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272 Chemistry and Biology of Beta-Lactams
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TABLE 9.2
Microorganisms Isolated from Intraoperative Bile Cultures in Patients
Undergoing Pancreatoduodenectomy
Non-PBD Non-PBD
Microbiology results
Positive bile culture 30 (26%) 74 (85%) 46 (90%)
Gram-negative bacilli 16 (14%) 48 (55%) 30 (59%)
Klebsiella species 5 (4%) 21 (24%) 11 (22%)
Enterobacter species 5 (4%) 12 (14%) 5 (10 %)
E. coli 4 (3%) 11 (13%) 1 (2%)
Citrobacter species 1 (1%) 7 (8%) 3 (6%)
Pseudomonas species 1 (1%) 2 (2%) 4 (8%)
S. marcescens 0 5 (6%) 3 (6%)
S. maltophilia 0 2 (2%) 5 (10 %)
Acinetobacter species 1 (1%) 2 (2%) 4 (8%)
M. morganii 2 (2%) 1 (1%) 1 (2%)
Gram-positive cocci 19 (16%) 65 (75%) 33 (65%)
Enterococcus species 15 (13%) 51 (59%) 23 (45%)
Streptococcus species 1 (1%) 8 (9%) 9 (18%)
Staphylococcus species 3 (3%) 9 (10%) 6 (12%)
MRSA 0 2 (2%) 2 (4%)
Source: Adapted with permission from Sudo T et al. (2014).
(n = 116) Internal (n = 87) External (n = 51)
P
<0.001
<0.001
<0.001
TABLE 9.3
Susceptibility to Antibiotics of Isolates from Intraoperative Bile Cultures Expressed on
the Patients’ Basis
Parameter Resistant isolates P
Non-PBD PBD
Sterile/isolate (n=116) 86/30 Internal (n = 87) 13/74 External (n = 51) 5/46
11 (9%) 34 (39%) 28 (55%)
7 (6%) 30 (34%) 24 (47%)
1 (1%) 8 (9%) 17 (33%)
1 (1%) 4 (5%) 10 (20%)
3 (3%) 9 (10%) 11 (22%)
Source: Adapted with permission from Sudo T et al. (2014).
<0.001
<0.001
<0.001
<0.001
<0.001
stable to this common enzyme because of another development in the pharmaceutical industry. There
was some evidence that these agents tended to have decreased potency against staphylococci but gained
antibacterial activity against Gram-negative pathogens.
It is important to consider the fact that cefuroxime, which is administered parenterally or as an axethyl
ester, was the only member of the second-generation cephalosporin class that had both oral and systemic
dosage forms, but its stability to beta-lactamase hydrolysis was reduced compared to that of the later
oral cephalosporins.96 In the same way as with cefuroxime, adequate oral bioavailability of cefpodoxime
required the addition of a proxetil group to achieve sufcient absorption for the drug’s efcacy, as with
cefuroxime. Cefdinir was found to be more stable than other oral antimicrobial agents approved after
1983, not only to the original TEM enzyme but also to the AmpC cephalosporinases, which are produced
at a basal level in many enteric bacteria and P. aeruginosa.
97, 98
As part of the parenteral antibiotic development of the 1980s, a number of parenteral antibiotics were
introduced, including cephamycin cefoxitin, cephalosporins from cephalosporin III, and cephalosporin
TABLE 9.4
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Postoperative Complications After Pancreatoduodenectomy
Non-PBD PBD
Postoperative parameters
Overall morbidity 27 (23%) 20 (23%) 13 (25%) 0.940
Clavien–Dindo grade III and higher complicationsa15 (13%) 13 (15%) 9 (18%) 0.728
Abdominal infectious complications 15 (13%) 15 (17%) 7 (14%) 0.683
Pancreatic stula Grade B
Pancreatic stula Grade C
Bile leakage 4 (3%) 3 (3%) 1 (2%)
Gastrointestinal anastomotic leakage 0 2 (2%) 0
Intra-abdominal abscess 1 (1%) 2 (2%) 0
Cholangitis 0 2 (2%) 1 (2%)
Wound infection 2 (2%) 1 (1%) 1 (2%)
Other complications 11 (9%) 5 (6%) 6 (12%) 0.426
Delayed gastric emptying 6 (5%) 1 (1%) 1 (2%)
Chylous ascites 1 (1%) 0 2 (4%)
Arterial hemorrhage 1 (1%) 1 (1%) 1 (2%)
Anastomotic ulcer 2 (2%) 0 0
Pneumonia 0 0 3 (6%)
Others 1 (1%) 3 (3%) 1 (2%)
a
Incidences of grade III and higher complications according to the Clavien–Dindo classication. b Pancreatic stula is
dened as grade B or C according to the International Study Group on Pancreatic Fistula (ISGPF).
b
b
(n = 116) Internal (n = 87) External (n = 51)
7 (6%) 6 (7%) 3 (6%)
2 (2%) 0 1 (2%)
P
273Medicinal Activities of Beta-Lactams as Antibacterials
IV subclasses, which are still widely used to treat serious infections caused by Gram-negative pathogens.
It has been found that the novel oxacephem moxalactam, or latamoxef, which has similar antimicrobial
activity to the cephalosporin III/IV subclasses, has excellent stability to hydrolysis by beta-lactamases.99
However, the drug did not prove to be a highly successful antibiotic due, in part, to the fact that patients
with this drug are more likely to be bleeding than patients without it.
100
Cephamycin cefoxitin is characterized by the presence of a characteristic 7-methoxy side chain that confers stability to beta-lactamases
with TEM-type structures, including those with extended-spectrum beta-lactamase (ESBL). In addition,
it exhibits useful antibacterial activity against MSSA as well as enteric bacteria that do not produce high
levels of ampC cephalosporinases.
101
A number of cephalosporins, including cefotaxime, cefoperazone, ceftriaxone, and ceftazidime,
belong to the cephalosporin III subclass, while cefepime belongs to the cephalosporin IV subclass,
which are also known as expanded-spectrum cephalosporins that have greater hydrolytic stability to the
common penicillinases, SHV-1 and TEM-1 beta-lactamase.
102
In comparison to earlier cephalosporins,
these agents have less activity against staphylococci and enterococci, but they are more potent against
Gram-negative organisms as compared to earlier cephalosporins. According to studies, cefepime has
lower minimum inhibitory concentrations than the other expanded-spectrum cephalosporins, a fact that
has been attributed to its greater penetration through the OmpF outer membrane porin protein.
103, 104
In
many cases, cefotaxime and ceftriaxone are used to treat susceptible streptococcal infections, and both
medications can be used to treat serious infections caused by enteric bacteria if the organisms prove to be
susceptible. The activity of ceftazidime and cefepime against P. aeruginosa has been observed to have
not changed in the past few years, with current susceptibility rates exceeding 80% (Tables 9.5 and 9.6).
105
The expanded-spectrum cephalosporins, however, did have a potential liability, and this problem
became evident only a few years after the introduction of cefotaxime, when ESBLs were discovered that
were capable of hydrolyzing all beta-lactam antibiotics, with the exception of carbapenems. As a result
of the presence of these enzymes, along with both serine and metallo-carbapenemases, most penicillins
and cephalosporins have been severely compromised, requiring the development of combination therapy
with other beta-lactams, beta-lactamase inhibitors, or antibiotics from other classes.
274 Chemistry and Biology of Beta-Lactams
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) 74 (98.8) 23 (99.4) 25 (100.0) 2 4
) 73 (92.4) 23 (96.1) 25 (100.0) 4 16
) 54 (94.2) 18 (96.7) 23 (100.0) 4 16
) 72 (94.4) 22 (97.0) 25 (100.0) 4 16
) 53 (87.9) 17 (93.0) 23 (100.0) 8 32
) 64 (92.1) 21 (95.7) 25 (100.0) 4 16
b
b
b
b
b
) 46 (87.3) 18 (92.6) 25 (100.0) 8 32
b
b
1,217 (76.7) 563 (91.2) 223 (96.9
No. of isolates (cumulative %) inhibited at ceftazidime-avibactam MIC (µg/ml) of MIC
(45.5)
1 (0.3) 4 (1.5) 45 (15.2) 87 (45.1) 100 (71.8
TABLE 9.5
Summary of Ceftazidime–Avibactam Activity Tested Against P. aeruginosa Isolates from US Hospitals (2012 to 2013), Including Antimicrobial-Resistant Subsets
Organism (no. tested)” ≤0.25 0.5 1 2 4 8 16 32 >32 50% 90%
All isolates (3,902) 60 (1.5) 194 (6.5) 1,523
CAZ-NS (634) 1 (0.2) 41 (6.6) 149 (30.1) 181 (58.7) 141 (80.9
MEM-NS (702) 8 (1.1) 63 (10.1) 172 (34.6) 218 (65.7) 146 (86.5
P-T-NS (330)
P-T-NS (837) 4 (0.5) 62 (7.9) 189 (30.5) 267 (62.4) 196 (85.8
MER-NS, CAZ-NS, and
MDR (580) 1 (0.2) 3 (0.7) 31 (6.0) 113 (25.5) 174 (55.5) 148 (81.0
XDR (338) 1 (0.3) 8 (2.7) 51 (17.8) 88 (43.8) 101 (73.7
Percent susceptible according to the US FDA breakpoint criteria.
CAZ, ceftazidime; MEM, meropenem; P-T, piperacillin–tazobactam; NS, nonsusceptible; MDR, multidrug resistant; XDR, extensively drug resistant.
Source: Adapted with permission from Sader HS et al. (2015).
a
b
TABLE 9.6
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Activity of Ceftazidime–Avibactam and Comparator Antimicrobial Agents When Tested Against P.
aeruginosa from US Hospitals (2012 to 2013)
MIC (μg /ml) %S/%I/%R according to indicated criteria
Antimicrobial agenta
All isolates (n=3,902)
Ceftazidime–avibactam 2 4
Ceftazidime 2 32
Cefepime 2 16
Piperacillin–tazobactam 8
Meropenem 0.5 8
Ciprooxacin 0.12
Levooxacin 0.5
Gentamicin
Amikacin 2 8
Colistin 1 2
MDR strains (n=580)
Ceftazidime–avibactam 4 16 0.25 to 32 81.0/0.0/19.0
Ceftazidime 32
Cefepime 16
Piperacillin–tazobactam
Meropenem 8
Ciprooxacin
Levooxacin
Gentamicin 4
Amikacin 4 32
Colistin 1 2
XDR strains (n=338)
Ceftazidime–avibactam 8 32
Ceftazidime 32
Cefepime
Piperacillin–tazobactam
Meropenem 8
Ciprooxacin
Levooxacin
Gentamicin
Amikacin 8 32
Colistin 1 2
a
MDR, multidrug resistant; XDR, extensively drug resistant.
b
S, susceptible; I, intermediate; R, resistant, according to criteria as published by the CLSI and EUCAST.
c
US FDA breakpoint criteria were applied.
d
EUCAST susceptibility criteria for ceftazidime alone were applied for comparison purposes only (16).
50% 90% Range CLSI EUCAST
0.03 to >32
0.06 to >32
≤0.5 to >16
>64 ≤0.5 to >64
≤0.06 to >8
>4 ≤0.03 to >4
>4 ≤0.12 to >4
≤1
8
≤1 to >8
≤0.25 to >32
0.12 to >8
>32 1 to >32
>16 1 to >16
>64 >64 1 to >64
>8 ≤0.06 to >8
>4 >4 ≤0.03 to >4
>4 >4 ≤0.012 to >4
>8 ≤1 to >8
≤0.25 to >32
0.25 to >8
0.5 to >32
>32 1 to >32
>16 >16 4 to >16
>64 >64 8 to >64
>8 0.12 to >8
>4 >4 0.12 to >4
>4 >4 0.25 to >4
>8 >8 ≤1 to >8
≤0.25 to >32
0.25 to >8
96.9/0.0/3.1
c
96.9/0.0/3.1
83.8/3.6/12.6 83.8/0.0/16.2
83.6/8.4/8.0 83.6/0.0/16.4
78.5/9.1/12.4 778.5/0.0/21.5
81.9/5.8/12.3 81.9/11.9/6.2
77.0/5.1/17.9 71.8/5.5/23.0
74.9/6.4/18.7 66.5/8.4/25.1
88.9/3.2/7.9 88.9/0.0/11.1
97.4/1.1/1.5 94.0/3.4/2.6
99.3/0.6/0.1 99.9/0.0/0.1
c
81.0/0.0/19.0
22.4/16.0/61.6 22.4/0.0/77.6
22.9/34.9/42.2 22.9/0.0/77.1
8.6/30.5/60.9 8.6/0.0/91.4
21.6/16.3/62.1 21.6/43.9/34.5
20.9/10.1/69.0 13.6/7.3/79.1
15.0/13.3/71.7 9.8/5.2/85.0
51.4/9.5/39.1 51.4/0.0/48.6
87.9/5.0/7.1 76.6/11.3/12.1
99.0/0.7/0.3 99.7/0.0/0.3
73.7/0.0/26.3
c
73.7/0.0/26.3
10.1/17.1/72.8 10.1/0.0/89.9
11.8/32.3/55.9 11.8/0.0/88.2
2.7/23.6/73.7 2.7/0.0/97.3
7.1/14.8/18.1 7.1/47.3/45.6
7.7/9.5/82.8 2.7/5.0/92.3
3.6/11.2/85.2 2.1/1.4/96.5
37.0/10.0/53.0 37.0/0.0/63.0
83.7/6.5/9.8 69.8/13.9/16.3
98.8/0.9/0.3 99.7/0.0/0.3
d
d
d
275Medicinal Activities of Beta-Lactams as Antibacterials
b
Recently, ceftolozane was approved as a treatment for complicated urinary tract infections and complicated intra-abdominal infections when combined with tazobactam. As you can see from Figure 9.2,
Tab le 9.7, and Table 9.8, ceftolozane also exhibits potent antipseudomonal activity, as well as activity
against enteric bacteria that are capable of producing some ESBLs,
107
lates.
One of the newest additions to the cephalosporin family is the siderophore-substituted cephalosporin S-649266, which is tted with a catechol in the 3-position, which enables the compound to enter
the cells via a mechanism involving iron transport.
106
especially CTX-M-producing iso-
108
As well as increased penetration, the cephalosporin
276 Chemistry and Biology of Beta-Lactams
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FIGURE 9.2 Structure–activity relationships for ceftolozane. Adapted with permission from Zhanel GG et al. (2014).
TABLE 9.7
In Vitro Activities of Ceftolozane and Ceftolozane–Tazobactam Against Anaerobes. MIC50 minimum
concentration (mg/L) to inhibit growth of 50% of isolates, MIC90 minimum concentration (mg/L) to inhibit
growth of 90% of isolates
Organism Ceftolozane Ceftolozane/tazobactam”
MIC 50 MIC90 Range MIC 50 MIC90 Range
Gram-negative anaerobes
Fusobacterium spp.
≤0.12
B. caccae 64
B. fragilis
B. ovatus
B. thetaiotaomicron
>32 >32 ≤0.12 to >256
>256 >256 1 to >256
>256 >256 0.25 to >256
B. vulgatus 128
P. distasonis
Other Bacteroides spp.
c
>256 >256 8 to >256
8
Prevotella spp. 16
Gram-positive anaerobes
C. difcile
>256 >256 32 to >256 >256 >256 0.25 to >256
C. perfringens 1 64 0.5 to 64 0.25 32
Clostridium spp.
d
>256 >256 0.5 to >256
Propionibacterium spp. 0.5 Anaerobic Gram-positive cocci 4 16
Source: Adapted with permission from et al. (2014).
a
Fixed tazobactam concentration of 4 mg/L.
b
MIC90 not calculated when there were less than ten isolates.
c
2 B. dorei, 4 P. goldsteinii, 2 B. intestinalis, 1 P. johnsonii, 1 P. merdae, 1 B. stercoris, 1 non-speciated.
d
3 C. septicum, 1 C. subterminale, 1 C. tertium, 1 C. cadaveris, 1 C. clostridioforme, 9 Clostridium spp.
16
>256 ≤0.12 to >256
≤0.12 to 16 ≤0.12
0.25 16
1 4
4 32
4 32
>256 0.25 to >256
4 32
16 32
>256 0.25 to >256
0.25 8
≥256 ≤0.12 to ≥256 ≤0.12
16
b
≤0.12 to 16 ≤0.12
≤0.12 to >256
2 8
0.25
≤0.12 to ≥256
≤0.12 to 16
≤0.12 to 256
≤0.12 to >256
≤0.12 to >128
<0.12 to >256
≤0.12 to 16
≤0.12 to 128
1
≤0.12 to 4
≤0.12 to 32
>256 ≤0.12 to >256
-
≤0.12
≤0.12 to 64
277Medicinal Activities of Beta-Lactams as Antibacterials
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90
MIC
>16
>16
50
MIC
90
MIC
50
2 32 4 32
– – – –
– – – –
4 16 – –
Ceftazidime Cefepime
a
Range MIC
≤0.12 to >128
90
2 to ≥16
≤0.25 to >16
b
– – – –
≤0.25 to >16
≤0.25 to >16
MIC
50
2 –
– – – – – – –
4 –
4 16 0.25 to 64 32 256 16 64
1 4
– – – – – – –
0.12 to ≥128
1 4
0.5 to >32
≤0.12 to ≥0.128
0.5 2
Range MIC
≤0.5 to >32
≤0.12 to >32
≤0.12 to ≥128
≤0.12 to ≥128
≤0.12 to ≥128
1 8 0.25 to 64 8 16 8 32
≤0.12 to ≥0.128
8
>32
8
0.25 to >32
16
>128
32 128 16 32
0.5 to >64
– – – –
32 128 16 64
64
64 256 16 64
0.5 to >64
0.5 to >128
0.5 to >64
≥32 1 to ≥32
– – – – – – –
1 8
2 4
2 64
2 16
1 2
0.25 to >32
≤0.12 to ≥0.128
≤0.12 to ≥0.128
≤0.12 to ≥0.128
0.5 to >128
0.12 to ≥0.128
TABLE 9.8
In Vitro Activities of Ceftolozane–Tazobactam and Comparators Against P. aeruginosa and Its Various Resistant Phenotypes. MIC50 minimum concentration
90
MIC
50
(mg/L) to inhibit growth of 50% of isolates, MIC90 minimum concentration (mg/L) to inhibit growth of 90% of isolates
P. aerug inosa phenotypes Ceftolozane Ceftolozane–tazobactam
MIC
All 0.5 2
Amikacin resistant 1 32
Aztreonam resistant/nonsusceptible 1 4
Cefepime resistant/nonsusceptible 1 4
Ceftazidime resistant/nonsusceptible 2 16
Ciprooxacin resistant 1 4
Doripenem nonsusceptible 1 4
Gentamicin resistant 1 4
Imipenem resistant/nonsusceptible 1 4
Levooxacin resistant/nonsusceptible 1 4
Meropenem resistant/nonsusceptible 1 8
Piperacillin–tazobactam resistant/nonsusceptible 2 4
Tobramycin resistant 2 64
2 16
c
Ceftazidime and imipenem nonsusceptible 4 16
Ceftazidime and meropenem nonsusceptible – – – 4
Multidrug resistant
– – 1 to 4 – – – – – – –
d
No data available. MIC90 not calculated when there were less than ten isolates.
Fixed tazobactam concentration of 4 mg/L.
Pan-β-lactam resistant
Source: Adapted with permission from Zhanel GG et al. (2014).
a
Resistant to all of ceftazidime, cefepime, piperacillin/tazobactam, imipenem, and meropenem.
Resistant to C3 antimicrobials of different classes (ceftazidime, imipenem, piperacillin/tazobactam, ciprooxacin/levooxacin, tobramycin).
b
c
d
278 Chemistry and Biology of Beta-Lactams
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is also stable to hydrolysis by a wide range of carbapenemases, which means that it has activity against a
wide range of beta-lactam-resistant enteric bacteria.
In the mid-1990s, reports began to emerge describing cephalosporins with MICs of less than 4 g/mL
against MRSA
109
as the result of their targeted binding to PBP2a. PBP2a is an acquired low-afnity PBP
that is responsible for the observed lack of antibacterial activity of most beta-lactams in MRSA isolates.
Two cephalosporins with IC50 values of 1 µg/mL for binding to staphylococcal PBP2a, ceftobiprole
and ceftaroline,
111
have been developed for clinical use. As far as inhibiting staphylococcal and strep-
110
tococcal growth is concerned, ceftaroline is approximately twofold to fourfold more potent than cefto-
112
biprole,
but ceftobiprole appears to be up to fourfold more potent against E. faecalis. In most cases,
ceftobiprole has MICs that are four to eight times lower than ceftaroline against enteric bacteria, P. aeru -
ginosa, and Acinetobacter species.
ESBLs or carbapenemases,
avibactam can overcome many of these problems.
have been converted into prodrugs that can be used therapeutically, such as ceftaroline fosamil
ceftobiprole medocaril.
110
113
114
There is no evidence that cephalosporins are stable to hydrolysis by
although the combination of ceftaroline and the beta-lactamase inhibitor
115, 116
As both of these drugs are highly insoluble, they
117
and
9.4 Antibacterial Activities of Penicillins
Penicillins (also known as PENs, P, and PCNs) are a group of beta-lactam antibiotics that are derived
from molds of the genus Penicillium, principally P. chrysogenum and P. ru bens. 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.
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. In spite of the fact that 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. Figure
9.3 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.
119
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.
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.
The rst beta-lactam used in clinical practice was penicillin G (benzylpenicillin), which was primarily
used for treating streptococcal infections, for which it had a particularly high potency.
naturally occurring penicillin, penicillin V (phenoxymethylpenicillin), in an oral formulation, is still
used therapeutically and prophylactically for the prevention and treatment of mild-to-moderate infections caused by susceptible Streptococcus spp., including those occurring in children.
118
In spite of the fact that a number of natural penicillins have been
120
As a result of their research, Chain, Fleming,
121, 122
As another
123
As a result of the
FIGURE 9.3 Chemical structure of the penicillin core, where “R” is the variable group.
279Medicinal Activities of Beta-Lactams as Antibacterials
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selection of penicillin-resistant penicillinase-producing staphylococci in patients treated with penicillin
G, this agent was then less commonly used, and the search was on for penicillins with a greater stability
against staphylococcal beta-lactamases.
124, 125
Among the penicillinase-stable penicillins that are clinically relevant are methicillin, oxacillin, cloxacillin, and nafcillin, with the latter being recommended as the beta-lactam of choice for skin infections,
catheter infections, and bacteremia caused by methicillin-susceptible S. aureus.
126
All of these antibiotics were used primarily to treat staphylococcal infections until the advent of methicillin-resistant S.
aureus (MRSA) in the early 1980s.
127, 128
A number of penicillins were developed in the 1970s that were more effective against Gram-negative
pathogens, including ampicillin and amoxicillin, which are both orally bioavailable. Initially, these
agents were used for the treatment of infections caused by Enterobacteriaceae; however, they were
unable to effectively inhibit the growth of P. aeruginosa, which became a greater concern in the late
1970s. It was carbenicillin that was the rst antipseudomonal penicillin to be introduced, but it was not
stable enough to withstand beta-lactamase hydrolysis, and it was also less potent compared to the later
antipseudomonal penicillins, piperacillin, and ticarcillin. In terms of their spectrum of activity, these
latter drugs were considered to be potent broad-spectrum penicillins that were capable of inhibiting
penicillin-susceptible staphylococci, enteric bacteria, anaerobes, and P. aeruginosa. In the past, they
have been used extensively to treat serious nosocomial infections, especially when they were used in
combination with beta-lactamase inhibitors.
During the late 1980s and early 1990s, two parenteral penicillins with unusual chemical structures,
mecillinam and temocillin, were introduced in order to treat infections caused by enteric bacteria before
the emergence of ESBLs on a global scale. A beta-lactam that binds exclusively to PBP2 in enteric
bacteria, mecillinam (also known as amdinocillin), has a 6-beta-amidino side chain, and it is a narrowspectrum beta-lactam.83 It is because of this specicity that it shows synergy in vitro in combination with
other beta-lactams that also bind to the PBPs 1a/1b and/or PBP3 in Gram-negative bacteria,
decreasing the possibility that a point mutation in just one PBP will lead to resistance (Fig ures 9.4 –9.6).
129
thereby
130
The 6-alpha-methoxypenicillin analog of ticarcillin, temocillin, has higher stability to hydrolysis
by serine beta-lactamases as compared to ticarcillin; however, it has less antibacterial activity against
Gram-positive bacteria, Gram-negative pathogens from anaerobic environments, and a number of enteric
bacteria, including Enterobacter spp. and S. marcescens, which are important pathogens.
131
It has been
well documented that mecillinam and temocillin are currently undergoing a resurgence of interest due
to their stability to many ESBLs,
temporary ESBL-producing Enterobacteriaceae (Fig ur es 9.7 –9.9).
132, 133
with over 90% susceptibility being reported in tests against con-
134, 135
FIGURE 9.4 A new multidrug in vitro kinetic model. The left panel shows a schematic view of the model setup simulat-
ing the human kinetics of three drugs independently. The right panel illustrates the logic behind the ARUDose 2.0 control
software, which calculates the amount of antibiotic needed to be added at each time point to adjust for the quicker dilution
rates. Adapted with permission from Hickman RA et al. (2014).
280 Chemistry and Biology of Beta-Lactams
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FIGURE 9.5 Static antibiotic-concentration time-kill assays. Time-kill data as a function of drug or drug combination
for three strains: (a) MG1655, (b) DA14833, and (c) DA15000. Symbols: X (growth control); closed triangle (FOF); closed
square (ATM); closed circle (MEC); open square ( FOF+ATM); open tria ngle (FOF+MEC); open circle (FOF+ATM+MEC).
All data points are the mean of three independent experiments. Adapted with permission from Hickman RA et al. (2014).
281Medicinal Activities of Beta-Lactams as Antibacterials
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FIGURE 9.6 Drug combinations assayed in the extended in vitro kinetic model. Time-kill curves are shown in panel (a)
where drugs were diluted at rates mimicking human pharmacokinetics. The vertical arrows indicate the time at which the
concentration of each drug was diluted to its MIC. In panel (b), drug-concentration curves as a function of time, and strain
MIC, are shown. The target strain, DA1500, is an MDR clinical isolate of K. pneumoniae. Symbols: X (growth control);
closed triangle (FOF); open square (FOF+ATM); open circle (FOF+ATM+MEC). All data points are the mean of three
independent experiments with standard deviations shown. Adapted with permission from Hickman RA et al. (2014).
FIGURE 9.7 Two-component regulatory system for modication of charge in LPS of Gram-negative bacilli. Membrane-
bound kinases affecting transcription of arn complex through intermediate PmrD are shown. Circled P denotes phosphorylation; circled minus sign denotes negative regulation of transcription; encircled plus sign denotes positive regulation. The
two most common sites of mutation are shown in bold. Adapted with permission from Giske CG (2015).
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