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282 Chemistry and Biology of Beta-Lactams
https://t.me/med1917
FIGURE 9.8 E. coli resistance levels to mecillinam and nitrofurantoin in a Swedish university hospital, 2011–2013.
Range of tested E. coli per year: 22,142 to 23,951. Number of ESBL-producing E. coli: range 637–830. Adapted with
permission from Giske CG (2015).
FIGURE 9.9 Mechanism of action for nitrofurantoin and genes affected by mutations in resistant isolates. Adapted with
permission from Giske CG (2015).
There is currently limited therapeutic use of penicillins as a monotherapy due to the increasing amount
of beta-lactamases that have compromised the use of penicillins as single agents.
ampicillin, amoxicillin, piperacillin, and ticarcillin are still useful, this is mainly because the combination of these antibiotics with a beta-lactamase inhibitor can make them more effective. It is worth noting
that even ampicillin, amoxicillin, penicillin G, and penicillin V are still effective at treating Group A
streptococci and T. pallidum as monotherapy, two of the few bacterial species which do not produce
beta-lactamases (Fig u re 9.10).
9.5 Antibacterial Activities of Carbapenems
A carbapenem (F igu re 9.11) 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
137
136
Despite the fact that
283Medicinal Activities of Beta-Lactams as Antibacterials
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FIGURE 9.10 OMVs from b-lactamase-positive NTHi and M. catarrhalis contain enzymatically active b-lactamases that rescue GAS from amoxicillin-induced killing. Adapted with
permission from Schaar V et al. (2014).
284 Chemistry and Biology of Beta-Lactams
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FIGURE 9.11 General str ucture of carbapenems.
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. In spite of 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 number of carbapenem antibiotics
have been approved for clinical use, including imipenem, meropenem, ertapenem, doripenem, biapenem,
and tebipenem.
Thienamycin was discovered as a potent broad-spectrum antibiotic in the mid-1970s, and it was found
to have the typical four-membered beta-lactam structure fused to a novel ve-membered ring, in which
carbon instead of sulfur was located at the 1 position.
138
The chemical instability of carbapenems has
never allowed them to be developed into therapeutic agents. However, this carbapenem was stabilized by
adding an N-formimidoyl group to the 2 position, resulting in imipenem as a result. Among the various
antibiotics used for treating infections caused by Gram-positive, Gram-negative, nonfermentative, and
anaerobic bacteria, imipenem is widely used because of its sustained high activity against these organisms, especially those that do not produce carbapenemase (Table 9.9, Table 9.10 and Fig ure 9.12).
139, 140
There is some evidence that carbapenems, in general, bind strongly to PBP2 in Gram-negative bacteria, but there is also evidence that they can bind to PBP1a, 1b, and 3, which may provide supplementary killing mechanisms that may help reduce the emergence of resistance.
141, 142
As a matter of fact,
carbapenems are remarkable for their ability to withstand most beta-lactamases, with the exception of
those emerging carbapenemases which are found primarily in Gram-negative bacteria.
143
As imipenem
is prone to hydrolysis by the human renal dehydropeptidase (DHP), this results in the inactivation of the
144
drug,
which is why it is administered in combination with cilastatin, another DHP inhibitor that is also
a nephroprotectant, in order to prevent inactivation.
145
A wide range of agents have been developed for
global use in recent years based on the potent broad-spectrum activity of the early carbapenems. These
agents include meropenem, ertapenem, and doripenem, which have generally the same group of organisms included in their activity spectrum.
146
Chemically, all of these carbapenems are more stable than
imipenem, so that the formulated drug is likely to last for a longer period of time, and there is a possibility of prolonged infusion times as a result (Figures 9.13 –9.15).
147, 148
Similarly to imipenem, they are stable against most beta-lactamases, with the exception of the car-
bapenemases.
136
As a result of the introduction of imipenem, later carbapenems contained a beta-methyl
group that conferred stability to the human DHP, thereby negating the necessity of co-administration
with an inhibitor such as cilastatin, in order to achieve the desired effect.
149
The antibacterial activity of
meropenem has generally been reported to be twofold to fourfold greater than that of imipenem against
enteric bacteria,
activity against Gram-positive bacteria.
150
to be similar in potency against P. aeruginosa, but to have twofold to eightfold lesser
151
There is also evidence that meropenem and doripenem have a
higher level of activity against isolates of P. aeruginosa lacking the outer membrane porin protein OprD
compared to imipenem (Fig u r e 9.16, Fig u re 9.17 and Tabl e 9.11).
152
Because of its excellent penetration into the meninges, meropenem is the only carbapenem that is
approved for use in patients with meningitis.
153
The antibacterial prole of doripenem, a carbapenem that
has a higher chemical stability than imipenem or meropenem, is very similar to that of meropenem, but it
has a slight advantage against Gram-negative organisms.
154
There is evidence to suggest that ertapenem
285Medicinal Activities of Beta-Lactams as Antibacterials
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MIC range
90
0.25 to >128
0.016 to >128
0.094 to >128
MIC
50
1.5 32
0.25 to >128
0.38 16
0.016 to >128
isolates
MIC range MIC
90
All
32 128
0.125 to >128
MIC
50
32 128
isolates
MIC range MIC
90
Non-ICU
0.094 to >128
MIC
50
ICU
isolates
agent
Antimicrobial
TABLE 9.9
Isolate (n; ICU/
MIC50 and MIC90 Values and MIC Range (mg/L) of Doripenem, Imipenem, and Meropenem Against Gram-Negative Study Isolates from Intensive Care Unit (ICU)
and non-ICU Patients
non-ICU )
MIC
Doripenem 0.38 8 0.032–64 0.25 8 0.012–128 0.38 8 0.012–128
(231/394)
P. aeruginosa
Imipenem 2 32 0.25–64 1.5 32
Doripenem 0.032 0.094 0.012–16 0.023 0.064 0.008–0.5 0.023 0.094 0.008–16
(160/340)
Meropenem 0.38 16 0.023–64 0.38 16
Enterobacteriaceae
Imipenem 0.25 0.5 0.094–8 0.25 0.38 0.019–64 0.25 0.5 0.019–64
Meropenem 0.032 0.094 0.012–16 0.032 0.094 0.008–1 0.032 0.094 0.008–16
A. baumannii (66/49) Doripenem 32 64 0.125–128 32 64 0.094–64 32 64 0.094–128
Imipenem 32 128
Meropenem 32 64 0.125–128 32 64 0.125–64 32 64 0.125–128
Source: Adapted with permission from Kiratisin P et al. (2012).
286 Chemistry and Biology of Beta-Lactams
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MIC range
0.023 to >128
0.032 to >128
90
MIC
50
MIC range MIC
MIC
MIC range MIC
MIC
90
50
90
50
0.38 32 0.016–128
0.25 to >128
0.5 64 0.023–128
0.25 tp >128
32 64 0.125–128
32 64 0.25–64
0.094 to >128
>128 0.19 to >128
MIC
Isolate Co untry (n) Doripenem Imipenem Meropenem
P. aeruginosa New Zealand (29) 0.25 1 0.064–2 1.5 4 0.5–32 0.38 1 0.047–8
Philippines (90) 0.38 16 0.012–64 2 32
Singapore (120) 0.38 8 0.047–128 1.5 16 0.25–128 0.5 8
Thailand (296) 0.25 8 0.032–128 1.5 16 0.38–128 0.38 16
Vietnam (90) 1 32 0.064–64 2 64
Enterobacteriaceae New Zealand (24) 0.032 0.125 0.016–0.38 0.38 1.5 0.19–8 0.023 0.064 0.016–0.125
Philippines (70) 0.032 0.094 0.012–0.5 0.25 0.5 0.125–64 0.032 0.064 0.016–1
Singapore (96) 0.047 0.094 0.016–0.38 0.25 0.5 0.19–4 0.047 0.094 0.016–0.19
Thailand (239) 0.023 0.047 0.08–16 0.19 0.38 0.019–8 0.023 0.064 0.008–16
Vietnam (71) 0.032 0.19 0.012–0.38 0.25 0.5 0.094–3 0.032 0.19 0.012–0.38
A. baumannii New Zealand (0) – – – – – – – – –
Philippines (16) 0.19 64 0.094–64 0.38 128 0.19–128 0.25 64 0.125–64
Singapore (21) 64 64 0.25–64 64 64 0.38–128 64 64 0.38–128
Thailand (59) 32 64 0.125–128 32 64
Vietnam (19) 32 64 0.25–64 64
TABLE 9.10
MIC50 and MIC90 Values and MIC Range (mg/L) of Doripenem, Imipenem, and Meropenem Against Gram-Negative Study Isolates from Each Country
Source: Adapted with permission from Kiratisin P et al. (2012).
287Medicinal Activities of Beta-Lactams as Antibacterials
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FIGURE 9.12 Cumulative MIC distribution for doripenem, imipenem, and meropenem against (a) P. aeruginosa, (b)
Enterobacteriaceae, and (c) A. baumannii. Adapted with permission from Kiratisin P et al. (2012).
has a long elimination half-life in humans because of its high protein binding ability.
other carbapenems which are administered most commonly twice or three times a day, ertapenem may
be given once daily.
the other carbapenems against Enterobacteriaceae, ertapenem differs from imipenem, meropenem, and
doripenem in the fact that it has no useful activity against P. aeruginosa.
155
In contrast to the
156
In spite of the fact that ertapenem’s antibacterial spectrum is similar to that of
157
288 Chemistry and Biology of Beta-Lactams
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FIGURE 9.13 Semilogarithmic plots PM/PIS = f(t) for the degradation of meropenem in dr y air (A) and PE/PIS = f(t) for the
degradation of ertapenem (B) at 76.4% RH, in solid state at various temperatures. Adapted with permission from CieleckaPiontek J et al. (2008).
FIGURE 9.14 The semilogarithmic relationship ki = f(1/T) for the degradation of ertapenem (E) and meropenem (M) in
dry air (A) and at 76.4% RH (B). Adapted with permission from Cielecka-Piontek J et al. (2008).
289Medicinal Activities of Beta-Lactams as Antibacterials
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FIGURE 9.15 The relationship ln ki = f(RH%) for the degradation of meropenem and ertapenem in solid state, at 333 K.
Adapted with permission from Cielecka-Piontek J et al. (2008).
FIGURE 9.16 Prevalence of ampC, mexB, mexF, and mexY overexpression according to doripenem MIC categories.
Adapted with permission from Riera E et al. (2011).
FIGURE 9.17 Comparative activity of meropenem and doripenem against isolates showing different mechanisms of
resistance. Adapted with permission from Riera E et al. (2011).
290 Chemistry and Biology of Beta-Lactams
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TABLE 9.11
Activity of Imipenem, Meropenem, and Doripenem Against Laboratory Mutants
Showing Different Resistance Mechanisms
MI C (mg / L)
Strain
PAO1 (wild type) 2 0.38 0.19
PAOD1 (oprD–)
PAΔD (ampD–, AmpC hyperproduction)
PAOMxR (mexR–, MexAB-OprM hyperproduction) 1.5 2 0.38
PAOD1ΔD (oprD–, ampD–) >32
PAOD1ΔmR (oprD–, mexR–) >32 >32
PAΔDMxR (ampD–, mexR–)
Source: Adapted with permission from Riera E et al. (2011).
Imipenem Meropenem Doripenem
>32
2 1.5 1
2 6 1.5
4 1.5
12 8
4
FIGURE 9.18 General structure of monobactam.
Two carbapenems that are approved for use only in Japan are biapenem and tebipenem, both of which
have a similar antimicrobial spectrum as meropenem and doripenem,
signicantly active against Pseudomonas.
160
It should be noted that tebipenem is unique for its dosage in
the form of the pivoxyl ester, rendering it orally bioavailable for use in pediatric respiratory infections.
158, 159
although tebipenem is not
161
As with all carbapenems, they are stable to hydrolysis by most serine beta-lactamase enzymes, but they
can be hydrolyzed by both serine and metallo-carbapenemase enzymes. When tested against organisms
producing IMP, VIM, or NDM MBLs, biapenem has been reported to have better hydrolytic stability as
compared to imipenem and meropenem
162
with at least fourfold lower MICs than imipenem.
163
9.6 Antibacterial Activities of Monocyclic β-Lactams
As four-membered cyclic amides, monocyclic beta-lactams have a nucleus that has been modied in a
number of ways, which allows them to have a diverse chemical reactivity as well as target specicity
(Fig u re 9.18). Unlike other beta-lactam families, this group of compounds consist of only the beta-lactam
ring bound to a side chain, but their structures lack the thiazolidine, oxazolidine, and dihydrothiazine
structures that characterize other beta-lactam families. There is an extensive history of their use based
on their antibacterial properties, but they have recently found use in a variety of other areas as well. In
most studies, monocyclic beta-lactams are identied as compounds that have antibacterial properties,
while in some recent studies, monocyclic beta-lactams have been shown to have neuroprotective, antiinammatory, anticancer, anticoagulant, and antihyperlipidemic properties.
As monocyclic beta-lactams have been used in the clinic for almost half a century, they can be considered safe and nontoxic drugs due to their long history of use in the clinic. In recent years, monocyclic
beta-lactams have been increasingly recognized for their nonantibiotic activities, which has led to the
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FIGURE 9.19 Ceftazidime, ceftazidime-avibactam, aztreonam, and aztreonam-avibactam MIC distributions for 291 Enterobacteriaceae isolates (excluding meropenem-nonsusceptible
isolates), 30 Acinetobacter isolates, and 25 P. aeruginosa isolates. Adapted with permission from Wang X et al. (2014).
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