Difference between revisions of "Penicillin" - New World Encyclopedia

From New World Encyclopedia
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==History==
 
==History==
The serendipitous discovery of penicillin is usually attributed to [[Scotland|Scottish]] scientist Alexander Fleming in 1928, though others had earlier noted the antibacterial effects of ''Penicillium.'' Fleming, at his laboratory in St. Mary's Hospital (Now one of Imperial College teaching hospitals) in London, noticed a halo of inhibition of bacterial growth around a contaminant blue-green mould on a ''Staphylococcus'' plate culture. Fleming concluded that the mould was releasing a substance that was inhibiting bacterial growth and lysing the bacteria. He grew a pure culture of the mould and discovered that it was a ''Penicillium'' mould, now known to be ''Penicillium chrysogenum''. Fleming coined the term "penicillin" to describe the filtrate of a broth culture of the ''Penicillium'' mould. Even in these early stages, penicillin was found to be most effective against Gram-positive bacteria, and ineffective against Gram-negative organisms and fungi. He expressed initial optimism that penicillin would be a useful disinfectant, being highly potent with minimal toxicity compared to antiseptics of the day, but particularly noted its laboratory value in the isolation of "''Bacillus influenzae''" (now ''Haemophilus influenzae'').<!--
+
The serendipitous discovery of penicillin is usually attributed to [[Scotland|Scottish]] scientist Alexander Fleming, though others had earlier noted the antibacterial effects of ''Penicillium.'' (Penicillium is a member of the deuteromycetes, fungi with no known sexual state. As it grows, it gives off the liquid referred to as penicillin.) In 1928 Fleming, at his laboratory in St. Mary's Hospital (now one of Imperial College teaching hospitals) in London, noticed a halo of inhibition of bacterial growth around a contaminant blue-green mold on a ''Staphylococcus'' plate culture. Fleming concluded that the mold was releasing a substance that was inhibiting bacterial growth and lysing the bacteria. He grew a pure culture of the mold and discovered that it was a ''Penicillium'' mold, now known to be ''Penicillium chrysogenum''. Fleming coined the term "penicillin" to describe the filtrate of a broth culture of the ''Penicillium'' mold. Even in these early stages, penicillin was found to be most effective against Gram-positive bacteria, and ineffective against Gram-negative organisms and fungi. (Gram-positive (as opposed to gram-negative) refers to the characteristic blue-violet color reaction of certain types of bacteria in what is called the Gram-staining procedure. A major feature of gram-positive bacteria is the high percentage of peptidoglycan (sugar + amino acid molecule) in the cell wall.) Fleming expressed initial optimism that penicillin would be a useful disinfectant, being highly potent with minimal toxicity compared to antiseptics of the day, but particularly noted its laboratory value in the isolation of "''Bacillus influenzae''" (now ''Haemophilus influenzae'').<!--
 
   —><ref name="Fleming1929">{{cite journal | author=Fleming A. | title=On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of ''B. influenzæ''. | journal=Br J Exp Pathol | year=1929 | volume=10 | issue=31 | pages=226–36}}</ref>
 
   —><ref name="Fleming1929">{{cite journal | author=Fleming A. | title=On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of ''B. influenzæ''. | journal=Br J Exp Pathol | year=1929 | volume=10 | issue=31 | pages=226–36}}</ref>
After further experiments, Fleming was convinced that penicillin could not last long enough in the human body to kill pathogenic bacteria and stopped studying penicillin after 1931, but restarted some clinical trials in 1934 and continued to try to get someone to purify it until 1940.
+
After further experiments, Fleming was convinced that penicillin could not last long enough in the human body to kill pathogenic bacteria and stopped studying penicillin after 1931, but restarted some clinical trials in 1934 and continued to try to find someone to purify it until 1940.
  
In 1939, Australian scientist Howard Walter Florey and a team of researchers (Ernst Boris Chain, A. D. Gardner, Norman Heatley, M. Jennings, J. Orr-Ewing and G. Sanders) at the Sir William Dunn School of Pathology, University of Oxford made significant progress in showing the ''in vivo'' bactericidal action of penicillin. Their attempts to treat humans failed due to insufficient volumes of penicillin, but they proved its harmlessness and effect in mice. Some of the pioneering trials of penicillin took place at the Radcliffe Infirmary in Oxford. On 1942-03-14 John Bumstead and Orvan Hess became the first in the world to successfully treat a patient using penicillin.<!--
+
In 1939, Australian scientist Howard Walter Florey and a team of researchers (Ernst Boris Chain, A. D. Gardner, Norman Heatley, M. Jennings, J. Orr-Ewing and G. Sanders) at the Sir William Dunn School of Pathology, University of Oxford made significant progress in showing the ''in vivo'' bactericidal action of penicillin.(Bactericidal refers to inhibition of the growth or activity of bacteria, thus the prevention of infection.) Their attempts to treat humans failed due to insufficient volumes of penicillin, but they proved its harmlessness and effect in mice. Some of the pioneering trials of penicillin took place at the Radcliffe Infirmary in Oxford. On March 14, 1942 John Bumstead and Orvan Hess became the first in the world to successfully treat a patient using penicillin.<!--
 
   —><ref>{{cite news | author=Saxon, W. | url=http://www.wellesley.edu/Chemistry/Chem101/antibiotics/obit-a-miller.html | title=Anne Miller, 90, first patient who was saved by penicillin | publisher=The New York Times | date=[[1999-06-09]]}}</ref><!--
 
   —><ref>{{cite news | author=Saxon, W. | url=http://www.wellesley.edu/Chemistry/Chem101/antibiotics/obit-a-miller.html | title=Anne Miller, 90, first patient who was saved by penicillin | publisher=The New York Times | date=[[1999-06-09]]}}</ref><!--
 
   —><ref>{{cite web | author=Krauss K, editor | title=Yale-New Haven Hospital Annual Report | url=http://www.ynhh.org/general/annreport/ynhh99ar.pdf | format=PDF | year=1999 | publisher=Yale-New Haven Hospital | location=New Haven}}</ref>
 
   —><ref>{{cite web | author=Krauss K, editor | title=Yale-New Haven Hospital Annual Report | url=http://www.ynhh.org/general/annreport/ynhh99ar.pdf | format=PDF | year=1999 | publisher=Yale-New Haven Hospital | location=New Haven}}</ref>
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The narrow spectrum of activity of the penicillins, along with the poor activity of the orally-active phenoxymethylpenicillin, led to the search for derivatives of penicillin which could treat a wider range of infections.
 
The narrow spectrum of activity of the penicillins, along with the poor activity of the orally-active phenoxymethylpenicillin, led to the search for derivatives of penicillin which could treat a wider range of infections.
  
The first major development was ampicillin, which offered a broader spectrum of activity than either of the original penicillins and allowed doctors to treat a broader range of both Gram-positive and Gram-negative infections. Further developments led to amoxicillin, with improved duration-of-action.
+
The first major development was ampicillin, which offered a broader spectrum of activity than either of the original penicillins and allowed doctors to treat a broader range of both Gram-positive and Gram-negative infections. Further developments led to amoxicillin, with improved duration of action.
  
 
Further development yielded beta-lactamase-resistant penicillins including flucloxacillin, dicloxacillin and methicillin. These were important for their activity against beta-lactamase-producing bacteria such as ''Staphylococcus'' species, but are ineffective against the methicillin-resistant ''Staphylococcus aureus'' strains that subsequently emerged.
 
Further development yielded beta-lactamase-resistant penicillins including flucloxacillin, dicloxacillin and methicillin. These were important for their activity against beta-lactamase-producing bacteria such as ''Staphylococcus'' species, but are ineffective against the methicillin-resistant ''Staphylococcus aureus'' strains that subsequently emerged.
  
The last in the line of true penicillins were the antipseudomonal penicillins, such as ticarcillin and piperacillin, useful for their activity against Gram-negative bacteria. However, the usefulness of the beta-lactam ring was such that related antibiotics, including the mecillinams, the carbapenems and, most importantly, the cephalosporins, have it at the centre of their structures.
+
The last in the line of true penicillins were the antipseudomonal penicillins, such as ticarcillin and piperacillin, useful for their activity against Gram-negative bacteria. However, the usefulness of the beta-lactam ring is evident from the fact that related antibiotics, including the mecillinams, the carbapenems and, most importantly, the cephalosporins, have it at the centre of their structures.
  
 
==Mode of action==
 
==Mode of action==
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===Benzathine benzylpenicillin===
 
===Benzathine benzylpenicillin===
'''Benzathine benzylpenicillin''' International Nonproprietary Name (rINN), also known as '''benzathine penicillin''', is slowly absorbed into the circulation, after intramuscular injection, and hydrolysed to benzylpenicillin ''in vivo''. It is the drug-of-choice when prolonged low concentrations of benzylpenicillin are required and appropriate, allowing prolonged antibiotic action over 2–4 weeks after a single IM dose. It is marketed by Wyeth under the trade name '''Bicillin'''.
+
'''Benzathine benzylpenicillin''' is the International Nonproprietary Name (rINN). Also known as '''benzathine penicillin,''' it is slowly absorbed into the circulation after intramuscular injection and hydrolyzed to benzylpenicillin ''in vivo''. It is the drug of choice when prolonged low concentrations of benzylpenicillin are required and appropriate, allowing prolonged antibiotic action over 2–4 weeks after a single IM (intramuscular) dose. It is marketed by Wyeth under the trade name '''Bicillin.'''
  
 
Specific indications for benzathine pencillin include: (Rossi, 2004)
 
Specific indications for benzathine pencillin include: (Rossi, 2004)
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===Benzylpenicillin (penicillin G)===
 
===Benzylpenicillin (penicillin G)===
Image:Penicillin-G.png|thumb|200px|Penicillin G (Benzylpenicillin)
+
'''Benzylpenicillin''', commonly known as '''penicillin G''', is the gold standard penicillin.  Penicillin G is typically given by a parenteral route (routes other than through the digestive tract) of administration because it is unstable to the hydrochloric acid of the stomach.  Because the drug is given parenterally, higher tissue concentrations of penicillin G can be achieved than is possible with phenoxymethylpenicillin. These higher concentrations translate to increased antibacterial activity.
Image:Penicillin_3D_Model.png|thumb|200px|3D-model of benzylpenicillin
 
'''Benzylpenicillin''', commonly known as '''penicillin G''', is the gold standard penicillin.  Penicillin G is typically given by a parenteral route of administration because it is unstable to the hydrochloric acid of the stomach.  Because the drug is given parenterally, higher tissue concentrations of penicillin G can be achieved than is possible with phenoxymethylpenicillin. These higher concentrations translate to increased antibacterial activity.
 
  
 
Specific indications for benzylpenicillin include: (Rossi, 2004)
 
Specific indications for benzylpenicillin include: (Rossi, 2004)
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==Semi-synthetic penicillins==
 
==Semi-synthetic penicillins==
Structural modifications were made to the side chain of the penicillin nucleus in an effort to improve oral bioavailability, improve stability to beta-lactamase activity, and increase the spectrum of action.
+
Structural modifications were made to the side chain of the penicillin nucleus in an effort to improve oral bioavailability, improve stability of beta-lactamase activity, and increase the spectrum of action.
  
 
===Narrow spectrum penicillinase-resistant penicillins===
 
===Narrow spectrum penicillinase-resistant penicillins===
This group was developed to be effective against beta-lactamases produced by ''Staphylococcus aureus'', and are occasionally known as anti-staphylococcal penicillins.
+
This group was developed to be effective against beta-lactamases produced by ''Staphylococcus aureus,'' and are occasionally known as anti-staphylococcal penicillins.
  
 
*Methicillin
 
*Methicillin
 
*Dicloxacillin
 
*Dicloxacillin
 
*Flucloxacillin
 
*Flucloxacillin
* Oxacillin
+
*Oxacillin
  
 
===Moderate spectrum penicillins===
 
===Moderate spectrum penicillins===
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==Adverse effects==
 
==Adverse effects==
 
===Adverse drug reactions===
 
===Adverse drug reactions===
Common adverse drug reactions (≥1% of patients) associated with use of the penicillins include: diarrhoea, nausea, rash, urticaria, and/or superinfection (including candidiasis). Infrequent adverse effects (0.1–1% of patients) include: fever, vomiting, erythema, dermatitis, angioedema, and/or pseudomembranous colitis.<ref name="AMH2006" />
+
Common adverse drug reactions (≥1% of patients) associated with use of the penicillins include diarrhea, nausea, rash, urticaria, and/or superinfection (including candidiasis). Infrequent adverse effects (0.1–1% of patients) include: fever, vomiting, erythema, dermatitis, angioedema, and/or pseudomembranous colitis.<ref name="AMH2006" />
  
 
Pain and inflammation at the injection site is also common for parenterally-administered benzathine benzylpenicillin, benzylpenicillin, and to a lesser extent procaine benzylpenicillin.
 
Pain and inflammation at the injection site is also common for parenterally-administered benzathine benzylpenicillin, benzylpenicillin, and to a lesser extent procaine benzylpenicillin.

Revision as of 19:55, 7 November 2006

Penicillin structure

Penicillin (sometimes abbreviated PCN) refers to a group of β-lactam antibiotics used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms. The name “penicillin” can also be used in reference to a specific member of the penicillin group. All penicillins possess the basic Penam Skeleton, which has the molecular formula R-C9H11N2O4S, where R is a variable side chain.

History

The serendipitous discovery of penicillin is usually attributed to Scottish scientist Alexander Fleming, though others had earlier noted the antibacterial effects of Penicillium. (Penicillium is a member of the deuteromycetes, fungi with no known sexual state. As it grows, it gives off the liquid referred to as penicillin.) In 1928 Fleming, at his laboratory in St. Mary's Hospital (now one of Imperial College teaching hospitals) in London, noticed a halo of inhibition of bacterial growth around a contaminant blue-green mold on a Staphylococcus plate culture. Fleming concluded that the mold was releasing a substance that was inhibiting bacterial growth and lysing the bacteria. He grew a pure culture of the mold and discovered that it was a Penicillium mold, now known to be Penicillium chrysogenum. Fleming coined the term "penicillin" to describe the filtrate of a broth culture of the Penicillium mold. Even in these early stages, penicillin was found to be most effective against Gram-positive bacteria, and ineffective against Gram-negative organisms and fungi. (Gram-positive (as opposed to gram-negative) refers to the characteristic blue-violet color reaction of certain types of bacteria in what is called the Gram-staining procedure. A major feature of gram-positive bacteria is the high percentage of peptidoglycan (sugar + amino acid molecule) in the cell wall.) Fleming expressed initial optimism that penicillin would be a useful disinfectant, being highly potent with minimal toxicity compared to antiseptics of the day, but particularly noted its laboratory value in the isolation of "Bacillus influenzae" (now Haemophilus influenzae).[1] After further experiments, Fleming was convinced that penicillin could not last long enough in the human body to kill pathogenic bacteria and stopped studying penicillin after 1931, but restarted some clinical trials in 1934 and continued to try to find someone to purify it until 1940.

In 1939, Australian scientist Howard Walter Florey and a team of researchers (Ernst Boris Chain, A. D. Gardner, Norman Heatley, M. Jennings, J. Orr-Ewing and G. Sanders) at the Sir William Dunn School of Pathology, University of Oxford made significant progress in showing the in vivo bactericidal action of penicillin.(Bactericidal refers to inhibition of the growth or activity of bacteria, thus the prevention of infection.) Their attempts to treat humans failed due to insufficient volumes of penicillin, but they proved its harmlessness and effect in mice. Some of the pioneering trials of penicillin took place at the Radcliffe Infirmary in Oxford. On March 14, 1942 John Bumstead and Orvan Hess became the first in the world to successfully treat a patient using penicillin.[2][3]

Penicillin was being mass-produced in 1944

During World War II, penicillin made a major difference in the number of deaths and amputations caused by infected wounds amongst Allied forces. Availability was severely limited, however, by the difficulty of manufacturing large quantities of penicillin and by the rapid renal clearance of the drug necessitating frequent dosing. Penicillins are actively secreted and about 80% of a penicillin dose is cleared within three to four hours of administration. During those times it became common procedure to collect the urine from patients being treated so that the penicillin could be isolated and reused.[4]

This was not a satisfactory solution, however, so researchers looked for a way to slow penicillin secretion. They hoped to find a molecule that could compete with penicillin for the organic acid transporter responsible for secretion such that the transporter would preferentially secrete the competitive inhibitor. The uricosuric agent probenecid proved to be suitable. When probenecid and penicillin are concomitantly administered, probenecid competitively inhibits the secretion of penicillin, increasing its concentration and prolonging its activity. The advent of mass-production techniques and semi-synthetic penicillins solved supply issues, and this use of probenecid declined.[4] Probenecid is still clinically useful, however, for certain infections requiring particularly high concentrations of penicillins.[5]

The chemical structure of penicillin was determined by Dorothy Crowfoot Hodgkin in the early 1940s, enabling synthetic production. A team of Oxford research scientists led by Australian Howard Walter Florey and including Ernst Boris Chain and Norman Heatley discovered a method of mass producing the drug. Florey and Chain shared the 1945 Nobel prize in medicine with Fleming for this work. Penicillin has since become the most widely used antibiotic to date and is still used for many Gram-positive bacterial infections.

Developments from penicillin

The narrow spectrum of activity of the penicillins, along with the poor activity of the orally-active phenoxymethylpenicillin, led to the search for derivatives of penicillin which could treat a wider range of infections.

The first major development was ampicillin, which offered a broader spectrum of activity than either of the original penicillins and allowed doctors to treat a broader range of both Gram-positive and Gram-negative infections. Further developments led to amoxicillin, with improved duration of action.

Further development yielded beta-lactamase-resistant penicillins including flucloxacillin, dicloxacillin and methicillin. These were important for their activity against beta-lactamase-producing bacteria such as Staphylococcus species, but are ineffective against the methicillin-resistant Staphylococcus aureus strains that subsequently emerged.

The last in the line of true penicillins were the antipseudomonal penicillins, such as ticarcillin and piperacillin, useful for their activity against Gram-negative bacteria. However, the usefulness of the beta-lactam ring is evident from the fact that related antibiotics, including the mecillinams, the carbapenems and, most importantly, the cephalosporins, have it at the centre of their structures.

Mode of action

Main article: beta-lactam antibiotic

β-lactam antibiotics work by inhibiting the formation of peptidoglycan cross links in the bacterial cell wall. The β-lactam moiety of penicillin binds to the enzyme (transpeptidase) that links the peptidoglycan molecules in bacteria, and this weakens the cell wall of the bacterium when it multiplies (in other words, the antibiotic causes cell cytolysis or death when the bacterium tries to divide). Scott Williams is generally credited with having postulated this hypothesis. In addition the build-up of peptidoglycan precursors triggers the activation of bacterial cell wall hydrolases which further digest the bacteria's existing peptidoglycan.

Variants in clinical use

The term “penicillin” is often used generically to refer to one of the narrow-spectrum penicillins, particularly benzylpenicillin.

Benzathine benzylpenicillin

Benzathine benzylpenicillin is the International Nonproprietary Name (rINN). Also known as benzathine penicillin, it is slowly absorbed into the circulation after intramuscular injection and hydrolyzed to benzylpenicillin in vivo. It is the drug of choice when prolonged low concentrations of benzylpenicillin are required and appropriate, allowing prolonged antibiotic action over 2–4 weeks after a single IM (intramuscular) dose. It is marketed by Wyeth under the trade name Bicillin.

Specific indications for benzathine pencillin include: (Rossi, 2004)

  • Prophylaxis of rheumatic fever
  • Early or latent syphilis

Benzylpenicillin (penicillin G)

Benzylpenicillin, commonly known as penicillin G, is the gold standard penicillin. Penicillin G is typically given by a parenteral route (routes other than through the digestive tract) of administration because it is unstable to the hydrochloric acid of the stomach. Because the drug is given parenterally, higher tissue concentrations of penicillin G can be achieved than is possible with phenoxymethylpenicillin. These higher concentrations translate to increased antibacterial activity.

Specific indications for benzylpenicillin include: (Rossi, 2004)

  • Bacterial endocarditis
  • Meningitis
  • Aspiration pneumonia, lung abscess
  • Community-acquired pneumonia
  • Syphilis
  • Septicaemia in children

Phenoxymethylpenicillin (penicillin V)

Phenoxymethylpenicillin, commonly known as penicillin V, is the orally-active form of penicillin. It is less active than benzylpenicillin, however, and is only appropriate in conditions where high tissue concentrations are not required.

Specific indications for phenoxymethylpenicillin include: (Rossi, 2004)

  • Infections caused by Streptococcus pyogenes
    • Tonsilitis
    • Pharyngitis
    • Skin infections
  • Prophylaxis of rheumatic fever
  • Moderate-to-severe gingivitis (with metronidazole)

Procaine benzylpenicillin

Procaine benzylpenicillin (International Nonproprietary Name (rINN)), also known as procaine penicillin, is a combination of benzylpenicillin with the local anaesthetic agent procaine. Following deep intramuscular injection, it is slowly absorbed into the circulation and hydrolyzed to benzylpenicillin — thus it is used where prolonged low concentrations of benzylpenicillin are required.

This combination is aimed at reducing the pain and discomfort associated with a large intramuscular injection of penicillin. It is widely used in veterinary settings.

Specific indications for procaine penicillin include: (Rossi, 2006)

  • Syphilis
  • Respiratory tract infections where compliance with oral treatment is unlikely
  • Cellulitis, erysipelas

Procaine penicillin is also used as an adjunct in the treatment of anthrax.

Semi-synthetic penicillins

Structural modifications were made to the side chain of the penicillin nucleus in an effort to improve oral bioavailability, improve stability of beta-lactamase activity, and increase the spectrum of action.

Narrow spectrum penicillinase-resistant penicillins

This group was developed to be effective against beta-lactamases produced by Staphylococcus aureus, and are occasionally known as anti-staphylococcal penicillins.

  • Methicillin
  • Dicloxacillin
  • Flucloxacillin
  • Oxacillin

Moderate spectrum penicillins

This group was developed to increase the spectrum of action and, in the case of amoxicillin, improve oral bioavailability.

  • Amoxicillin
  • Ampicillin

Extended Spectrum Penicillins

This group was developed to increase efficacy against Gram-negative organisms. Some members of this group also display activity against Pseudomonas aeruginosa.

  • Piperacillin
  • Ticarcillin
  • Azlocillin
  • Carbenicillin

Penicillins with beta-lactamase inhibitors

Penicillins may be combined with beta-lactamase inhibitors to increase efficacy against β-lactamase-producing organisms. The addition of the beta-lactamase inhibitor does not generally, in itself, increase the spectrum of the partner penicillin.

  • Co-amoxiclav|Amoxicillin/clavulanic acid
  • Ampicillin/sulbactam
  • Ticarcillin|Ticarcillin/clavulanic acid
  • Piperacillin/tazobactam

Adverse effects

Adverse drug reactions

Common adverse drug reactions (≥1% of patients) associated with use of the penicillins include diarrhea, nausea, rash, urticaria, and/or superinfection (including candidiasis). Infrequent adverse effects (0.1–1% of patients) include: fever, vomiting, erythema, dermatitis, angioedema, and/or pseudomembranous colitis.[5]

Pain and inflammation at the injection site is also common for parenterally-administered benzathine benzylpenicillin, benzylpenicillin, and to a lesser extent procaine benzylpenicillin.

Allergy/hypersensitivity

Allergic reactions to any β-lactam antibiotic may occur in up to 10% of patients receiving that agent. Anaphylaxis will occur in approximately 0.01% of patients.[5] There is perhaps a 5-10% cross-sensitivity between penicillin-derivatives, cephalosporins and carbapenems; but this figure has been challenged by various investigators.

Nevertheless, the risk of cross-reactivity is sufficient to warrant the contraindication of all β-lactam antibiotics in patients with a history of severe allergic reactions (urticaria, anaphylaxis, interstitial nephritis) to any β-lactam antibiotic.


References
ISBN links support NWE through referral fees

  1. Fleming A. (1929). On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzæ.. Br J Exp Pathol 10 (31): 226–36.
  2. Saxon, W.. "Anne Miller, 90, first patient who was saved by penicillin", The New York Times, 1999-06-09.
  3. Krauss K, editor (1999). Yale-New Haven Hospital Annual Report (PDF). Yale-New Haven Hospital.
  4. 4.0 4.1 Silverthorn, DU. (2004). Human physiology: an integrated approach.. Upper Saddle River (NJ): Pearson Education. ISBN 0-8053-5957-5. 
  5. 5.0 5.1 5.2 (2006) in Rossi S, editor: Australian Medicines Handbook. Adelaide: Australian Medicines Handbook. ISBN 0-9757919-2-3. 

External links


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