Journal of Investigative Surgery, 25, 67–77, 2012

Copyright
C 2012 Informa Healthcare USA, Inc.

ISSN: 0894-1939 print / 1521-0553 online

DOI: 10.3109/08941939.2012.664099

HISTORICAL NOTE

History of Antibiotics. From Salvarsan to Cephalosporins

Lorenzo Zaffiri, Jared Gardner, Luis H. Toledo-Pereyra

Michigan State University, Kalamazoo Center for Medical Studies, Kalamazoo, Michigan 49008

ABSTRACT
Infections have represented for a long time the leading cause of death in humans. During the 19th century, pneu-
monia, tuberculosis, diarrhea and diphtheria were considered the main causes of death in children and adults.
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Only in the late 19th century did it become possible to correlate the existence of microscopic pathogens with the
development of various diseases. Within a few years the introduction of antiseptic procedures had begun to re-
duce mortality due to postsurgical infections. Sanitation and hygiene played a significant role in the reduction
of the mortality due to several infectious diseases. The introduction of the first compounds with antimicrobial
activity succeeded in conquering many diseases.
In this review we analyzed, from a historical perspective, the development of antibiotics and the circumstances
that led to their discovery. The first compound with antimicrobial activity was introduced in 1911 by Erlich.
He focused his research activity on the discovery of a “magic bullet” to treat syphilis. Afterwards, Foley and
colleagues brought penicillin to the forefront. Streptomycin represents the first drug discovered for the treatment
For personal use only.

of tuberculosis, and its development included the first use of clinical trials. Finally, with the development of
cephalosporins, the introduction of new antimicrobial compounds with broad activity against Gram-positive
and also some Gram-negative bacteria began.

INTRODUCTION chemotherapy helped in decreasing the surgical infec-

Antibiotics have had an effect not only on the treat-
ment of infectious disease but also on society by chang-
ing morbidity and mortality. Since the introduction of
the first antimicrobials (1911), several new drugs have
been discovered, providing clinicians with more ther-
apeutic options for previously life-threatening disease.
However, the wide use of antimicrobial drugs has in-
troduced a new era in which clinicians have to face the
emergence of drug-resistant pathogens.
During the 19th century, infections such as pneu-
monia, diarrhea and diphtheria represented the main
causes of death. Moreover, the Industrial Revolution
and upcoming urbanization led to a shift of popula-
tion to the cities, which consequently increased the
incidence of diseases like tuberculosis and syphilis.
Despite the introduction of antisepsis (1867), follow-
ing the work of Semmelweis (1818–1865) and Lister
(1827–1912), hospital and post-surgical infections in-
duced by Gram-positive bacteria remained a common
cause of death. The introduction of antimicrobial
tion rates from 40% to 2% [1]. This review will examine
the discovery of the first groups of antibiotics intended
to defeat the most common and threatening infectious
disease of the 19th century: salvarsan, penicillin,
streptomycin and finally cephalosporins (Table 1).
FROM SALVARSAN TO ANTIBACTERIAL
SULFONAMIDES
Arsphenamine, introduced in 1910, was the first sulfa
drug [2]. A few months after its discovery, it was
already being widely used against syphilis and tri-
panosomiasis. Working in Paul Ehrlich’s (1854-1915)
(Figure 1a) laboratory on several arsenical compounds,
Sahachiro Hata (1873-1938) was able to identify ar-
sphenamine (Figure 2a) in the fall of 1909. It was con-
sidered the “magic bullet” for the treatment of syphilis
[3]. Ehrlich’s theory was that the human immune sys-
tem could have been aided by the use of chemical
compounds [4]. Arsphenamine was initially known as

Received 10 January 2012; accepted 20 January 2012.

Address Reprint Requests to Dr. Luis H. Toledo-Pereyra at Michigan State University, Kalamazoo Center for Medical Studies, 1000 Oakland
Drive, Kalamazoo, MI X 49008. E-mail: Toledo@kcms.msu.edu

67
 68 Zaffiri et al.
TABLE 1 Historical brief overview from the development of sulfa antimicrobials to antibiotic therapy up to cephalosporins
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“606” due to the fact that it was the 606th compound
tested by Ehrlich. This organoarsenic compound was
later called Salvarsan. It represented the most used an-
timicrobial drug until the 1940s [5]. However, despite
its wide use and success, the mechanism of action re-
mained unclear. Arsphenamine was known to convert
to an active form in the body where it was toxic for
spirochetes and other parasites.
Prontosil (1932) represents not the first discovered
antimicrobial but, more importantly, the first to be
widely known [6]. Continuing Ehrlich’s work on the
effect of dye on microorganisms, two chemists, Klarer
(1898–1953) and Mietzsch (1896–1958), synthesized
sulfonamidochrysoidine as part of a research study to
prove the efficacy of dye as an antibacterial [7]. How-
ever, only through Domagk’s efforts (1895–1964) in
1932, was the first sulfa antibiotic introduced. He was
able to prove the property of this component of the sul-
fonamides in a murine model of Streptococcus pyogenes
systemic infection [8]. Subsequent studies directed by
Forneau (1872–1949) and Tréfouël (1897–1977) in 1935
demonstrated that Prontosil was a prodrug that was
metabolized to sulfanilamide. This was then commer-
cialized as Prontolyin [9]. Sulfonamide antibiotics have
been used for almost a century. They reached particular
popularity in the United States when, despite the early
doubts of the medical community, Prontosil was used
to cure Franklin Delano Roosevelt, Jr. (1914–1988), the
U.S President’s son, who was affected by a septic strep
throat infection [10].
HISTORICAL USE AND MECHANISM
OF ACTION OF SULFONAMIDES
Sulfonamides are bacteriostatic antimetabolite drugs
which induce the inhibition of folate synthesis. They
are analogues of para-aminobenzoic acid (PABA)
and act as competitive inhibitors of the enzyme
dihydropteroate synthetase (DHPS). Blocking the
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FIGURE 1 a) Paul Ehrlich (1854–1915); b) Alexander Fleming (1881–1955); c) Howard Florey (1898–1968); d) Selman Waksman
(1888–1973); e) Albert Schatz (1922–2005); f) Giuseppe Brotzu (1895–1955); g) Edward Abraham (1913–1999); h) Guy Newton
(1919–1969).
synthesis of folates, they induce the inhibition of DNA,
RNA and protein synthesis [11]. Sulfonamides have
broad- spectrum activity against both Gram-positive
and Gram-negative bacteria. They were used mostly
to cure uncomplicated urinary tract infections and
Nocardia-related infections [12,13]. Sulfacetamide is
used for topical and ophthalmic bacterial infections
[14,15]. Sulfadoxine is largely used in combination with
pyrimethamine to treat or prevent malaria, especially
when caused by Plasmodium falciparum [16,17]. The
most widely used sulfonamide is sulfamethoxazole,
which is usually combined with pirymethoxazole due
to their synergistic activity in inhibiting subsequent
steps in folate synthesis [11]. They are bacteriostatic
antibiotics active against susceptible forms of strep-
tococci, Staphylococcus aureus, including cutaneous
infection from community acquired methicillin re-
sistant Staph. aureus (MRSA) [18,19]. Moreover, the
sulfonamides are active against oral anaerobes and
some Gram- negative rods such as Escherichia coli and
Haemophilus influenza [20,21]. In addition, the combi-
nation is used for the treatment and the prophylaxis
of two of the most common opportunistic infections in
immunocompromised patients: Pneumocystis jiroveci
pneumonia and toxoplasmosis [22,23]. Resistance


C 2012 Informa Healthcare USA, Inc.
History of Antibiotics 69
to sulfonamides is very common and mediated by
different mechanisms: decreased permeability, active
efflux pump, genetically mutated forms of DHPS, and
increased production of PABA [11,18,24–25].
FLEMING, FLOREY AND THE
SERENDIPITOUS DISCOVERY OF
PENICILLIN
The concept of the antimicrobial treatment was revolu-
tionized by the work of Alexander Fleming (1881–1955)
(Figure 1b) and his famous discovery. He joined the In-
oculation Department at St. Mary Hospital in London
at the beginning of the 20th century. His interest in mi-
crobiology and antiseptics brought him to the discov-
ery of one the most important drugs of the last century,
penicillin [26].
While studying the antimicrobial properties of
lysozyme, which he discovered earlier by adding his
own nasal mucous to a culture plate [27], Fleming no-
ticed an unusual phenomenon on an old culture plate
of Staphylococcus aureus [28]. The growth of these com-
mon bacteria was inhibited by the presence of a con-
taminating blue mold. Interestingly, he reported in his
 70 Zaffiri et al.
paper (1928) that those plates were exposed and, there-
fore, contaminated with several micro-organisms, in-
cluding Penicillium notatum. However, the rest of the
experiments conducted by Fleming and his colleagues
truly opened the way for the antibiotic era. He de-
scribed in detail the characteristics and the growth re-
quirement of the mold, and he tested other molds to
evaluate their antimicrobial activity. He developed a
technique to detect the amount of penicillin produced
in a culture broth, called the ditch-plate method. Fi-
nally, he described the amount of inhibition and the
effect of doubling the dilutions of his “inhibitor” yel-
low fluid, similar to our concept of minimum inhibitory
concentration (MIC) and disk diffusion, and still ex-
tremely valuable today in the clinical setting [28–29].
Unfortunately, Fleming was not able to demonstrate
the therapeutic value of penicillin due to the instability
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of this new substance, the difficulty in the extraction,
and probably the fear of toxic chemical compounds.
The antimicrobial properties of Penicillium nota-
tum were discovered again at the beginning of 1930.
Howard Florey (1898–1968) (Figure 1c) and Ernst
Chain (1906-1979), with the help of a team of scientists
gathered at Oxford University, started a series of
assiduous experiments on the antimicrobial properties
of molds following Fleming’s articles and Paine’s work
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on conjunctivitis (1930–1931).
The first paper demonstrating the antimicrobial
value of penicillin for the treatment of experimentally
infected animals was published in August of 1940 [30].
In 1941, the first human patient started receiving peni-
cillin and rapidly improved. Unfortunately, the out-
come was negative given the lack of enough penicillin
to continue his treatment [31]. In March 1942, the first
adult patient affected by streptococcal septicemia was
successfully treated, and, later in 1943, Florey himself
successfully tested the effect of penicillin on wounded
soldiers in North Africa during World War II [32,33].
However, the penicillin used to treat the first patients
FIGURE 2 Chemical structure of (a) arsphenamine, (b) penicillin, (c) streptomycin, and
(d) cephalosporin c.
was completely extracted from cultures of Penicillium
notatum isolated by Fleming himself. The need to pro-
duce larger quantities of penicillin, especially for the
treatment of soldiers involved in the war, led Florey to
collaborate with researchers in the U.S. (1941–1942). In
1943, Mary Hunt, also known as Moldy Mary, work-
ing in the Northern Regional Research Laboratory at
Peoria, Illinois, isolated Penicillium chrysogenum from
a moldy cantaloupe found in a grocery market [34].
By the end of the same year, mass production of peni-
cillin began in several countries including the U.S., UK
and Australia, where the new antibiotic was first made
available for civilian use.
HISTORICAL USE AND MECHANISM OF
ACTION OF PENICILLINS
All the members of the penicillin class are derivates
of 6-aminopenicillanic acid and contain a beta-lactam
ring structure that is essential for antimicrobial activity
(Figure 2b) [35]. Penicillins, as well as the other beta-
lactam antibiotics, have an indirect bactericidal activ-
ity. They inhibit the formation of the peptidoglycan
crosslink in the bacterial cell wall, attaching to bacterial
enzymes called penicillin binding proteins (PBPs) and
thereby activating cell wall autolysis [36]. Modification
of the target PBPs is a well known mechanism of resis-
tance acquired by pneumococci, MRSA and enterococci
[37,38].
Classification of the penicillins depends on the
base of additional chemical substitutes added on the
side chains, which mostly induce differences in the
bioavailability and the spectrum of activity through
extension of the activity toward the Gram-negative
bacteria compared to penicillin G. We recognize 4 peni-
cillin subclasses on the basis of the spectrum of activity:
narrow-spectrum or natural penicillin, very-narrow-
spectrum (or penicillinase-resistant penicillins),
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extended-spectrum or aminopenicillins, and broad-
spectrum or antipseudomonal penicillins.
The emergence of resistance has been one of the ma-
jor drives in the development of new types of peni-
cillins. The cleavage of the beta-lactam ring is the major
mechanism of resistance to beta-lactam antibiotics [39].
The penicillinases are a specific group of enzymes of
the beta-lactamase family, which have the ability to hy-
drolyze the beta-lactam ring. They were initially identi-
fied in 1940 in E. coli strains but rapidly spread to other
bacteria [40]. In order to fight the spreading of the re-
sistance mediated by beta-lactamase, inhibitors of these
enzymes were developed, starting in 1970 with the in-
troduction of clavulanic acid and followed by sulbac-
tam and tazobactam, which are now broadly used in
combination with broad- and extended-spectrum peni-
cillins [41].
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The narrow-spectrum penicillin group includes
penicillin V (1944), penicillin G (1945), procaine peni-
cillin (1947), and benzathine penicillin (1954). Penicillin
G is active against Gram-positive cocci and rods and
Gram-negative cocci, and variably active against anaer-
obes. Unfortunately, the widespread use of penicillin
G after its introduction induced a generation of re-
sistant strains of bacteria. By 1957, more than 80% of
hospitals already reported the presence of a penicillin-
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resistant strain of Staph. aureus [42,43]. In addition, the
percentage of penicillin-resistant strains of Streptococ-
cus pneumoniae also kept increasing in the U.S. [44]. Fi-
nally, strains of Neisseria gonorrhea have demonstrated
resistance to penicillin G when it was widely used for
the treatment of meningitis [45]. Despite the synergistic
effect on enterococci when administered together with
an aminoglycoside, resistant strains of enterococci with
intrinsic resistance to penicillin G are increasing [46].
However, penicillin G is still considered the recom-
mended treatment for S. pyogenes, Streptococcus agalac-
tiae, group C and G streptococci, and Listeria monocyto-
genes infections [47–50].
Probably the two most dramatic effects of the in-
troduction of the penicillin were the treatment of
rheumatic fever and syphilis [51–54]. While acute
rheumatic fever and the consequent rheumatic heart
disease remain a major cause of morbidity and mor-
tality throughout the world, with an estimated 12 mil-
lion people affected globally, in the U.S. a recent study
showed an incidence of 14.8 cases per 100,000 hospi-
talized children [55]. The continuous decline in the in-
cidence of acute rheumatic fever is mostly due to the
widespread use of antibiotic for the treatment of acute
pharyngitis [56]. The benzathine penicillin G, which is
still the recommended treatment for early and latent
syphilis, induced a decline in morbidity and mortal-
ity of syphilis by almost 90% between 1945 and 1975
[57,58].
The rapid emergence of penicillin-resistant staphy-
lococci prompted research for pharmacological alter-
natives. At the end of the 1950s, the semi-synthesis


C 2012 Informa Healthcare USA, Inc.
History of Antibiotics 71
around the 6-aminopenicillanic acid presented a new
class of penicillinase-resistant penicillins: oxacillin, me-
thicillin, cloxacillin and dicloxacillin [35,59–61]. These
antibiotics are also known as anti-staphylococcal peni-
cillins, because they present a narrow spectrum of ac-
tivity compared to penicillin G. They are only used
for the treatment of methicillin-sensitive Staphylococ-
cus aureus (MSSA). It is important to highlight the very
narrow spectrum of activity and the rapid emergence
of MRSA (methicillin resistant Staphylococcus aureus)
strains. The first report of the emergence of a MRSA
strain was in England in 1961[62] and in less than 20
years MRSA was endemic in the U.S. [63].
The major expansion of the penicillins came through
the work of Dr. Rolison at the Beecham Research Lab-
oratories between 1940 and 1960. The goals were to
identify the chemical structure with antibacterial activ-
ity, to expand the spectrum of activity, and to improve
the bioavailability and oral absorption. Isolation of the
6-aminopenicillanic acid (1959) made possible the
development of semisynthetic penicillins and the in-
troduction of methicillin (1960) [60] and ampicillin
(1961) [64].
Ampicillin and amoxicillin were the first antibi-
otics of the second generation of penicillins or broad-
spectrum penicillins. Ampicillin was introduced to
achieve better coverage against Gram-negative bacte-
ria, but it was soon recognized that strains of these
organisms possess variable susceptibility. They pre-
sented identical chemical structure but amoxicillin
demonstrated higher serum concentration when ad-
ministered orally [65]. Second-generation penicillins
are active against many bacteria including non-
penicillinase-producing strains of streptococci and
staphylococci, enterococci, L. monocytogenes, Clostridia
spp. and Bacillus anthracis. Among the Gram-negative
bacteria these penicillins are active against H. influen-
zae, E. coli, Salmonella, and Shigella [34].
Amoxicillin (1972) is considered the drug of choice
in the treatment of acute otitis media and upper airway
infections caused by Strep. pyogenes [66,67]. Amoxi-
cillin also demonstrates activity against Enterococcus
faecalis in the treatment of uncomplicated urinary
tract infections but, considering the high incidence
of resistance of E. coli and Enterobacteriaceae strains,
amoxicillin is not widely used for these pathogens
[68]. Extremely important is the role of amoxicillin
in the treatment and eradication of Helicobacter pylori,
given the carcinogenic risk associated with this in-
fection [69–71]. Finally, amoxicillin is widely used for
the treatment of urethritis and cervicitis in pregnant
women [72,73]. Ampicillin remains the drug of choice
for the treatment of pneumococcal pneumonia in
infants and children when the strains are sensitive, as
well as the drug of choice for listeriosis [50,74].
The next generation of penicillins is represented by
carbenicillin (1957), tircacillin (1971) and piperacillin
(1977). These extended-spectrum antibiotics are active
 72 Zaffiri et al.
against Gram-positive cocci, anaerobes and Gram-
negative bacteria. Moreover, these drugs resist the
chromosomal beta-lactamases of certain organisms,
such as Enterobacter species and Pseudomonas aerugi-
nosa. The combination piperacillin- tazobactam (1989)
was introduced in 1995 and is probably the most
widely used, given its high activity against Gram-
positive bacteria, including streptococci and entero-
cocci, but it is not active against methicillin-resistant
staphylococci. However, the major advantage of this
combination is activity against Gram-negative bacilli
and in particular P. aeruginosa [75].
THE FIGHT AGAINST TUBERCULOSIS
AND THE DISCOVERY OF STREPTOMYCIN
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Streptomycin was the first of the aminoglycosides to be
isolated (1943) [76,77], and the first antibiotic remedy
for tuberculosis. In addition, streptomycin opened the
way for the development of clinical research. In fact, it
is the first drug used for a randomized control trial for
the treatment of pulmonary tuberculosis carried out in
1946 by Medical Research Council (MRC) in the U.K.
[78]. Throughout the 19th century, tuberculosis, with all
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its clinical manifestations, represented the most com-
mon cause of death in young adults. Other than un-
successful attempts with tuberculin, isolated by Koch
(1843–1910) in 1892 [79,80], and light radiation, intro-
duced by Finsen (1860–1904) at the beginning of the
19th century [81], there was no real hope for the treat-
ment of Mycobacterium tuberculosis infections. Isolation
in a sanatorium provided the rest and improvement in
the sanitary conditions necessary for the initial recov-
ery, while confining the source of the infection from the
general population [82].
Following the discovery of penicillin and its suc-
cess in the treatment of bacterial infections, the drug
company Merck strongly sustained the research of a
soil scientist at Rutgers University in New Jersey [77].
Selman Waksman (1888–1973) (Figure 1d) was born in
Ukraine and emigrated to the U.S. in 1910, where he
started working in the field of soil microbiology. His
systematic and repetitive methods of working allowed
him to expand the knowledge about soil bacteriology
and the microbiological influence of different species
on each other. He established that as many as 50% of
the actinomyces found in soil were able to exert an in-
hibitory effect on the growth of microorganisms. Waks-
man essentially introduced the concept of antimicro-
bial activity, describing the effect of small molecules
made by a microbe which antagonized the growth of
other microbes [83]. Already in 1932, The American Na-
tional Association against Tuberculosis was supporting
Waksman’s search for an antibiotic substance against
the mycobacterium tuberculosis produced by soil mi-
crobes.
Between 1940 and 1952, Waksman isolated and re-
ported on more than 10 different chemical substances
with antimicrobial activity [84]. Of these, the most fa-
mous and influential was streptomycin [85]. In Septem-
ber 1943, the assiduous work of one of Waksman’s
collaborators, Albert Schatz (1922–2005) (Figure 1e),
brought about the isolation of streptomycin from a
culture of Streptomyces griseus [86]. In less than a
month, a sample of streptomycin was sent to Mayo
Clinic in order to allow William Feldman (1892–1974)
to conduct toxicology studies in animal models [87].
Subsequently, the collaboration between Feldman and
Hinshaw (1902–2000) led to the first clinical trials on
tuberculosis patients, less than a year after discovery
[88,89]. However, the effect of streptomycin on severe
cases of diffuse tuberculosis was undermined
was undermined by the serious side effects and the
rapid isolation of resistant strains of M. tuberculosis
[90,91].
The shortage of economic funds and the necessity of
a promising cure for tuberculosis induced the British
Medical Research Council, guided by Sir Geoffrey
Marshal (1887–1982), to perform the first multicenter,
randomized, double-blind, placebo-controlled clinical
trials throughout the U.K. The results of the trial were
published in 1952 [92,93]. Fortunately, soon after-
ward, the para-amino salt of salicylic acid (1944) was
synthesized by Lehman (1898–1989) [94,95], rapidly
followed by the isonicotinic acid hydrazide (INH) in
1952 [96]. This “triple therapy” resulted in predictable
cures for 90% to 95% of patients with tuberculosis
[93,97].
HISTORICAL USE AND MECHANISM
OF ACTION OF STREPTOMYCIN
Streptomycin (Figure 2c) is a protein synthesis inhibitor
and a bactericidal antibiotic. It binds to the small 16S
r RNA of the 30S subunit of bacterial ribosome, lead-
ing to codon misreading and inhibition of protein
synthesis [98]. The principal use remains against my-
cobacterial infections, and as a fourth agent along with
isoniazid, rifampin and pyrazinamide in treating tu-
berculosis [99,100]. Mutations of the ribosomal proteins
are the basis of streptomycin resistance in mycobacte-
ria [101]. Moreover, the risk of ototoxicity and nephro-
toxicity limit the contemporary use of streptomycin in
favor of ethambutol [99].
Streptomycin has been shown to be active in
vitro and in vivo against Gram-negative microorgan-
isms such as Brucella spp., Klebsiella granulomatis and
Klebsiella pneumoniae, E. coli, Proteus spp., Aerobac-
ter aerogenes, Francisella tularensis, Haemophilus ducreyi,
Haemophilus influenzae and Yersinia pestis, as well as
Gram-positive bacteria such as Streptococcus viridans
and Enterococcus faecalis [102–107].
Journal of Investigative Surgery

FROM THE SEWER SYSTEM TO
INDUSTRIAL PRODUCTION:
CEPHALOSPORINS
Chronologically, the cephalosporins are the second
class among beta-lactam antibiotics to be discovered
and developed, following the penicillins. The chemical
structure of cephalosporins contains a beta-lactam ring
fused to a six-membered ring containing a sulfur and a
nitrogen atom. Among the most frequently prescribed
and clinically relied upon antibiotics in the U.S., these
pharmaceutical agents account for a significant share
of hospital expenditures [108].
In July 1945, Giuseppe Brotzu (1895–1955) (Figure
1f) isolated a fungus identified as Cephalosporium acre-
monium from sewer water in Cagliari in Sardinia, Italy.
The starting point of his research was the observa-
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tion that the incidence of typhoid fever in the city of
Cagliari was curiously less than in the rest of Italy or
Europe. Using culture filtrates from the sewer system,
Brotzu found that this fungus inhibited the growth of
certain Gram-negative organisms: Salmonella typhi, S.
paratyphi B, Y. pestis, Brucella melitensis, Vibrio cholerae
and Staph. aureus. By contrast, strains of E. coli and
Shigella dysenteriae that he tested exhibited resistance
[109]. Since then, other natural cephalosporins have
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been found to be produced by species of soil bacte-
ria. Unable to proceed with further development in
Italy by himself, in 1946 Brotzu provided cultures of his
fungus to Oxford University. In September 1948, Ed-
ward Abraham (1913–1999) (Figure 1g), a Fleming stu-
dent, commenced investigations into the products of
Brotzu’s microorganism. Abraham subsequently col-
laborated with Guy Newton (1919–1969) (Figure 1h),
at Sir William Dunn School of Pathology.
Among the first compounds isolated in July 1949
was cephalosporin P, so named because it was ac-
tive only against Gram-positive bacteria [110]. Shortly
thereafter, a second compound was found in culture
filtrates from which cephalosporin P had been re-
moved. This second compound was initially named
cephalosporin N, as it was active against Gram-
negative bacteria, as well as Gram-positive ones.
Cephalosporin N was subsequently determined to be
a penicillin, having a D-α-aminoadipoyl side chain,
and it was renamed penicillin N [111]. While investi-
gating penicillin N, a third compound was separated
upon fractionation that was also determined to have
antibacterial activity and was called cephalosporin C
(Figure 2d). Abraham and Newton published their ob-
servations and the structure of cephalosporin C in 1961
[112].
While cephalosporin C was believed to have poten-
tial by itself as a therapeutic agent, because it was not
degraded by staphylococcal penicillinase, its intrinsic
activity was so low that clinical use would mandate
very large doses. Upon continuing their investigations,
Abraham and Newton found that its antistaphylococ-


C 2012 Informa Healthcare USA, Inc.
History of Antibiotics 73
cal activity could be increased markedly by N-acylation
of the side chain [114,115]
Further industrial development of semisynthetic
cephalosporins depended upon their ability to mod-
ify the α-aminoadipoyl side chain in cephalosporin C
to other chemical moieties that confer advantageous
antimicrobial activity [116,117]. The first cephalosporin
released for clinical use developed in this manner
was cephalothin (cefalothin), introduced in 1964 by Eli
Lilly and Company, and it was available only for par-
enteral use. Another among the early semisynthetic
modifications of the C-7 side chain of the cephem nu-
cleus was the addition of a d-phenylglycyl moiety
that produced cephalexin, the first oral cephalosporin
[118]. Since then, a large number of semisynthetic
derivatives with increased potency and antibacterial
spectrum have been introduced, with selection for clin-
ical use based on antibacterial spectrum, pharmacoki-
netics, side effects and cost [119].
HISTORICAL USE AND MECHANISM
OF ACTION OF CEPHALPSPORINS
As ß-lactam antibiotics, cephalosporins are primarily
bactericidal, and a key mode of action involves inter-
ference with bacterial cell wall synthesis. Antibacte-
rial activity of individual cephalosporins is variable
and affected by several factors, including the abil-
ity to resist degradation by enzymes and the ability
to penetrate the bacterial cell wall. Classification of
cephalosporins by generation is a convention whereby
individual agents are grouped and described accord-
ing to in vitro antimicrobial activity [119]. In general,
cephalosporins have not historically been antibiotics
of choice for therapy against penicillin-resistant Strep-
tococcus pneumonia, MRSA or Staphylococcus epidermis,
E. faecalis, Mycoplasma pneumoniae, Clostridium difficile,
or Chlamydia pneumoniae [119]. Progressive generations
of cephalosporins exhibit incremental improvements
with respect to Gram-negative antimicrobial properties
over the preceding generation, often with decreased ac-
tivity against Gram-positive organisms.
The first-generation cephalosporins, such as the par-
enteral drugs cephalothin (1962) and cefazolin (1970),
as well as the oral agent cephalexin (1967), are the most
active of all cephalosporins against Gram-positive bac-
teria, methicillin-susceptible staphylococci, and non-
enterococcal streptococci [118, 120–123]. One of the
second-generation semisynthetic derivatives, cefaclor
(1977), became available in the United States in 1979.
As a group, the second-generation cephalosporins are
less effective against Gram-positive microbes while
being more effective in clinical use with Gram-
negative microbes, including H. influenzae, E. aerogenes
and certain Neisseria, than those agents classified as
first-generation. Of note, the only second-generation
cephalosporin that crosses the blood brain barrier is ce-
furoxime, which is used to treat meningitis [124–128].
 74 Zaffiri et al.
Collectively, third- and fourth-generation agents are
generally considered to be extended-spectrum in their
activity, despite the fact that certain members have
decreased activity against Gram-positive organisms,
but further increased activity against Gram-negative
organisms as compared with the first and second
generations. The third generation cephalosporins may
be clinically useful in treating hospital-acquired and
more especially community infections, although in-
creasing levels of extended-spectrum beta-lactamases
are reducing the clinical utility of this class of an-
tibiotics [129–132]. Third-generation cephalosporins
are also able to penetrate the central nervous sys-
tem, making them useful against meningitis caused
by pneumococci, meningococci, H. influenzae, and
susceptible E. coli, Klebsiella, and penicillin-resistant
N. gonorrhoeae. More specifically, third-generation
J Invest Surg Downloaded from informahealthcare.com by RMIT University on 08/28/14
cephalosporins have frequently been a clinical
treatment of choice for gonorrhea [130,133]. Fourth-
generation cephalosporins including, for example,
cefpirome (1983), cefepime (1987) and cefaclidine
(1989), are extended-spectrum cephalosporins with
improved activity against Enterobacter spp., Citrobacter
fieundiiand, and Serratia marcescens. The class also
provides increased treatment options in combination
therapy with certain aminoglycosides or fluoro-
For personal use only.
quinolones for the treatment of severe P. aeruginosa
infections [134–138].
Further development of advanced-generation
cephalosporins for clinical use is ongoing. Cefto-
biprole (2002), which has antipseudomonal activity,
and ceftaroline (2005) have been suggested as fifth-
generation cephalosporins, although this terminology
remains controversial. Ceftobiprole and ceftaroline
may be less susceptible to development of resistance,
thereby offering treatment options for MRSA [139].
CONCLUSIONS
The history of the development of antibiotics is a fas-
cinating journey through the development of scientific
research but also through the development of modern
society. In fact, it is possible to see how the compelling
need to treat infections, which represented the most
common cause of death at the beginning of the 19th
century, strongly influenced the development of vari-
ous antibiotics. We presented the history of antibiotics
developed for the treatment of syphilis and tuberculo-
sis first, and then turned to the development of antibi-
otics, such as penicillins and cephalosporins, against
Gram-positive bacteria.
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