Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5594_Библиотеки_им_академика_М_И_Перельмана
.pdf
12 Chemistry and Biology of Beta-Lactams
https://t.me/med1917
of this study indicate that TBL uptake is metabolically linked, which means that the concentration
of the toxin in planta does not have to be very high in order to disrupt nitrogen metabolism in plants
effectively.
1.2.4 Tigemonam
Tigemonam (Figure 1.12), a monobactam antibiotic, is a powerful antibacterial agent.
86, 87
As a Gram-
positive bacterium, it has a stable inhibitory activity against ß-lactamases; however, it has no inhibitory
activity against Pseudomonas. A salt of tigemonam, tigemonam dicholate, is an orally absorbed salt of
tigemonam that is very effective.
Monobactams such as tigemonam are administered orally. The majority of strains of E. coli, Klebsiella
spp., E. aerogenes, C. diversus, Providencia spp., A. hydrophila, Salmonella spp., Shigella spp., S. marc-
escens, Y. enterocolitica, and Proteus spp. were inhibited at less than or equal to 1 microgram/mL.87 This
product inhibited the growth of Haemophilus species, Neisseria species, and B. catarrhalis at concentrations less than or equal to 0.25 microgram/mL. This product did not inhibit the growth of Pseudomonas
spp. or Acinetobacter spp. In tests performed with tigemonam, it has been shown to be more effective
in inhibiting major members of the Enterobacteriaceae family that are resistant to trimethoprim-sulfamethoxazole and gentamicin than cephalexin and amoxicillin-clavulanate. In some cases, E. cloacae
and C. freundii strains resistant to aminothiazole iminomethoxy cephalosporins and AZM were also
resistant to tigemonam.
As shown in Table 1.3, tigemonam has the ability to inhibit Gram-positive and anaerobic bacteria. The
MIC was 16 micrograms/mL for 90% of the hemolytic streptococci of groups A, B, and C as well as for
S. pneumoniae, but it was 64 micrograms/mL for 90% of enterococci, Listeria species, Bacteroides spe-
cies, and viridans group streptococci. There was no hydrolysis of tigemonam by the usual plasmid betalactamases like TEM-1 and SHV-1 or by the chromosomal beta-lactamases of Enterobacter, Morganella,
Pseudomonas, and Bacteroides species. There was an inhibition of beta-lactamases in E. cloacae and P.
aeruginosa, despite the fact that they did not induce beta-lactamases in them. The growth medium had a
minimal effect on the in vitro activity of tigemonam, and the MICs and MBCs were in close agreement
with each other (Ta ble 1.4).
1.2.5 Other Related Compounds
Carumonam (INN) is an antimicrobial drug that belongs to the monobactam family.88 Due to its high
resistance to beta-lactamases, it is very difcult for bacteria to break it down through the use of betalactamase enzymes. Figure 1.13 shows the chemical structure of the compound. Basically, carumonam
is a sulfonated monocyclic lactam antibiotic, which targets the PBP in bacteria. There is a high degree
of activity of carumonam against Enterobacteriaceae, P. aeruginosa, as well as H. inuenzae, while it
exerts only weak and inactive activity against S. pneumoniae and S. aureus. It has been found that carumonam is resistant to the hydrolysis caused by beta-lactamases.
The antibacterial activity of carumonam (AMA-1080), a synthetic sulfazecin derivative, has been
compared with the activity of AZM, cefoperazone, ceftazidime, and cefsulodin in vitro and in vivo.89
FIGURE 1.12 Chemical structure of tigemonam.
89
TABLE 1. 3
https://t.me/med1917
Activity of Tigemonam Against Gram-Positive and Anaerobic Bacteria
MIC (µg/m L)
Antibiotic Organism
Tigemonam B. fragilis
Aztreonam
Tigemonam C. perfringens
Aztreonam
Tigemonam L. monocytogenes
Aztreonam
Tigemonam Viridans group streptococci
Aztreonam
Tigemonam S. faecalis
Aztreonam
Tigemonam S. pneumoniae 8–32 8 16
Aztreonam
Tigemonam Group A, B, C, G, and F streptococci 1–6 8 8
Aztreonam
Tigemonam S. epidermidis
Aztreonam
Tigemonam S. aureus
Aztreonam
Range 50% 9 0%
>128 >128 >128
>128 >128 >128
8–>32
>32 >32 >32
>128 >128 >128
>128 >128 >128
>128 >128 >128
>128 >128 >128
>128 >128 >128
>128 >128 >128
>32 >32 >32
>32 >32 >32
>128 >128 >128
>128 >128 >128
>128 >128 >128
>128 >128 >128
16 16
13Beta-Lactams
TABLE 1.4
Comparison of MICs and MBCs of Tigemonam
MBC (µg/m L) MIC (µg/m L)
Organism
S. marcescens 0.5–8 1.5 0.25–1 0.4
P. mirabilis 0.12–8 1.5 0.03–0.12 0.05
M. morganii 0.25–2 0.7 0.03–0.25 0.1
E. cloacae 0.06–4 0.3 0.06–4 0.6
C. freundii 0.06–1 0.4 0.5–4 1.7
K. pneumoniae 0.25–8 1.7 0.06–2 0.5
E. coli 0.25–2 0.6 0.12–1 0.3
Range Geometric mean Range Geometric mean
FIGURE 1.13 Chemical structure of carumonam.
14 Chemistry and Biology of Beta-Lactams
https://t.me/med1917
For 90% of the 1,156 clinical Enterobacteriaceae isolates that were tested, the MIC for carumonam was
in the range of 0.013 and 25 micrograms/mL, which was the lowest value among the antibiotics tested.
As an example, the MIC of carumonam was 0.2 micrograms/mL for 90% of K. oxytoca, while the MIC
of AZM was 50 micrograms/mL for 90% of K. oxytoca. As the results of the tests carried out against
K. pneumoniae and E. cloacae demonstrated, carumonam is superior to AZM as well as the reference
cephalosporins.
For 90% of P. aeruginosa isolates, the MIC of carumonam was 12.5 micrograms/mL, which was comparable to the MICs of AZM and ceftazidime. In addition, carumonam was found to have a high afnity
for the PBP-3 of Gram-negative bacteria but not for the PBPs of S. aureus and B. fragilis. Carumonam
is resistant to hydrolysis by 12 beta-lactamases from plasmids, as well as by 7 beta-lactamases from
chromosomes. In comparison with AZM, it was more stable to hydrolysis by the beta-lactamase of K.
oxytoca. This stability can be explained by the superiority of carumonam’s in vitro and in vivo effects
over those of AZM against this species both in vitro and in vivo. In general, the protective activities of
carumonam and reference antibiotics (50% effective dose) in mice with experimental intraperitoneal
infections correlated with their in vitro activities (MIC). It has been shown that carumonam has excellent
antibacterial activity against most aerobic Gram-negative bacteria.
The antibiotic pirazmonam (Figure 1.14) is a monocyclic beta-lactam. In terms of activity against
nonfermentative Gram-negative bacteria, pirazmonam is more effective than aztreonam.
Monosulfactam (2-oxoazetidine-1-oxysulfonates) is a type of monocyclic beta-lactam that differs from
the general class of monobactams by belonging to a synthetic group of monocyclic beta-lactams bearing an OSO3− substituent at the N1 position of the beta-lactam ring. According to research reports,
some of these compounds (Fig u re 1.15) are capable of possessing broad-spectrum antibacterial activit y.90 Furthermore, these compounds were also found to be active against Gram-positive organisms (with
MICs as low as <0.05 to 100+ g/mL) and only slightly affected by the introduction of a methyl group at
position 4 of the beta-lactam ring in these compounds. Also, it was shown that beta-lactam hydroxamates
(compounds that contain an N1-linked hydroxyl group that is not substituted) were inactive, possibly as
a result of the lack of beta-lactam reactivity and the improper placement of the essential anionic charge.
A monophospham is a monocyclic beta-lactam derivative, in which position 1 is derivatized with
a phosphonate- or phosphinate-bearing group (Fig u r e 1.16). It should be noted that the phosphoruscontaining group is either directly attached to the ring nitrogen or separated from the ring nitrogen by
an oxygen atom, which is situated between the azetidin-2-one nitrogen and the acidic moiety. It has
been described that the groups mentioned above function as activators of the β-lactam amide bond. In
the monophospham series, the side chain containing the C3-aminothiazoleoxime proved to be optimal
and provided compounds showing a potent antibacterial effect. As a result of an increase in the size and
lipophilicity of the phosphonate esters at position 1, the intrinsic activity of these compounds decreased.
The monophosphams differ from their direct sulfonated counterparts in that they lack activity against
Gram-positive bacteria and they have less intrinsic antibacterial properties. When compared with the
corresponding monobactams, however, most commonly they are more stable toward beta-lactamases.
FIGURE 1.14 Chemical structure of pirazmonam.
15Beta-Lactams
https://t.me/med1917
FIGURE 1.15 Examples of monosulfactams.
FIGURE 1.16 Examples of monophosphams.
A monocarbam is a monocyclic beta-lactam antibacterial agent that is synthesized from monocyclic
beta-lactams that possess an activating sulfamoylcarbamoyl group on the beta-lactam nitrogen atom
(Fig u re 1.17). There have been a variety of compounds prepared, and it has been observed that the
-CONHSO2R activating group can tolerate multiple substituents (e.g., H, alkyl, aryl, amino, or methoxy).
It was found that all of these compounds were stable toward beta-lactamases as well as highly active
against aerobic Gram-negative bacteria. A side chain containing aminothiazoleoxime is required for
the highest level of activity at the beta-lactam-3 position, just like in the previously described monocyclic beta-lactam classes, whereas the C4-substitution pattern did not appear to have any effect on the
observed activity and could even have led to a reduction in power. Overall, Gram-positive bacteria were
less susceptible to these compounds than Gram-negative bacteria in general. In spite of this, the compound demonstrated an enhanced ability to suppress the growth of Enterobacteriaceae. In some cases,
some compounds were capable of inhibiting Pseudomonas growth.
The chlorocardicin (Figu re 1.18) is a naturally occurring antibiotic, which is a close analog of the
nocardicin A antibiotic. Several soil samples from Pima County, Arizona, were used to isolate the
organism that produces it. As a secondary metabolite of Streptomyces sp., chlorocardicin differs only
16 Chemistry and Biology of Beta-Lactams
https://t.me/med1917
FIGURE 1.18 Chemical structure of chlorocardicin.
FIGURE 1.17 Example of monocarbams.
FIGURE 1.19 Chemical structure of formadicins.
in the position of the chlorine atom on the p-hydroxyphenylglycine structural element from nocardicin A. Chlorocardicin was found to have an antimicrobial activity similar to that of nocardicin A,
which extends the spectrum of action to Gram-positive microorganisms as well. A number of L-amino
acids strongly antagonize the effects of chlorocardicin, and when combined with D-cycloserine, chlorocardicin exhibits a synergistic effect. The same observations were also conrmed for nocardicin
A, indicating that the nocardicins, as a class of antibiotics, may have alternative or complementary
pharmacodynamics.
Formadicins are another type of naturally occurring antibiotic that is closely related to nocardicins. It
was found that they were produced by a Gram-negative bacterium, F. alginoliquefaciens. The structure
of these compounds resembles that of nocardicin A, but they are additionally embellished with a 3-formylamino moiety, the name of which is derived from the moiety of this compound class (Figure 1.19). A
total of four members are included in the class of formadicins. There are some formadicins that exhibit
potent antibacterial properties with a narrow spectrum of activity against bacteria. It has been found
that some of these compounds are extremely effective against Pseudomonas, Proteus, and Alcaligenes
species with MIC values in the low μg/mL range. Similarly to chlorocardicins and nocardicins, the formadicins also exhibited an antagonistic effect on several L-amino acids.
Also, other related compounds, such as N1-oxy-substituted monocyclic β-lactams, N1-sulfonyloxysubstituted monocyclic β-lactams, N1-thio-substituted monocyclic β-lactams, N1-aza-substituted
monocyclic β-lactams, N1-sugar-substituted monocyclic β-lactams, N1-unsubstituted monocyclic
β-lactams, N1-aromatic or N1-heterocyclic substituted monocyclic β-lactams, siderophore-conjugated
17Beta-Lactams
https://t.me/med1917
monocarbams, siderophore-conjugated monobactams, and siderophore-conjugated monosulfactams,
have been reported in the literature.
90
1.3 Bicyclic β-Lactams
In general, bicyclic beta-lactams (such as penicillins and cephalosporins) are synthesized by fermentation or modication of fermentation-derived materials. There is an exception to this rule, and that is
carbapenems, which are used to treat infections, including multidrug-resistant bacteria.91 In the pharmaceutical industry, carbapenems, which have at least three chiral centers, are produced in different ways
via synthesis. This method has cost implications and limits as to the derivatives that can be developed.
In terms of their activities and pharmacokinetic proles, carbapenem substitution patterns have a signicant effect on their activity.92 In order to increase potency and avoid hydrolysis by dehydropeptidases, all
carbapenems in clinical use have the (6R)-hydroxyethyl side chain, and most of these are C1 substituted
to increase potency.
cost-effective asymmetric routes, where the cost of goods is of primary importance.
1.3.1 Penicillins
Penicillins (also known as PENs, P, and PCNs, Fig ure 1.20) are a group of beta-lactam antibiotics that
are derived from molds of the genus Penicillium, principally P. chrysogenum and P. rubens. A majority of penicillins that are currently in clinical use are synthesized by P. chrysogenum by means of deep
tank fermentation and then puried afterward.95 In spite of the fact that a number of natural penicillins
have been discovered, only two puried compounds are currently in clinical use: penicillin G (injected
intramuscularly or intravenously) and penicillin V (taken by mouth). A number of bacterial infections
caused by staphylococci and streptococci were treated with penicillins as one of the rst medications
that proved effective against them. Although many types of bacteria have developed resistance to these
antibiotics after extensive use, they are still widely used today for a variety of bacterial infections. The
gure below shows the structure of the penicillin core.
As a crude extract of P. ru bens, penicillin was discovered by the Scottish scientist Alexander Fleming
in 1928.96 Cecil George Paine, a student of Fleming, was the rst person to successfully use penicillin to
treat a bacterial eye infection (neonatal conjunctivitis) in 1930. A research team led by Howard Florey
and Ernst Boris Chain at the University of Oxford isolated the puried compound (penicillin F) in 1940.
The compound was the product of years of research and development. Puried penicillin was rst used
by Fleming to treat streptococcal meningitis in 1942.97 As a result of their research, Chain, Fleming,
and Florey were awarded the Nobel Prize in Physiology or Medicine in 1945. Semisynthetic penicillins,
such as antistaphylococcal penicillins, aminopenicillins, and antipseudomonal penicillins, can be used
against a wide variety of bacteria.
A penicillium fungus, which occurs naturally in nature, was the rst to be used to produce penicillin
G, also known as benzylpenicillin (Figure 1.21). In order to improve the yield in the manufacturing process, a strain of fungus was created by genetic engineering that is used today to manufacture penicillin
G in order to increase its potency. There is currently no clinical use of any of the other natural penicillins
(F, K, N, X, O, U1, or U6). Several bacterial infections can be treated with penicillin G.98 Pneumonia,
strep throat, syphilis, necrotizing enterocolitis, diphtheria, gas gangrene, leptospirosis, cellulitis, and
93, 94
In order to produce antibiotics efciently, there is a need to develop extremely
FIGURE 1.20 Chemical structure of the penicillin core, where “R” is the variable group.
18 Chemistry and Biology of Beta-Lactams
https://t.me/med1917
FIGURE 1.21 Skeletal formula of benzylpenicillin (penicillin G).
FIGURE 1.22 Structure of phenoxymethylpenicillin.
tetanus are among these diseases. Pneumococcal meningitis is not treated with this drug as a rst-line
agent. Because of its restricted bioavailability for oral use, benzylpenicillin is generally administered as
an injection containing sodium, potassium, benzathine, or procaine salts. In order to administer benzylpenicillin, it is injected into the vein or muscle. There are two long-acting types of penicillin available for
injection into muscles only. They are benzathine benzylpenicillin and procaine benzylpenicillin.
In accordance with the World Health Organization (WHO), benzylpenicillin is one of the essential
medicines. It is possible that adverse effects may include hypersensitivity reactions such as urticaria,
fever, joint pain, rashes, serum sickness-like reactions, as well as anaphylaxis and angioedema. There is
a rare possibility of central nervous system toxicity, such as convulsions (especially with high doses or
in patients with severe renal impairment), interstitial nephritis, hemolytic anemia, leukopenia, thrombocytopenia, and coagulation disorders. There have also been reports of diarrhea (including antibioticassociated colitis). The toxicity of benzylpenicillin is relatively low, except for the nervous system, where
it is one of the most active beta-lactam agents on the market. Aside from that, benzylpenicillin is an
irritant, a health hazard, and an environmental hazard as well.
The production of benzylpenicillin occurs when P. chr ysogenum is fermented. There are several steps
involved in the production of benzylpenicillin, including fermentation, recovery, and purication of the
penicillin.99 The fermentation process of benzylpenicillin production creates the product. In the presence
of the product in solution, the reaction is inhibited, and the rate and yield of the product are reduced. It is
therefore continuously extracted in order to obtain as much product as possible and to increase the rate at
which the reaction occurs. It is done by adding a mixture of glucose, sucrose, lactose, starch, or dextrin
to the mold, along with nitrate, ammonium salt, corn steep liquor, peptone, meat or yeast extract, and a
small amount of inorganic salts.
Benzylpenicillin recovery is one of the most important parts of the production process because if the
recovery of the benzylpenicillin is done incorrectly, the later purication steps will be adversely affected.
Benzyl penicillin can be recovered in several ways, such as aqueous two-phase extractions, liquid membrane extractions, microltrations, and solvent extractions, all of which can be used to recover it. In the
recovery process, extraction is more commonly used. It is in the purication step that benzylpenicillin is
separated from the extraction solution in order to be puried. As a result, a separation column is usually
used in this process.
100
Phenoxymethylpenicillin (Fig ure 1.22), also known as penicillin V (PcV) and penicillin VK, is an
antibiotic that has been used to treat a variety of bacterial infections over the years. A specic use for this
drug is to treat strep throat, otitis media, and cellulitis, among others. In addition to this, it can also be
used to prevent rheumatic fever and to prevent infections after the spleen has been removed. The method
of administration is oral. The side effects of this drug include diarrhea, nausea, and allergic reactions
including anaphylaxis. Penicillin allergy sufferers should avoid taking this medication unless they have
19Beta-Lactams
https://t.me/med1917
a medical reason to do so. The use of this product during pregnancy is relatively safe. In most cases, it
results in the death of the bacteria. First, phenoxymethylpenicillin was made by Eli Lilly in 1948. As one
of the essential medicines, it appears on the WHO’s list of essential medicines. As a generic medication,
it can be found on the market.
In addition to penicillins, there are three groups of semisynthetic antibiotics that are related to the
penicillins. They are synthesized by adding various side chains to the precursor 6-APA, which is isolated
from penicillin G, as a means of synthesis. Among these are the antistaphylococcal antibiotics, broadspectrum antibiotics, and antipseudomonal antibiotics.
This is because antistaphylococcal antibiotics are so named due to the fact that they cannot be broken
down by staphylococcal penicillinase. As a result, they are also referred to as penicillinase resistant. The
list includes cloxacillin, dicloxacillin, ucloxacillin, methicillin, nafcillin, and oxacillin. An antibiotic
known as cloxacillin (Fig ure 1.23) can be used to treat a wide variety of bacterial infections. Impetigo,
cellulitis, pneumonia, septic arthritis, and otitis externa are some of the diseases that fall under this
category. There is no evidence that it is effective against methicillin-resistant Staphylococcus aureus
(MRSA). In addition to being used by mouth, it can also be injected. Nausea, diarrhea, and allergic reactions, including anaphylaxis, are some of the side effects of this medication. It is also possible to get diarrhea caused by Clostridium difcile. The drug is sold under a variety of trade names, such as Cloxapen,
Cloxacap, Tegopen, and Orbenin, among others. In 1964, the drug cloxacillin was approved for use by
the Food and Drug Administration, and it was patented in 1960. A list of essential medicines has been
compiled by the WHO that includes this medication.
As for dicloxacillin (Figure 1.2 4) itself, it is a beta-lactam antibiotic with a narrow spectrum of action.
This antibiotic is used to treat infections caused by Gram-positive bacteria that are susceptible (nonresistant) to antibiotic treatment. It is effective against beta-lactamase-producing organisms such as
Staphylococcus aureus that would otherwise be resistant to most forms of penicillin. There are a number of trade names available for dicloxacillin including Diclocil (BMS).
approved for use in medicine in 1968.
102
Generic versions of this medication are available on the market.
101
It was patented in 1961 and
The drug dicloxacillin is used for the treatment of mild-to-moderate staphylococcal infections. It is
FIGURE 1.23 Structural diagram of cloxacillin.
FIGURE 1.24 Skeletal structure of dicloxacillin.
20 Chemistry and Biology of Beta-Lactams
https://t.me/med1917
recommended that dicloxacillin be used to treat infections that are suspected or proven to be caused by
beta-lactamase-producing bacteria in order to decrease the development of resistance.
The pharmacokinetics of dicloxacillin, its antibacterial activity, as well as its indications are similar
to those of ucloxacillin, and they are considered interchangeable. Compared with ucloxacillin, it is
believed that it has a lower incidence of severe hepatic adverse effects, but a higher incidence of renal
adverse effects than ucloxacillin. Dicloxacillin is used for the treatment of infections caused by susceptible bacteria. A list of specically approved indications includes staphylococcal skin infections and
cellulitis, such as impetigo, otitis externa, folliculitis, boils, carbuncles, mastitis, pneumonia, osteomyelitis, septic arthritis, throat infections, septicemia, empirical treatment for endocarditis, and surgical
prophylaxis. In the commercial world, dicloxacillin is available as the sodium salt, dicloxacillin sodium,
in capsules and as a powder for reconstitution. Dicloxacillin works by inhibiting the synthesis of bacterial cell walls, similar to other beta-lactam antibiotics. As a matter of fact, it inhibits the cross-linking
between linear chains of peptidoglycan polymer chains that make up one of the most important components of the cell wall of Gram-positive bacteria.
The antibiotic oxacillin, which is also known as ucloxacillin (Fig ure 1.25), is used to treat infections of the skin and external ear, ulcers of the leg, diabetic foot infections, and infections of the bone.
Like other medications, this medication can be used in conjunction with other medications to treat pneumonia and endocarditis. In addition, it may also be used prior to surgery in order to prevent the spread
of Staphylococcus bacteria. The antibiotic is not effective against methicillin-resistant Staphylococcus
aureus (MRSA). The medication can be either taken orally or injected into a vein or muscle, depending
on the specic case. During the 1960s, a patent was granted for the antibiotic ucloxacillin.
There are a number of common side effects associated with the use of ucloxacillin, including diarrhea, nausea, rash, urticaria, pain and inammation at the injection site, superinfections (including candidiasis), allergy, and transient increases in liver enzymes and bilirubin. As a consequence, ucloxacillin
can reduce the excretion of methotrexate, potentially resulting in an increased risk of methotrexate toxicity. There is a possibility that ucloxacillin levels in the blood may increase in kidney failure and with
the use of probenecid.
103
It is more acid-stable than many other penicillins, so it can be given either orally
or via parenteral routes. Despite this, it is less potent than benzylpenicillin when it comes to combating
Gram-positive bacteria that do not produce beta-lactamases. The drug is sold under various trade names,
including Floxapen, Flopen, Flubex, Flupen, Phylopen, and Staphylex, among others. Co-uampicil is a
combination of ucloxacillin and ampicillin that is used for treating infections.
Methicillin (USAN), also known as meticillin (INN), is a type of beta-lactam antibiotic with a narrow
spectrum of action. The discovery of methicillin (Fig u re 1.26) was made in the year 1960.
104
Compared
to other penicillins that may face antimicrobial resistance as a result of beta-lactamases, this antibiotic
is less active, can only be used parenterally, and is more likely to produce an adverse effect known as
interstitial nephritis, which is otherwise very rare when it comes to penicillins. It was previously used
as a treatment for infections that were caused by susceptible Gram-positive bacteria, particularly those
that produced penicillinase, such as S. aureus, which is otherwise resistant to most penicillins. The role
of methicillin in therapy has been signicantly replaced by oxacillin, ucloxacillin, and dicloxacillin,
FIGURE 1.25 Skeletal formula of ucloxacillin.
FIGURE 1.26 Chemical structure of methicillin.
https://t.me/med1917
FIGURE 1.27 Structural diagram of nafcillin.
21Beta-Lactams
but the term methicillin-resistant S. aureus (MRSA) continues to be used to describe S. aureus strains
resistant to all penicillins.
Nafcillin sodium is a beta-lactam antibiotic that has a narrow spectrum
lin class.
107
The beta-lactamase-resistant nature of this penicillin makes it very useful for treating infec-
105
106
and it belongs to the penicil-
tions caused by Gram-positive bacteria, including species of staphylococci resistant to other penicillins.
In spite of the fact that nafcillin (Figure 1.27) is considered to be therapeutically equivalent to oxacillin,
one retrospective study has found that nafcillin is associated with higher rates of hypokalemia and acute
kidney injury than oxacillin.
108
The use of nafcillin is indicated for the treatment of staphylococcal infections, except for those caused by MRSA. U.S. clinical practice guidelines recommend either nafcillin or
oxacillin as the rst-line treatment of choice for patients without articial heart valves suffering from
staphylococcal endocarditis.
109
A few mild side effects of this medication include hypokalemia;
110
nausea
and vomiting; diarrhea; abdominal pain; yeast infections (thrush) affecting the mouth, tongue, or vagina;
agranulocytosis; and neutropenia. Nafcillin has been shown to induce cytochrome P-450 enzymes, specically CYP2C9. There are several drugs with a narrow therapeutic window, such as warfarin and
nifedipine, that are metabolized by the CYP2C9 enzyme.
111
In order to maintain the stability of nafcillin, salts are added as a stabilizing agent. There is a possibility that these added salts will cause edema
or uid accumulation in the body. In the case of congestive heart failure or kidney disease, it would be
prudent to avoid this medication if there were any concerns about these conditions.
The beta-lactam antibiotic oxacillin (trade name Bactocill, Figure 1.28) belongs to the penicillin fam-
ily and is a narrow-spectrum beta-lactam antibiotic that was developed by Beecham.
112
The invention was
patented in 1960, and it was approved for medical use in 1962. Oxacillin is classied as a penicillinaseresistant beta-lactam antibiotic. The action of this antibiotic is similar to that of methicillin, and it has
replaced methicillin in clinical practice. Despite the fact that this antibiotic is resistant to penicillinase
enzymes, such as those produced by S. aureus, it is widely used in the United States for the treatment of
S. aureus which is penicillin resistant. As a result of the widespread use of both oxacillin and methicillin
over the past few decades, antibiotic-resistant strains of S. aureus, such as methicillin-resistant and oxacillin-resistant S. aureus (MRSA/ORSA), have become more prevalent globally. In the case of MRSA/
ORSA, vancomycin or other new antibiotics can be used as a treatment. A number of adverse effects
have been reported associated with the use of oxacillin, including skin rash, diarrhea, nausea, vomiting,
Соседние файлы в папке Библиотека им академика М.И. Перельмана