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32 Chemistry and Biology of Beta-Lactams
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FIGURE 1.41 Continued
There are several uses for cefoxitin, including treating skin infections caused by Staphylococcus bacteria, urinary tract infections, bronchitis, tonsillitis, ear infections, bacterial pneumonia, sepsis, bone
and joint infections, abscesses and infections in the abdomen, perineum injuries, pelvic inammatory
disease, gonorrhea, infections caused by susceptible bacteria. The side effects associated with cefoxitin
are considered to be mild. The most common side effects include local tenderness or pain at the site of
injection, skin color change, mild diarrhea, mild nausea, headache, loss of appetite, vaginal discharge
and itching, swelling of the feet or legs, and dizziness.
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FIGURE 1.41 Continued
34 Chemistry and Biology of Beta-Lactams
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FIGURE 1.42 Fourth-generation cephalosporin antibiotics: cefepime, cefquinome, cederocol, cefclidine, ceuprenam,
cefoselis, cefozopran, and cefpirome.
Cefotetan is an injectable antibiotic of the cephamycin type that is used for prophylaxis and treatment
of infection caused by bacteria. It is often grouped together with second-generation cephalosporins and
has a similar antibacterial spectrum but has an additional anti-anaerobe coverage as well. This drug was
developed by Yamanouchi. The drug is marketed outside of Japan under the brand names Apatef and
Cefotan by AstraZeneca.
There is a wide range of applications for cefotetan, which has been used for the treatment of bacterial
infections of the bone, skin, urinary tract, and lower respiratory tract. There are several notable species
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FIGURE 1.42 (Continued).
of bacteria, including Bacteroides, Streptococcus, and E. coli. The following represents MIC susceptibil-
ity data for a few medically signicant bacteria: E. coli: 0.06 µg/mL, B. fragilis: ≤0.06–512 µg/mL, and
C. perfringens: 1–4 µg/mL.
There is an N-methylthiotetrazole (NMTT or 1-MTT) side chain within the chemical structure of
cefotetan, similar to the side chains in several other cephalosporins. As the antibiotic is broken down in
the body, it releases free NMTT, which can cause hypoprothrombinemia (likely due to inhibition of vitamin K epoxide reductase), and a reaction with ethanol similar to that caused by disulram (Antabuse), as
it inhibits the enzyme aldehyde dehydrogenase.
138
1.3.4 Oxacephem
Oxacephems are beta-lactam molecules similar to cephems; however, they differ in that oxygen replaces
the sulfur atom in the cephem molecule. They are synthetic compounds that are not found in nature,
and they are generally used as beta-lactam antibiotics. Latamoxef and omoxef are examples of such
139, 140
drugs.
An oxacephem antibiotic, like latamoxef (or moxalactam as it is often called, Fig ure 1.46), is generally
grouped with cephalosporins. The use of latamoxef has been associated with prolonged bleeding time,
and several cases of coagulopathy, some of which were fatal, have been reported during the 1980s.
142
The drug latamoxef is no longer available in the United States. The disulram reaction is induced
141,
by the methylthiotetrazole side chain of latamoxef when it is mixed with alcohol, as is the case with
other cephalosporins with this side chain. Furthermore, the methylthiotetrazole side chain inhibits the
gamma-carboxylation of glutamic acid. As a result, vitamin K can be interfered with by this compound.
According to research, it belongs to the third generation of cephalosporins.
143
Shionogi developed omoxef (Fig ure 1.47) as a new oxacephem antibiotic for treating bacterial infections. There has been some controversy regarding whether or not it is a second-generation cephalospo-
144
rin
or a fourth-generation cephalosporin.
145
As of 1988, the drug was approved for medical use under
the trade name Flumarin, which was patented in 1982.
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FIGURE 1.43 Fifth-generation cephalosporin antibiotics: ceftaroline fosamil, ceftolozane, and ceftobiprole.
FIGURE 1.44 Core structure of the cephamycins.
FIGURE 1.45 Structure of the classical cephamycins (cefoxitin and cefotetan).
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FIGURE 1.46 Skeletal formula of latamoxef.
37Beta-Lactams
FIGURE 1.47 Chemical structure of omoxef.
FIGURE 1.48 General structure of carbapenems.
1.3.5 Carbapenem
A carbapenem (Fig ure 1.48) antibiotic is one of the most commonly used antibiotics in treating severe
bacterial infections. In most cases, this class of antibiotics is used in cases where there is a known or
suspected multidrug-resistant (MDR) bacterial infection. As a beta-lactam antibiotic, carbapenems are
a member of the same drug class as penicillins and cephalosporins; they kill bacteria by binding to
the PBP found in bacteria, thus inhibiting bacterial cell wall synthesis. Despite this, these antibiotics
each have a broader spectrum of activity than the majority of cephalosporins and penicillins. Further,
carbapenems are generally not affected by emerging antibiotic resistance, even when it comes to other
beta-lactam antibiotics. The carbapenems, in terms of their chemical structure, are very similar to the
penicillins (penams). In this structure, however, the sulfur atom at position 1 has been replaced with a
carbon atom, and an unsaturation has been introduced as a result of the substitution, thus resulting in the
name carbapenems, the name given to this group of antibiotics.
A carbapenem antibiotic was developed by Merck & Co. from a naturally occurring product of S.
cattleya, the carbapenem thienamycin.
146
Increasing rates of carbapenem resistance have been raised in
recent years as a result of the lack of therapeutic options that are available for treating infections that
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are caused by carbapenem-resistant bacteria (such as K. pneumoniae and other carbapenem-resistant
Enterobacteriaceae).
147–149
A number of carbapenem antibiotics have been approved for clinical use, including imipenem, meropenem, ertapenem, doripenem, biapenem, and tebipenem (Figure 1.49). It was Merck & Co. that developed
imipenem, the rst carbapenem that was clinically used. In 1985, the US FDA approved the use of this
drug for therapeutic purposes. This drug is formulated with the dehydropeptidase inhibitor cilastatin in
order to counteract the fact that imipenem is hydrolyzed in the mammalian kidney by a dehydropeptidase enzyme into a nephrotoxic intermediate. There are two types of imipenem treatments available:
intravenous and intramuscular.
Meropenem does not require the simultaneous administration of cilastatin with meropenem, as it
is stable to mammalian dehydropeptidases. In 1996, the US FDA approved the use of this drug. For
most indications, it is convenient to administer it three times a day instead of four times a day as is the
case with imipenem. The administration of smaller doses, such as less than 1 gram, can be done as an
IV bolus, whereas imipenem is usually given as an infusion which lasts from 20 minutes to 1 hour.
FIGURE 1.49 Carbapenems approved for clinical use: imipenem, meropenem, ertapenem, doripenem, biapenem, and
tebipenem.
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Compared to imipenem, meropenem has a slightly lower potency against Gram-positive pathogens and a
slightly higher potency against Gram-negative pathogens. When compared to imipenem, meropenem is
effective at treating bacterial meningitis without causing seizures.
150
The administration of ertapenem may be given either intravenously or intramuscularly once a day.
Neither P. aeruginosa nor Acinetobacter species are affected by the drug. These two bacteria are important causes of hospital-acquired infections. There is a great deal of similarity between the spectrum of
activities of doripenem and meropenem. Due to its increased stability in solution, it is possible to use
extended infusions, and it is somewhat less likely to cause seizures than other carbapenems.
151
In terms
of efcacy and adverse event rates, biapenem (Japanese approval 2001) is comparable to other carbapen-
152
ems.
Tebipenem (Japanese approval 2015) was the rst carbapenem whose prodrug form, the pivalyl
ester, was approved for oral administration.
153
There are several carbapenems that are not approved or experimental, including razupenem (PZ-601),
lenapenem, sulopenem, thienamycin (thienpenem), and tomopenem (Figure 1.50). There is currently
research being conducted on razupenem, a carbapenem antibiotic which is being tested to see if it can
be used against strains that are resistant to other carbapenems as well. PZ-601, despite its promising
phase 2 results, was recently dropped by Novartis (which acquired PZ-601 through a merger agreement
with Protez Pharmaceuticals), citing a high rate of adverse reactions during testing as the reason. A drug
called sulopenem is undergoing clinical trials for the treatment of drug-resistant urinary tract infections.
The rst carbapenem that was discovered was thienamycin (thienpenem).
1.3.6 Carbacephem
The carbacephems are a class of synthetic antibiotics, based on a structure that closely resembles that of
cephalosporin, which is a type of cephem. Carbacephems are similar to cephems, but instead of a sulfur
atom, a carbon atom replaces that atom in the chemical structure. By inhibiting the synthesis of the cell
wall, it prevents the division of bacteria.
Medications such as loracarbef (Figure 1.51) are antibiotics.
154
In spite of the fact that it is a carbacephem, it is often grouped together with cephalosporins of the second generation. As a synthetic “carba”
analog of cefaclor, loracarbef is more stable. As of 1991, loracarbef was approved by the FDA under the
FIGURE 1.50 Chemical diagram for razupenem, lenapenem, sulopenem, thienamycin (thienpenem), and tomopenem.
40 Chemistry and Biology of Beta-Lactams
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FIGURE 1.51 Structural diagram of loracarbef.
FIGURE 1.52 Skeletal formula of clavulanic acid.
trade name Lorabid and was marketed under this name. The use of this drug was discontinued in 2006 as
a result of health concerns. A number of infections of the kidney, lungs, maxillary sinuses, throat, skin,
and urinary tract were treated with loracarbef in the past. Loracarbef was shown to be effective against
both Gram-negative and Gram-positive bacteria in both respiratory tract infections and sinus infections,
tonsillitis, staph infections, skin infections, urinary tract infections, and kidney infections. In the study,
it was found that the drug was particularly effective against infections caused by E. coli, S. pyogenes, S.
aureus, S. saprophyticus, S. pneumoniae, H. inuenzae, and M. catarrhalis. The most common adverse
effect associated with loracarbef is diarrhea. Children under the age of 12 are more likely to experience
side effects than those over the age of 12.
1.3.7 Clavulanic Acid, Sulbactam, and Tazobactam
Clavulanic acid (Figu re 1.52) is a beta-lactam drug that acts as an inhibitor of beta-lactamases based on
the mechanism through which the drug works. In spite of the fact that it is not an effective antibiotic on
its own when combined with penicillin-group antibiotics, it can be used to overcome antibiotic resistance
in bacteria that secrete beta-lactamase, which is an enzyme that otherwise inactivates most penicillins.
Typically, potassium clavulanate (clavulanic acid as potassium salt) is combined with one of the two
antibiotics: amoxicillin and ticarcillin in its most common preparation. It was in 1974 that clavulanic
acid was patented. The name comes from the strains of S. clavuligerus, which produce clavulanic acid
as a by-product.
155, 156
Amoxicillin–clavulanic acid is an antibiotic that is used as a rst-line treatment for a wide variety of
infections, including sinus infections, urinary tract infections, and pyelonephritis, among others. There
are a number of reasons why this is the case. One of them is its efcacy against Gram-negative bacteria, which are often more difcult to control than Gram-positive bacteria when using chemotherapeutic
antibiotics. It has been reported that the use of clavulanic acid with penicillins has been associated with
an increased incidence of cholestatic jaundice and acute hepatitis during or shortly after the therapy. As
far as the jaundice associated with this condition is concerned, it is usually self-limiting and very rarely
fatal. There have been reports of allergic reactions associated with this drug.
157
Although clavulanic acid has a beta-lactam structure that is structurally similar to that of penicillin,
the biosynthesis of this compound involves a different biochemical pathway as opposed to that of penicillin. As a starting material, glyceraldehyde-3-phosphate and L-arginine are used in the production of
clavulanic acid by the bacteria S. clavuligerus.
158, 159
The exact mechanism for each of the enzymatic
reactions in the pathway is not completely understood yet, despite the fact that the intermediates of the
pathway are known. There are three main enzymes involved in the process: clavaminate synthase, betalactam synthase, and N2-(2-carboxyethyl)-L-arginine (CEA) synthase.
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FIGURE 1.53 Skeletal formula of sulbactam.
FIGURE 1.54 Chemical structure of tazobactam.
A semisynthetic penicillinate sulfone with a beta-lactam ring produced from 6-aminopeniclanic acid
is called sulbactam (Figure 1.53). It is known that sulbactam is an inhibitor of beta-lactamase enzymes.
Combining this drug with beta-lactam antibiotics gives a better chance of inhibiting beta-lactamase, an
enzyme produced by bacteria that is responsible for destroying antibiotics.
160
The invention was patented
in 1977, and it was approved for medical use in 1986. The combination of ampicillin and sulbactam is
available on the market in the United States. Sulperazon is a combination of cefoperazone and sulbactam
that is available in many countries around the world. May 2023 will be the rst year that the co-packaged
combination of sulbactam/durlobactam is approved for medical use in the United States. In terms of its
use, sulbactam is mostly used as a suicide inhibitor of beta-lactamase. It shields more potent beta-lactams
such as ampicillin from interacting with it.
lactam ring, which gives it some antibacterial action by inhibiting the PBPs 1 and 3, but not 2.
161
Sulbactam is a beta-lactam antibiotic containing a beta-
162
A drug called tazobactam (Figure 1.54) is a pharmaceutical agent that is used to inhibit the action of
bacterial beta-lactamases, especially those belonging to the SHV-1 and TEM groups. Usually, it is used
in the form of its sodium salt, tazobactam sodium, because it is more readily absorbed. There is a combination of tazobactam and the extended-spectrum beta-lactam antibiotic piperacillin, which is used in
the treatment of P. aeruginosa infections, known as piperacillin/tazobactam. In addition to broadening
the spectrum of piperacillin, tazobactam enhances its effectiveness against bacteria that express betalactamase and would normally degrade the antibiotic under normal conditions.
163
It was patented in 1982,
and in the early 1990s, tazobactam became available for medical use for the rst time.
1.4 Tricyclic β-Lactams
Tricyclic beta-lactams, also known as trinems or tribactams, are another type of beta-lactam. There is
a distinct characteristic of tribactams in that these compounds consist of beta-lactam ring A, an unsaturated carbocyclic ve-membered ring B, and a third ring C which is in general a carbocyclic or heterocyclic ve-, six-, or seven-membered ring (Fig ure 1.55). Using SAR studies, it is possible to further rene
the properties of ring C by adding substrates, thus allowing a better optimization of biological properties.
Generally, tribactams are very effective at killing Gram-positive bacterial strains. In the case of Gramnegative bacteria, on the other hand, their activity is greatly affected by the nature of the substituent and
the conguration of the stereogenic centers. A successful and clinically promising drug candidate in the
form of 4a-methoxy-tribactam can be seen in Figure 1.56.
Sanfetrinem is a tricyclic beta-lactam antibiotic that is readily available as an orally administered
drug, with broad-spectrum activity against several kinds of bacteria, including Gram-positive and
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