-lactam overview covers allergy, cross-reactivity and what a label is worth. The penicillins' adverse reactions, allergy first:

• Life-threatening
  Anaphylaxis, or a severe skin reaction such as Stevens–Johnson syndrome. Both are rare.
• Serious
  Liver injury, rarely fatal. Co-amoxiclav is a leading cause of idiosyncratic drug-induced liver injury; the hepatitis, often cholestatic, can appear after the course has ended. Flucloxacillin can cause cholestatic liver injury too, up to two months after the course, more often in women and in patients over 50, and in some studies after courses longer than two weeks; carriers of HLA-B*57:01 have an 80-fold higher risk.
• Serious
  C. difficile colitis. The broad penicillins, co-amoxiclav above all, can bring it on.
• Serious
  Neurotoxicity. Very high doses of penicillin G, especially when the kidneys clear it slowly, can cause seizures.
• Serious
  Bleeding. High doses of penicillin G and piperacillin can impair platelet aggregation.
• Mild
  The aminopenicillin rash. Given during infectious mononucleosis (Epstein–Barr virus), ampicillin and amoxicillin often bring out an itchy maculopapular rash, in about four patients in ten in one series of ampicillin; the first small reports, in the 1960s, gave 80 to 100%, and some sources still say more than nine in ten. It is often recorded as a penicillin allergy, though it comes from the drug and the infection together.
• Mild
  The Jarisch–Herxheimer reaction. Within 24 hours of starting any treatment for syphilis, a patient can develop fever, headache and myalgia. It comes from the bacteria being killed, not from allergy, and is commonest in early syphilis. Antipyretics ease it; treatment goes on. In pregnancy it can bring on early labour or fetal distress (Pregnancy and lactation, below).

06Side effects

• Mild
  Diarrhoea, common. It is commoner with co-amoxiclav than with amoxicillin alone, and with ampicillin than with amoxicillin.
• Mild
  Nausea, common with amoxicillin, and vomiting less often.
• Mild
  Thrush, in the mouth or the vagina, common with co-amoxiclav.

07Contraindications

• Contraindicated
  An allergy to any penicillin, or a severe immediate reaction, such as anaphylaxis, to another β-lactam. Flucloxacillin's licence rules it out after any β-lactam allergy.
• Contraindicated
  A depot penicillin into a vein. Benzathine and procaine penicillin G go into muscle only: injected into a vein, benzathine penicillin has caused cardiorespiratory arrest and death.
• Contraindicated
  Liver injury from the same drug before. Jaundice or liver dysfunction with flucloxacillin rules out flucloxacillin, and with co-amoxiclav, co-amoxiclav.
• Avoid
  Amoxicillin or ampicillin in suspected glandular fever, because of the rash.
• Caution
  Flucloxacillin with paracetamol. Together they can cause a high anion gap metabolic acidosis, more likely in severe kidney failure, sepsis or malnutrition, so the acid–base balance is watched.
• Caution
  Methotrexate. Penicillins slow its excretion and can make it toxic; its levels are watched.
• Caution
  Warfarin. Amoxicillin and flucloxacillin can change the INR, so it is checked when the penicillin starts and stops.
• Caution
  Piperacillin–tazobactam with vancomycin. Studies looking back have found more acute kidney injury than with vancomycin alone, so kidney function is watched.
• Caution
  Allopurinol with amoxicillin, which makes allergic skin reactions likelier.

08Pregnancy and lactation

• Compatible
  Pregnancy. Penicillin V, amoxicillin and co-amoxiclav are commonly prescribed in pregnancy, with no concern that they harm the baby. Flucloxacillin is less studied in pregnancy, but it belongs to a family not known to cause harm, and the few reported cases show none.
• Compatible
  Syphilis in pregnancy. Penicillin G is the only treatment shown to work, so a pregnant woman who reports a penicillin allergy is desensitised and given it. The Jarisch–Herxheimer reaction can bring on early labour or fetal distress, but that should not delay treatment.
• Compatible
  Group B streptococcus in labour. A mother who carries group B streptococcus is given penicillin G into a vein from the start of labour until the birth, to protect the baby from early infection.
• Avoid
  Co-amoxiclav after preterm rupture of the membranes. Given to prevent infection after preterm prelabour rupture of the membranes, it was linked to necrotising enterocolitis in the newborn, so another antibiotic is used. Its licence says to avoid it in pregnancy unless it is essential.
• Caution
  Piperacillin–tazobactam. There are few data in pregnancy and both drugs cross the placenta, but no harm is known; it is used for serious infections that need it. Its licence says to use it only if clearly indicated.
• Compatible
  Breastfeeding. Penicillins pass into milk in small amounts, flucloxacillin only in traces. The baby may get diarrhoea or thrush, and could in theory be sensitised.