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22 Chemistry and Biology of Beta-Lactams
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FIGURE 1.28 Skeletal formula of oxacillin.
FIGURE 1.29 Skeletal formula of amoxicillin.
hematuria, agranulocytosis, eosinophilia, leukopenia, neutropenia, thrombocytopenia, hepatotoxicity,
acute interstitial nephritis, and fever.
A broad spectrum of antibiotics are referred to as broad-spectrum antibiotics because they are effective against a wide range of Gram-negative bacteria, such as E. coli and S. typhi, which penicillin does
not have the ability to kill. An example of this would be the antibiotics amoxicillin and ampicillin. There
is, however, a growing incidence of resistance among these organisms.
In the penicillin family of antibiotics, amoxicillin (Figur e 1.29) belongs to the aminopenicillin class,
which is a subclass of penicillin antibiotics. Infectious diseases such as middle ear infections, strep throat
infections, pneumonias, skin infections, odontogenic infections, and urinary tract infections can all be
treated by taking this drug. In most cases, it is taken by mouth, but injections are less common. Nausea
and rash are two of the most common adverse effects associated with this medication. Additionally, as a
result of the combination of clavulanic acid and this drug, it appears to increase the risk of yeast infections as well as diarrhea.
In 1958, the discovery of amoxicillin took place, and it was rst used in medicine in 1972.
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In the
United States, amoxil has been approved for medical use since 1974, and in the United Kingdom, it has
been approved since 1977. It is on the list of essential medicines, which is maintained by the WHO.
There are many reasons why this antibiotic is one of the most commonly prescribed to children.
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As a
generic medication, amoxicillin is available on the market. Approximately 15 million prescriptions were
written for this medication in the United States in 2020, making it the 40th most commonly prescribed
medication in the country.
Among the semisynthetic derivatives of penicillin known as amoxicillin, such as amino-p-hydroxybenzyl penicillin, amoxicillin has a structure similar to ampicillin; however, it has a better absorption
rate when taken by mouth, giving rise to higher concentrations in the blood and urine.2 It is easy for
amoxicillin to diffuse into tissues and body uids due to its high solubility. A small amount of it will pass
through the placenta and will be excreted in small quantities into the breastmilk. As soon as amoxicillin
attaches to the cell wall of susceptible bacteria, it causes them to die. Furthermore, it is also a bactericidal
compound that can kill bacteria. There is good evidence that this product is effective against streptococci, pneumococci, enterococci, H. inuenzae, E. coli, P. mirabilis, N. meningitidis, N. gonorrhoeae,
Shigella, C. trachomatis, Salmonella, B. burgdorferi, and H. pylori.
Among the penicillin family of antibiotics, ampicillin is a member of the aminopenicillin class. A
variety of bacterial infections can be treated and prevented using this drug, such as respiratory tract
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infections, urinary tract infections, meningitis, salmonellosis, and endocarditis, among others. A group
B streptococcal infection may also be prevented in newborns with the use of this medication. The medicine can be taken by mouth, by injection into a muscle, or by intravenous administration. Among the
most common side effects of this medication are rash, nausea, and diarrhea. In the case of people who
are allergic to penicillin, the drug should not be used. Anaphylaxis and C. difcile colitis are examples
of serious side effects that may occur.
In 1958, the ampicillin (Figure 1.30) antibiotic was discovered and was made commercially available
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in 1961.
It is listed on the list of essential medicines of the WHO. According to the WHO, ampicillin
is one of the most critical antibiotics for human medicine. There is a generic version of this medication
available on the market.
Infections caused by many different types of bacteria, both Gram-positive and Gram-negative, can
be treated with ampicillin. In addition to the fact that it was the rst penicillin with “broad spectrum”
activity against Gram-positive bacteria, it was also effective against S. pneumoniae, S. pyogenes, some
isolates of S. aureus (not penicillin-resistant or methicillin-resistant strains), Trueperella, and some
Enterococcus strains. It is also one of the few antibiotics that work against multidrug-resistant E. faecalis
and E. faecium.
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This compound is effective against different strains of Gram-negative bacteria, including N. meningitidis, some strains of H. inuenzae, and some strains of Enterobacteriaceae (although most
strains of Enterobacteriaceae and Pseudomonas are resistant).
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This antibiotic’s spectrum of activity
can be enhanced by co-administration of sulbactam, a drug that inhibits beta-lactamase, an enzyme
produced by bacteria that is responsible for inactivating ampicillin and other related antibiotics.
120, 121
There are times when this antibiotic is used in conjunction with other antibiotics that have different
mechanisms of action, such as vancomycin, linezolid, daptomycin, and tigecycline.
16, 122
In terms of its activity, it is roughly equivalent to that of amoxicillin. This antibiotic is capable of
penetrating Gram-positive as well as some Gram-negative bacteria. It differs from penicillin G, or benzylpenicillin, only by the presence of an amino group, which makes it unique. The amino group present
on both ampicillin and amoxicillin is what allows these antibiotics to pass through the pores of the outer
membrane of Gram-negative bacteria, including E. coli, P. mirabilis, S. enterica, and Shigella.
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The action of ampicillin can be described as an irreversible inhibitor of the enzyme transpeptidase,
which is necessary for bacteria to make their cell walls in order to survive. As ampicillin inhibits the
third and nal stages of bacterial cell wall synthesis in binary ssion, which ultimately leads to the
lysis of bacteria, ampicillin is usually considered a bacteriolytic drug. There are a number of ampicillin
precursors that are currently available on the market. In the gut, these compounds are broken down to
release ampicillin, which acts as a drug. It is important to note that none of the following prodrugs of
ampicillin are currently being used: pivampicillin, metampicillin, bacampicillin, hetacillin, talampicillin, and epicillin (F igure 1.31).
There is another class of antibiotics known as antipseudomonal antibiotics. Gram-negative bacteria,
such as P. aeruginosa, are naturally resistant to a wide range of antibiotics. A number of efforts were
made during the 1960s and 1970s in order to discover antibiotics that were active against Pseudomonas
species. Within this group of antibiotics, there are two types: carboxypenicillins and ureidopenicillins.
In all cases, the drugs are administered by injection: none of them can be taken orally. Carbenicillin,
ticarcillin, and temocillin are some of the carboxypenicillins that are included in this group. There are
three types of ureidopenicillins: mezlocillin, piperacillin, and azlocillin.
In 1970, scientists at Beecham discovered carbenicillin (Figu re 1.32) and marketed it under the name
Pyopen.
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It covers a wide range of Gram-negative bacteria, which includes P. aeruginosa, as well as a
FIGURE 1.30 Chemical structure of ampicillin.
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FIGURE 1.31 Chemical structures of pivampicillin, metampicillin, bacampicillin, hetacillin, talampicillin, and epicillin.
FIGURE 1.32 Structural diagram of carbenicillin.
limited range of Gram-positive bacteria. There is a tendency for carboxypenicillins to be degraded by
beta-lactamase enzymes, although they are more resistant to degradation than ampicillin is to it. There
is also evidence that carbenicillin is more stable at lower pH levels than ampicillin.
The substance in question is a semisynthetic analog of the naturally occurring benzylpenicillin. It is
possible to experience bleeding when taking carbenicillin at high doses. In the distal convoluted tubules
of the kidney, carbenicillin can cause hypokalemia by promoting potassium loss as a result of its use.
Several studies have shown that carbenicillin is effective in the treatment of urinary tract infections
caused by bacteria such as P. aeruginosa, E. coli, and some species of Proteus. Listed below is some
information regarding the susceptibility data of a few medically signicant organisms to carbenicillin. It
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is important to note that these are not all the species of bacteria that are susceptible to carbenicillin: E.
coli 1.56– 64 μg/mL, P. mirabilis 1.56 –3.13 μg/mL, and P. aeruginosa 3.13–>1024 μg/mL.
Ticarcillin (Fig ure 1.33) is a carboxypenicillin that belongs to the group of antibiotics. It can be sold
and used as ticarcillin/clavulanic acid when combined with clavulanate. This antibiotic is primarily used
in the treatment of Gram-negative bacteria, particularly P. aeruginosa and P. vulgaris, which are the
most common Gram-negative bacteria. In addition to that, it is one of the few antibiotics that are capable
of treating infections caused by S. maltophilia. This product is available in two types of powder: white
and pale yellow. It is a highly soluble compound in water, but it should only be dissolved immediately
prior to use to prevent it from degrading. As far back as 1963, the invention was patented. In molecular
biology, ticarcillin is commonly used to test the uptake of marker genes into bacteria instead of ampicillin, which is an antibiotic used to treat bacteria. In addition, it prevents the appearance of satellite colonies, which may occur in the medium if ampicillin is broken down. Molecular biology uses it as well to
kill Agrobacterium, which is used to deliver genes into the cells of plants.
A beta-lactamase-resistant penicillin, temocillin (Figure 1.34), has been introduced by Beecham and
is marketed by Eumedica Pharmaceuticals under the brand name Negaban.
125, 126
This drug is primarily
used for treating multiple drug-resistant Gram-negative bacteria that are resistant to multiple types of
antibiotics. The compound is a 6-methoxy penicillin; it is also a carboxypenicillin.
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There are several
different organisms that it is normally effective against, including M. catarrhalis, B. abortus, B. cepacia,
C. species, E. coli, H. inuenzae, K. pneumoniae, P. multocida, P. mirabilis, S. typhimurium, and Y.
enterocolitica. Furthermore, it has also been shown to be effective against some species of Enterobacter,
M. morganii, and Serratia. In the case of Acinetobacter species or P. aeruginosa, temocillin does not
exhibit any useful activity. In general, its primary use is against Enterobacteriaceae, and in particular
against strains that produce extended-spectrum beta-lactamases or AmpC beta-lactamases.
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Mezlocillin (Figure 1.35) is a generally recognized penicillin antibiotic that has a wide spectrum of
activity. The antibiotic is effective against both Gram-negative bacteria and some Gram-positive bacteria. In contrast to most other extended-spectrum penicillins, it is excreted by the liver, making it an
excellent choice for treating infections of the biliary tract, such as ascending cholangitis. In the same
way as all other beta-lactam antibiotics, mezlocillin inhibits the third and last stages of the synthesis of
the bacterial cell wall by binding to PBPs found on bacteria. Ultimately, this will result in the lysis of
FIGURE 1.33 Structural diagram of ticarcillin.
FIGURE 1.34 Chemical diagram for temocillin.
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FIGURE 1.35 Structural diagram of mezlocillin.
FIGURE 1.36 Skeletal formula of piperacillin.
the cells. It is possible to make mezlocillin in a variety of ways, including by reacting ampicillin with
chlorocarbamate-1 in the presence of triethylamine.
Piperacillin (Figur e 1.36) belongs to the ureidopenicillin class of beta-lactam antibiotics.
various types of infections that can be treated with piperacillin, such as abdominal infections, bacteremia, gynecological infections, respiratory infections, and urinary infections, that are caused mostly by
P. aeruginosa and other bacteria of infectious origin.
ureidopenicillins is characterized by the incorporation of a polar side chain that enhances the penetration
of the antibiotic into Gram-negative bacteria and reduces the susceptibility to cleavage by Gram-negative
beta-lactamase enzymes. As a result of these properties, the product is able to inhibit the growth of
the important hospital pathogen P. aeruginosa. As a result, piperacillin is sometimes referred to as an
“antipseudomonal penicillin”.
Piperacillin, when used alone, is not very effective against Gram-positive pathogens, such as S.
aureus, as the beta-lactam ring is hydrolyzed by the beta-lactamase of the bacteria. In 1974, the drug was
patented, and it was approved for medical use in 1981. The most common way to use piperacillin is to
combine it with the beta-lactamase inhibitor tazobactam (piperacillin/tazobactam), which will increase
piperacillin’s effectiveness by inhibiting many of the beta-lactamases to which it is susceptible. As a
result of the co-administration of tazobactam, there is no evidence that it confers activity against MRSA,
as penicillin (and most other beta-lactams) do not avidly bind to the PBPs of this pathogen.
to the WHO, piperacillin is one of the most critical compounds in human medicine. The most common side effects associated with the administration of piperacillin–tazobactam include gastrointestinal
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There are
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The chemical structure of piperacillin and other
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According
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symptoms such as constipation, diarrhea, nausea, and vomiting; dermatologic symptoms such as erythema, pain, phlebitis, and rash; and neurologic symptoms such as headaches and insomnia.
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Azlocillin (Figure 1.37) is an acyl ampicillin antibiotic with a broad spectrum of activity, as well as a
higher permeation rate in vitro as compared to carboxy penicillin antibiotics. The properties of azlocillin
are similar to those of mezlocillin and piperacillin. The antibiotic exhibits antibacterial activity against
a wide range of bacteria, including P. aeruginosa, and, unlike most cephalosporins, it demonstrates
antimicrobial activity against enterococci, in contrast to other antibiotics. Here is a look at some data
regarding MIC susceptibility for a few medically signicant bacteria: E. coli 1–32 μg/mL, Haemophilus
spp. 0.03–2 μg/mL, and P. aeruginosa 4–6.25 μg/mL.
1.3.2 Cephalosporins
A cephalosporin (Figu re 1.38) is a class of beta-lactam antibiotics that are derived from the fungus
Acremonium, which was formerly known as Cephalosporium. As a group with cephamycins, they are
considered to be a subgroup of beta-lactam antibiotics known as cephems. Cephalosporin was rst discovered in 1945, and its rst sales took place in 1964.16 There are six dihydrothiazine rings in a cephalosporin molecule. In general, substitutions at position 3 affect the pharmacology of the drug; substitutions
at position 7 affect the antibacterial activity of the drug, but this is not always the case.
Cephalosporin antibiotics can be prescribed for the prophylaxis and treatment of infections caused
by bacteria that are susceptible to this particular form of antibiotic. A majority of the rst-generation
cephalosporins are active against Gram-positive bacteria, such as Staphylococcus and Streptococcus.
Therefore, they are mostly used in the treatment of skin and soft tissue infections, as well as the prevention of hospital-acquired surgical infections.
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Over time, successive generations of cephalosporins have
increased their activity against Gram-negative bacteria, even though they have often reduced their activity against Gram-positive organisms. Due to the different structure of the beta-lactam antibiotics, the
antibiotic may be used in patients who are allergic to penicillin. It is possible for the drug to be excreted
in the urine after it has been taken.
FIGURE 1.37 Skeletal formula of azlocillin.
FIGURE 1.38 Core structure of the cephalosporin antibiotics.
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Cephalosporin therapy is associated with a number of adverse drug reactions (ADRs) that may include
diarrhea, nausea, rash, electrolyte disturbances, as well as pain and inammation at the injection site.
ADRs that are uncommon include vomiting, headaches, dizziness, vaginal and oral candidiasis, pseudomembranous colitis, superinfections, eosinophilia, nephrotoxicity, neutropenia, thrombocytopenia, and
fever.
Cephalosporin is a beta-lactam antibiotic that is bactericidal, and, as with other beta-lactam antibiotics, it disrupts the synthesis of the peptidoglycan layer that makes up the bacterial cell wall. In order to
maintain the structural integrity of the cell wall, the peptidoglycan layer is important. During the process
of synthesizing the peptidoglycan, the nal step of transpeptidation is carried out by PBPs. It is known
that PBPs bind to the D-Ala-D-Ala at the end of muropeptides (peptidoglycan precursors) in order to
cross-link the peptidoglycan. Beta-lactam antibiotics mimic the D-Ala-D-Ala site, thereby irreversibly
inhibiting PBP cross-linking of peptidoglycan.
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There are different ways in which the nucleus of cephalosporin can be modied in order to gain different properties. Depending on the antimicrobial properties of a cephalosporin, they can be grouped into
“generations”. It should be noted that the rst cephalosporins were classied as rst-generation cephalosporins; however, later, more extended-spectrum cephalosporins were classied as second-generation
cephalosporins. It is a well-known fact that each newer generation has greater Gram-negative antimicrobial properties than the preceding generation, and, in most cases, their activity against Gram-positive
organisms has decreased as well. There is, however, a true broad spectrum of activity with the fourthgeneration cephalosporins.
The rst generation includes cefalexin, cefadroxil, cefazolin, cefapirin, cefacetrile, cefaloglycin,
cefalonium, cefaloridine, cefalotin, cefatrizine, cefazaur, cefazedone, cefradine, cefroxadine, and ceftezole (Figure 1.39).
Second generation includes cefuroxime, cefprozil, cefaclor, cefonicid, cefuzonam, cefamandole
cefmetazole, cefminox, and cefbuperazone (Figure 1.4 0).
Third generation includes cefdinir, ceftriaxone, ceftazidime, cexime, cefpodoxime, ceftiofur, cefotaxime, ceftizoxime, cefditoren, ceftibuten, cefovecin, cefdaloxime, cefcapene, cefetamet, cefmenoxime,
cefodizime, cefpimizole, cefteram, ceftiolene, cefoperazone, and cefotiam (Figure 1.41). Flomoxef and
latamoxef are in a new, related class called oxacephems.
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Fourth generation includes cefepime, cefquinome, cederocol, cefclidine, ceuprenam, cefoselis,
cefozopran, and cefpirome (Figu re 1.42).
Fifth generation includes ceftaroline fosamil, ceftolozane, and ceftobiprole (Figure 1.43).
1.3.3 Cephamycins
There is a group of antibiotics called cephamycins (Figure 1.4 4), which are beta-lactams. As a matter
of fact, they are very similar to cephalosporins, and cephamycins are sometimes classied as cephalosporins as well. Similarly to cephalosporins, cephamycins are also based upon the cephem nucleus. In
contrast to most cephalosporins, cephamycins are very effective against bacteria that live in anaerobic
conditions. In the beginning, cephamycins were produced by Streptomyces, but synthetic versions have
also been developed.
There is a methoxy group at the position 7-alpha of cephamycins. A further advantage of cephamycins is that they are stable against organisms that produce extended-spectrum beta-lactamase (ESBL),
although their use in clinical practice for this indication is not yet widespread. One of the most commonly used cephamycins is cefoxitin, while cefotetan is another (Figure 1.45).
As a second-generation cephamycin antibiotic, cefoxitin was formulated by Merck & Co., Inc. in the
year following the discovery of cephamycin C, in 1972, and is derived from cephamycin C. Cefoxitin was
synthesized in order to create an antibiotic that has a broader spectrum of activity.
Cefoxitin has demonstrated in vitro antimicrobial activity against a broad range of Gram-positive
and Gram-negative bacteria, including anaerobes, in many different experiments. In addition to this,
it is inactive against most strains of P. aeruginosa as well as many strains of E. cloacae. In addition,
staphylococci that are resistant to methicillin and oxacillin should also be considered clinically resistant
to cefoxitin, even if they test susceptible to the drug in vitro. The following are the major bacterial strains
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FIGURE 1.39 First-generation cephalosporin antibiotics: cefalexin, cefadroxil, cefazolin, cefapirin, cefacetrile, cefalo-
glycin, cefalonium, cefaloridine, cefalotin, cefatrizine, cefazaur, cefazedone, cefradine, cefroxadine, and ceftezole.
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FIGURE 1.40 Second-generation cephalosporin antibiotics: cefuroxime, cefprozil, cefaclor, cefonicid, cefuzonam, cefa-
mandole cefmetazole, cefminox, and cefbuperazone.
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FIGURE 1.41 Third-generation cephalosporin antibiotics: cefdinir, ceftriaxone, ceftazidime, cexime, cefpodoxime,
ceftiofur, cefotaxime, ceftizoxime, cefditoren, ceftibuten, cefovecin, cefdaloxime, cefcapene, cefetamet, cefmenoxime,
cefodizime, cefpimizole, cefteram, ceftiolene, cefoperazone, and cefotiam.
that are susceptible to cefoxitin: methicillin-susceptible S. aureus, Streptococcus sp., E. coli, Salmonella
sp., P. vulgaris, Flavobacterium sp., and Klebsiella sp.
The most common bacteria resistant to cefoxitin
L. monocytogenes, Enterobacter sp., and Bacteroides sp. The following is a list of medically important
microorganisms for which susceptibility data have been collected, measured by an MIC, which is an
alternative, liquid medium test for susceptibility: E. coli: 0.2–64 μg/mL, H. inuenzae: 0.5–12.5 μg/mL,
and S. pneumoniae: 0.2–1 μg/mL.
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include methicillin-resistant S. aureus, enterococci,
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