J Antimicrob Chemother

doi:10.1093/jac/dkaa183

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Oral cephalosporin and b-lactamase inhibitor combinations for ESBL-
producing Enterobacteriaceae urinary tract infections
1,2 1,3 1,4 5,6
Adam G. Stewart , Patrick N. A. Harris , Andrew Henderson , Mark A. Schembri and David
1,2
L. Paterson *
1
Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Royal Brisbane and Women’s Hospital
Campus, Brisbane, Australia; 2Department of Infectious Diseases, Royal Brisbane and Women’s Hospital, Brisbane,
Queensland, Australia; 3Department of Microbiology, Pathology Queensland, Royal Brisbane and Women’s Hospital, Brisbane,
Queensland, Australia; 4Infection Management Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia; 5School
of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia; 6Australian Infectious
Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia

*Corresponding author. E-mail: d.paterson1@uq.edu.au

ESBL-producing Enterobacteriaceae as uropathogens have given rise to a sizeable amount of global

morbidity. Community and hospital surveillance studies continue to report increasing proportions of these
organisms as causes of urinary tract infection (UTI). Due to limited treatment options and the presence of
cross-resistance amongst oral antibiotics of different classes, patients often require IV therapy, thereby
increasing healthcare costs and reducing the effectiveness of delivering healthcare. Oral cephalosporin
antibiotics are well known for their ability to achieve high urinary concentrations, in addition to achieving clinical
success for treatment of un-complicated UTI with a drug-susceptible pathogen. Novel cephalosporin/b-
lactamase inhibitor combinations have been developed and demonstrate good in vitro activity against ESBL-
producing isolates. A pooled analysis of in vitro activity of existing oral cephalosporin/clavulanate combinations
in ESBL-producing Enterobacteriaceae has shown MIC50s of 0.5–1, 0.125–1 and 0.25 mg/L for cefpodoxime,
ceftibuten and cefixime, respectively. A novel cyclic boronic acid b-lactamase inhibitor, QPX7728, was able to
produce MIC50 values of 0.5 and 0.06 mg/ L when paired with cefpodoxime and ceftibuten, respectively. Other
novel combinations, cefpodoxime/ETX0282 and ceftibuten/VNRX7145, have also demonstrated excellent
activity against ESBL producers. Clinical trials are now awaited.

Introduction not exhibit cross-class resistance with other classes of antibiotics

by Uppsala Universitetsbibliotek user on 23 May 2020

Antimicrobial resistance continues to be a major threat to the de-
livery of effective healthcare worldwide. MDR Gram-negative infec-
tions are now commonly seen in a variety of infections and
1
contribute substantially to this global public health problem. In the
USA, of the 140 000 healthcare-associated Enterobacteriaceae
infections per year, 26 000 (18.6%) are MDR (predominantly due to
2
EBSL-producing organisms), resulting in close to 1700 deaths.
Likewise, a point prevalence survey of US hospitals in 2017
revealed over 290 000 non-duplicate ESBL-producing
3
Enterobacteriaceae isolates. Gram-negative uropathogens caus-
ing urinary tract infection (UTI) are a major contributor to global
4 antibacterial potency, is stable to b-lactamase hydrolysis and shows
antibiotic use and resistance. Treatment options for ESBL-
producing uropathogens are often limited compared with non-ESBL-
producing pathogens. IV antimicrobial therapy is frequently
unavoidable as coexisting resistance to other oral agents (e.g. fluo-
roquinolones and sulphonamides) is often seen among ESBL pro-
ducers. Nitrofurantoin and fosfomycin have provided some benefit in
5
this patient group in the setting of uncomplicated UTI. They do
and their usage increased significantly in the late 2000s, associ-ated
with the reported rise in ESBL-producing bacteria. As such, they
have now become first-line agents for uncomplicated UTI in several
6
international guidelines. This now requires monitoring due to an
observed decline in efficacy due to their inability to adequate-ly treat
complicated UTI and the slow development of resistance owing to
7
their increased use. In addition, fosfomycin activity against
Klebsiella spp. has recently been challenged in an in vitro dynamic
8
bladder model. The older extended-spectrum penicillins,
pivmecillinam (also known as pivoxil amdinocillin) and temocillin,
have also demonstrated good in vitro and in vivo activity against
5,9–12
EBSL producers causing UTI. Pivmecillinam has significant
synergy when paired with b-lactamase inhibitors against ESBL-
13,14
producing Enterobacteriaceae. A recent cohort study showed
that oral pivmecillinam 400 mg three times daily yielded equivalent
clinical outcomes in UTI caused by ESBL producers when
10
compared with alternative oral antibiotics. More robust data from a
randomized controlled trial are necessary in order for

VC The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
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1 of 10
Review
this strategy to be adopted worldwide. Recently, new compounds cefpodoxime, cefprozil, cefuroxime, cefalexin and loracarbef) and
pairing orally bioavailable cephalosporin antibiotics with novel b- where tested as non-susceptible to cefazolin, laboratories may go
lactamase inhibitors have been developed. This promises the po- on to test cefdinir, cefpodoxime and cefuroxime due to resistance
tential to improve oral treatment options and reduce healthcare over-calling by cefazolin.24 costs in patients with UTIs due to ESBL-
producing organisms.
Epidemiology of ESBL-producing organisms
causing UTI
ESBLs render penicillins (except mecillinam and temocillin), first-,
second- and third-generation cephalosporins and monobactams
5,15
ineffective via hydrolysis of the b-lactam ring. Uropathogens
harbouring ESBLs, for example Escherichia coli ST131, are often
re-sistant to other commonly used antibiotics, for example fluoroqui-
16,17
nolones via point mutations in the gyrA and parC genes. The
presence of ESBL genes among Enterobacteriaceae isolates has
been progressively increasing in both hospital and community set-
tings, representing 15% of all Klebsiella spp. isolates and 12% of E.
18
coli captured among 79 US hospitals. Considerable global
variability exists between countries, however, with Europe exhibiting
6.8%–38.7% of E. coli and 4.5%–77.7% of Klebsiella pneumoniae
19
as resistant to third-generation cephalosporins. Similarly, the
incidence of community-acquired ESBL-producing
Enterobacteriaceae as a cause of UTI has increased worldwide,
20
with some areas reporting rates of over 40% of all UTIs. Case–
control studies have identified numerous classical risk factors for
acquisition of ESBL-producing Enterobacteriaceae, which include
recent antibiotic use (in particular fluoroquinolones), hospital
21
admission and surgery. The urinary tract is the most common site
of infection caused by ESBL producers and results in a sizeable
22
economic and public health burden. The hospitalization cost of an
ESBL-producing E. coli UTI compared with a non-ESBL-producing
23
E. coli was estimated to be e4980 versus e2612.
The most common globally disseminated ESBL genes found
amongst uropathogenic Enterobacteriaceae are those of the
CTX-M group.4 In the modern era of increasing rates of MDR
Enterobacteriaceae among urinary tract pathogens, oral agents
are likely to be less active compared with the time when many
guidelines were written. Unless novel oral antimicrobials are
devel-oped, the requirement for IV therapy will contribute
significantly to the burden of care administered in hospitals and
will no doubt drive a large increase in healthcare costs.
Oral cephalosporins (without b-lactamase
inhibitors) and their activity against
Enterobacteriaceae
Orally bioavailable cephalosporins are represented in first-, se-cond-
and third-generation classes. All have some level of in vitro activity
against non-ESBL-producing Enterobacteriaceae com-monly
isolated from urine. EUCAST has specified clinical break-points for
uncomplicated UTI against Enterobacteriaceae (Table 1) for
cefadroxil, cefuroxime, cefalexin, cefixime, cefpodoxime and
ceftibuten (susceptible if MICs are 16 mg/L, 8 mg/L, 16 mg/L, 1
mg/L, 1 mg/L and 1 mg/L respectively). However, CLSI has
recommended utilizing the cefazolin breakpoint for
Enterobacteriaceae due to uncomplicated UTI (susceptible 16 mg/L)
as a surrogate for oral agents (cefaclor, cefdinir,
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First-generation cephalosporins
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Cefalexin has activity against most Enterobacteriaceae causing UTIs;
however, this activity is significantly reduced against ESBL producers. In
one study of non-ESBL-producing uropathogens, overall susceptibility
was 85% (Table 2). However, susceptibility of 981 ESBL-producing E.
coli and 439 ESBL-producing K. pneumoniae urinary isolates was only
6.32% and 0.91%, respectively, in one large study. 25 Cefadroxil, another
first-generation cephalosporin, revealed average potency overall and a
broad MIC50 range of 4 to >32 mg/L in a pooled analysis of 164
isolates.26,27
Second-generation cephalosporins
Second-generation oral cephalosporins such as cefaclor exhibit
greater activity against WT Gram-negative bacilli than does
cefa-lexin. Although still displaying a broad range of
susceptibility results—the majority reported against EUCAST
breakpoints—cefa-clor (47.5%–90.5%), cefuroxime (50.5%–
86.4%) and cefprozil (90%–93.2%) were active against the
majority of uropathogens (Table 2). As with first-generation
cephalosporins, however, these antibiotics have poor
susceptibility profiles against ESBL producers.28
Third-generation cephalosporins
Oral third-generation cephalosporins perform better still, with MICs
among Enterobacteriaceae consistently below EUCAST/CLSI
breakpoints for UTI. They demonstrate good in vitro efficacy against
uropathogenic Enterobacteriaceae and also exhibit some resistance
to hydrolysis by common ESBLs (Table 3). Cefpodoxime is a
cephalosporin with activity against Gram-negative bacteria and
shows stability to many b-lactamases.
29,30
It exists as a pro-drug,
cefpodoxime proxetil, that undergoes de-esterification in the
intestinal wall before active cefpodoxime (typically 50%) is released
31
into the circulation. Optimal absorption requires low gastric pH and
a mean peak serum concentration of 2.18 g/L can be expected 3 h
32
post administration of a 200 mg dose. A dose of 100 mg 12 hourly
33
has been recommended for uncomplicated UTI. Similarly,
ceftibuten is another third-generation cephalo-sporin with stability to
34
plasmid-mediated b-lactamases. Ceftibuten resists hydrolysis by
commonly occurring narrow-spectrum b-lactamases (e.g. OXA-1,
35
TEM-1 and SHV-1 types). However, it is readily hydrolysed by
36
SHV-4/5 produced by some Klebsiella isolates. Ceftibuten is
absorbed (75%–90%) in its active form from the gastrointestinal
tract, achieving peak plasma anti-biotic levels of 9.9 mg/L and 17
37
mg/L after single oral doses of 200 mg and 400 mg, respectively.
Drug clearance is split be-tween renal (56%) and faecal (39%)
excretion. Typical doses are 400 mg daily for respiratory tract
38
infection; however, no dosing recommendations exist for UTI.
Among 301 US Enterobacteriaceae isolates, cefpodoxime dem-
onstrated a higher susceptibility rate than cefuroxime (94% versus
83%).39 Cefpodoxime and ceftibuten also performed well against 155
ESBL-negative MDR E. coli and K. pneumoniae urinary isolates,
Review JAC C8
5
>>0
e, 11.
f 665
p8
o7
ttt
d,
ooo
Table 1. Oral cephalosporin EUCAST and CLSI breakpoints for UTI o
x9
8
i 3>>>
EUCAST susceptible breakpoint (mg/L)
a
CLSI susceptible breakpoint
a,b
(mg/L) m86661.
Cephalosporin
e6444
1
First generation 2
,
cefadroxil 16 NA
cefalexin 16 NA C 81
Second generation e5, 6
f
cefuroxime 8 4
t
9t
cefaclor NA 8 i8
o
cefprozil NA 8 b,
u1
loracarbef NA 8
t902>
Third generation e94–6N6.
cefpodoxime 1 2 n484A
C 7
cefixime 1 1 e,
3

cefdinir NA 1 f
ceftibuten 1 8 p7
o5
cefetamet NA 4 d–7
o7
x,
NA, data not available. i
a
Uncomplicated UTI only. m 8

b e1
Cefazolin may be used as a surrogate (susceptible: 16 mg/L). /
c0
0
l .
.
Table 2. Pooled WT MIC data of oral cephalosporins against Enterobacteriaceae for which UTI breakpoints exist a 50
v6
u
t
l t
Total no. of isolates tested o
a0o8.
Oral cephalosporin Reference(s) across all studies MIC50 (mg/L) MIC90 (mg/L) Range (mg/L) Susceptibility (%) n1.
94, 95
a15>>
t94–33
Cefalexin 126 4–8 8–32 1 to >256 54.5–85
e14122
26, 27 C
Cefadroxil 164 8–16 4 to >32 4 to >32 — e
f
94, 95 t
Cefprozil 126 2 4–8 0.5 to >16 90–93.2 i
b
42, 95, 96
u
Cefaclor 27, 42, 94, 95 1432 2–16 4 to >32 0.5 to >128 47.5–90.5 t
Cefuroxime 837 2–8 4 to >32 0.25 to >32 50.5–86.4 e
n
94, 95 /
Cefdinir 126 0.12–0.5 0.5–1 0.12 to >4 90–95.2 c
l
42, 97
a
Cefixime 42, 95, 97 969 0.06–0.5 0.5 to >8 0.06 to >16 58.2–81.3 v
Cefpodoxime 1011 0.12–1 0.5 to >8 0.06 to >16 53.5–95.2 u00
l ..
27, 42 a11
Ceftibuten 711 0.12–0.25 0.5 to >16 0.01 to >16 66.3–91.3 n22
a55
t ––N
e411A
C 720
00
8
e,7...6.
f 6270
Table 3. In vitro activity of oral cephalosporins with or without b-lactamase inhibitors against ESBL-producing Enterobacteriaceae
i7559
x9 –
Oral cephalosporin ± Total no. of isolates tested MIC50 MIC90 Range Susceptibility i, 2
m4
b-lactamase inhibitor Reference(s) across all studies (mg/L) (mg/L) (mg/L) (%)
e8
1
/
Cefixime 78, 81 214 6 >64 0.5 to >64 7–8.6 c
 84, 85

Cefpodoxime/QPX7728 NA 0.5 4 NA NA
84, 85

Ceftibuten/QPX7728 87, 100 NA 0.06 1 NA NA

Cefpodoxime/ETX0282 88, 89, 99, 101 937 0.015–0.5 0.03–1 0.12–2 NA
Ceftibuten/VNRX7145 884 0.06 to <1 0.12–1 NA 96.9–100

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NA, data not available.
3 of 10
Review
showing 94% susceptibility each for cefpodoxime and 100% each
40
for ceftibuten. Among 1190 Enterobacteriaceae isolates causing
UTI in Europe, ceftibuten and cefpodoxime had susceptibility rates
of 94% and 92%, respectively, with ceftibuten demonstrating in vitro
41
efficacy similar to that of ceftriaxone. Furthermore, 567
community-acquired UTI Enterobacteriaceae isolates from
Argentina, Mexico, Venezuela, Russia and the Philippines showed
ceftibuten in vitro potency, being able to outperform other oral
42
cephalosporins. The ceftibuten susceptibility rate was 77% by
EUCAST, with MIC50/90 of 0.25/16 mg/L and a range of 0.06 to
>16 mg/L. Cefixime, cefpodoxime, cefuroxime and cefaclor had
42
in vitro susceptibilities of 67%, 65%, 65% and 58%, respectively.
Ceftibuten alone was tested in vitro against CTX-M-producing E. coli
isolates and showed a disparity in susceptibility between
CTX-M group 1 and group 9, with MIC 50/90 values of 8/32 and 1/1
mg/L, respectively, and susceptibility rates of 9.8% and 94.5%,
respectively.12
Antibiotic concentrations in the urinary tract
First-generation cephalosporins
Oral cephalosporins have been shown to have favourable pharma-
cokinetics and to achieve high concentrations of active drug in the
urine. Cefalexin is excreted unchanged in the urine, with 70%–
100% of the dose found in the urine 6–8 h after a dose and concen-
trations many times greater than the MIC for a typical urinary
43
pathogen (urine cefalexin concentration 500–1000 mg/L).
Although increasing resistance rates to cefalexin have been noted,
these high urinary concentrations may allow it to retain effective-
44
ness for uncomplicated UTIs. Similarly, cefadroxil is excreted in
urine (via glomerular filtration and tubular secretion), with 93% of the
dose passing through the urine in the first 24 h, achieving con-
26
centrations between 400 and 2400 mg/L. Its urinary excretion rate
45
is more prolonged when compared with cefalexin.
Second-generation cephalosporins
Cefaclor achieves slightly lower urinary antibiotic concentrations
overall (50–1000 mg/L), with 70% of active drug passing through the
46
urine in the first 6 h. It also has other major non-renal routes of
47
elimination, such as the biliary tract. Cefprozil shows slightly
poorer urinary concentrations, excreting around 61% of the
administered dose and achieving urinary concentrations of 175 mg/L
48
and 658 mg/L at 4 h after a 250 mg and 1 g dose, re-spectively.
Cefuroxime axetil (oral formulation) has its parent compound,
cefuroxime, eliminated unchanged in the urine (42%– 57% in 24 h
after a single oral 250 mg dose) and achieves high concentrations in
49
the renal parenchyma. It achieves peak con-centrations of 400
50
mg/L at 4 h after a 500 mg oral dose.
Third-generation cephalosporins
Third-generation or extended-spectrum oral cephalosporins also
penetrate the kidneys and urinary tract well. Cefpodoxime clear-
ance occurs primarily through the renal route by both glomerular
filtration and tubular secretion.32 Over various approved doses
(100–400 mg), 29%–33% of administered cefpodoxime was
excreted unchanged in urine in a 12 h period. 51 This increased
to 42.8% over 24 h after a 100 mg dose was given to healthy
4 of 10
32
subjects. Urinary excretion is 80% of the absorbed oral dose (ap-
proximately 50% of total administered dose). After 8 days of 400 mg
twice-daily oral dosing of cefpodoxime proxetil, 146 mg (35.6%) and
Downloaded from https://academic.oup.com/jac/advance-article-abstract/doi/10.1093/jac/dkaa183/5842233
122 mg (30.6%) had been excreted in the urine in 12 h in young and
52
elderly healthy adults, respectively. Ceftibuten demonstrates a
fractional excretion of unchanged drug in the urine, with 56%–70%
over 24 h. After an oral dose of 200 mg of ceftibuten, it can achieve
53
a maximum urinary concentration of ap-proximately 800 mg/L.
Cefixime undergoes less urinary clear-ance. After administering 200
54
mg, 53.3 mg (27%) can be recovered from the urine after 24 h. In
another study, adminis-tering 200 mg and 400 mg of cefixime
55
yielded urinary recovery of 20% and 16% of the dose. Maximum
concentrations achieved in the urine were 107 mg/L and 164 mg/L
for a 200 mg and 400 mg dose, respectively. Cefdinir has an even
lower fractional elimin-ation of unchanged drug in the urine (13%–
56
23%). In one study, the mean percentage of the dose recovered
unchanged in the urine following 300 mg and 600 mg doses was
57
18.4% and 11.6%, respectively, over 24 h. Although third-
generation cephalospor-ins achieve lower urinary concentrations
when compared with first-generation cephalosporins, both
cefpodoxime and ceftibuten appear to be superior to cefixime and
cefdinir.
Oral clavulanate
Clavulanate is usually paired with amoxicillin and has been used
in the treatment of UTI. Clavulanate is also excreted in the urine
in its active unchanged form, although far less than many oral
cephalo-sporins. After administration of 125 mg of clavulanic
acid, cumula-tive excretion at 2, 4 and 6 h was 14%, 25.7% and
27.8%, respectively.58 Other studies have documented similar
values of between 18% and 38% of total excretion. Clavulanate
reaches a maximum urinary concentration of 40 mg/L, 4–6 h
after a 125 mg oral dose. Approximately half of the drug is
metabolized elsewhere in the body.59
Clinical trials of orally administered
by Uppsala Universitetsbibliotek user on 23 May 2020
cephalosporins (without b-lactamase
inhibitors) for UTI
Numerous clinical trials have been conducted examining the use
of oral cephalosporins in the treatment of UTI. The majority of
patients enrolled in these trials had uncomplicated infection with
urinary pathogens without ESBL production.
First-generation cephalosporins
Oral cefalexin has been utilized as a comparator arm in many
therapeutic trials for uncomplicated UTI. In 109 patients receiving
oral cefalexin 250 mg four times a day for acute uncomplicated UTI,
93.6% and 80.6% were able to achieve clinical cure and micro-
60
biological cure, respectively. In a trial comparing cefalexin 500 mg
with ampicillin 500 mg, each four times a day, 30/31 (96.8%)
patients who received cefalexin achieved clinical cure and 20/31
(64.5%) had a sterile urine sample collected 3 weeks after
61
commencement of therapy. Furthermore, in another double-blind
clinical trial, of 115 patients with complicated UTI receiving oral
cefalexin 500 mg four times a day, clinical cure was reported in only
75 (65.2%) patients.
62
Cefadroxil 1 g twice daily was
Review
compared with norfloxacin 400 mg twice daily in the treatment of
acute pyelonephritis in a multicentre clinical trial that enrolled 197
63
patients. Although cefadroxil produced an inferior microbiologic-al
cure rate (65% versus 98%), the clinical response rate did not dif-fer
between groups. With regard to clinical cure, 7 days of oral
cefadroxil 1 g daily performed just as well as amoxicillin 375 mg
64
three times a day in women with uncomplicated UTI.
Second-generation cephalosporins
The second-generation cephalosporins cefprozil and cefaclor have
been compared against each other in a number of clinical trials for
uncomplicated UTI. In one study of cefprozil 500 mg daily and
cefaclor 250 mg three times daily, clinical response was 87% ver-
65
sus 84% and microbiological cure was 83% versus 85%. Among
108 college women with acute UTI, the clinical response was 94%
versus 94% and microbiological cure was 93% versus 94%, re-
66
spectively. Oral cefuroxime axetil 125 mg twice daily was com-
pared with enoxacin (a fluoroquinolone) in a small clinical trial
involving 33 patients with recurrent UTI and achieved clinical re-
sponse and microbiological cure rates of 71.4% and 71.4%, com-
pared with 92.3% and 85.7% in the enoxacin group. In a large
67
clinical trial involving 672 women with uncomplicated UTI, treated
with cefuroxime axetil 125 mg twice daily or 250 mg twice daily,
68
628/672 (93.4%) achieved clinical cure.
Third-generation cephalosporins
Cefdinir 100 mg twice daily was compared with cefaclor 250 mg
three times a day, both for 5 days in uncomplicated UTI, in a large
69
multicentre trial involving 661 participants. Cefdinir achieved a
clinical response and microbiological cure rate of 85.9% and 91.3%,
respectively, with cefaclor achieving similar results (80.5% and 93%,
respectively). With regard to extended-spectrum oral
cephalosporins, cefpodoxime 100 mg twice daily did not meet the
criteria for non-inferiority when compared with oral ciprofloxacin in a
70
randomized trial in acute uncomplicated cystitis. Patients who
received oral cefpodoxime proxetil 100 mg twice daily for 3 days
achieved an overall clinical cure rate at 30 day follow-up in the ITT
population of 82% (123/150) compared with 93% (139/
70
150) in those receiving oral ciprofloxacin 250 mg twice daily. The
authors of that study speculate that the lower clinical response
seen with b-lactam therapy may be due to their poorer activity in
70
eradicating uropathogens from the vaginal flora. Cefpodoxime 100
mg twice daily was also compared with trimethoprim/sulfa-
methoxazole in acute uncomplicated cystitis in a small open-label
multicentre trial, which showed that 3 days of cefpodoxime was
as effective as trimethoprim/sulfamethoxazole.71 Another small
randomized clinical trial compared ceftibuten 200 mg twice daily
and cefixime 200 mg twice daily in the treatment of complicated
UTI and showed similar clinical and microbiological outcomes
be-tween the two drugs.72 Thus, it is unclear from clinical trial
data which oral third-generation cephalosporin is superior with
regard to clinical and microbiological cure. It should also be
pointed out that all of these studies were performed in scenarios
where ESBL-producing strains were rarely encountered.
Review
JAC
Oral cephalosporin and clavulanic acid combinations
Clavulanic acid is a highly effective inhibitor of ESBLs in vitro and is
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typically combined with amoxicillin in both oral and IV formula-
73
tions. Compared with other b-lactam/b-lactamase (BLBLI) com-
binations, amoxicillin is less stable to ESBLs even in the presence of
clavulanate. Oxyimino-cephalosporins are weaker substrates than
73
amoxicillin for ESBLs and have a higher affinity for PBPs. A fixed-
dose combination of cefuroxime/clavulanic acid has been approved
and introduced in some countries, although currently this is not
74
approved by the US FDA. Many oral cephalosporin anti-biotics
have been tested in vitro, in combination with clavulanic acid,
against ESBL-producing Enterobacteriaceae (Table 3). Among 380
ESBL-producing E. coli and 226 Klebsiella spp. isolates, cef-
podoxime combined with clavulanate produced MIC50/90 values of
73
0.5/2 and 0.5/1 mg/L, respectively. Twenty-eight of 37 (75.6%)
ESBL-producing E. coli from India had MIC values less than the
cefpodoxime-susceptible breakpoint when combined with clavu-
75
lanate. In another in vitro study, 101 ESBL-producing
Enterobacteriaceae were tested against cefdinir and cefpodoxime,
in combination with amoxicillin/clavulanate at fixed concentra-tions
76
of 8 mg/L and 4 mg/L respectively. Utilizing CLSI cefdinir and
cefpodoxime breakpoints prior to 2011, susceptibility amongst CTX-
M producers was reported at 90.9% and 89.3%, respectively, whilst
producers of SHV-type ESBLs were reported as susceptible for 60%
and 58.8%, possibly due to differences in substrate affinity for CTX-
M enzymes and SHV ESBL enzymes towards cefdinir and
cefpodoxime (Table 4). In addition, against 303 CTX-M-producing E.
coli, cefpodoxime/clavulanate demonstrated potent activity
(MIC50/90 0.5/0.5 mg/L) but, not surprisingly, was less active
against those hyperproducing AmpC (MIC50/90 4/4 mg/L).77
Cefixime plus amoxicillin/clavulanate tested against 64 ESBL-
producing E. coli isolates produced MIC50/90 values of 0.25/75 mg/L
(range 0.09–24 mg/L).78 Cefixime/clavulanate also performed well in
vitro against non-AmpC ESBL producers in 62 E. coli and K. pneu-
moniae isolates.79 Both of these studies, however, demonstrated
synergy using non-standardized methods not recommended by
either EUCAST or CLSI, thereby limiting the value of their interpret-
ation. Cefdinir plus a fixed concentration of amoxicillin/clavulanate
(8/4 mg/L) was tested against CTX-M (46 isolates) and SHV/TEM
(11 isolates) producers, which revealed in vitro MIC50/90 values of
0.25/2 mg/L (89.1% cefdinir susceptible) and 0.06/8 mg/L (81.8%
cefdinir susceptible), respectively.80
The addition of amoxicillin/clavulanate to oral cephalosporins
was shown to have high rates of synergy when tested using disc
approximation and disc replacement methods amongst 150 ESBL-
producing E. coli isolates predominantly isolated from urinary sour-
81
ces. The frequency of synergy using this method with cefixime and
cefpodoxime was 84% and 75.5%, respectively. Moreover, 86.3%
and 74.1% of isolates were in the susceptible range when cefixime
and cefpodoxime were added to amoxicillin/clavulanate and
interpreted using CLSI disc diffusion breakpoints. Twenty patients
with confirmed ESBL-producing E. coli UTI, 85% of whom had
demonstrable positive in vitro synergy, received cefixime and
amoxicillin/clavulanate, with a 90% clinical cure rate observed. A
case series of 10 patients treated with ceftibuten plus amoxicillin/
clavulanate for ESBL-producing E. coli and K. pneumoniae UTI
82
showed all patients achieving clinical cure. Overall, the addition of
clavulanic acid to a third-generation cephalosporin was able to
5 of 10
Table 4. Typical MICs (mg/L) of orally administered third-generation cephalosporins for selected b-lactamase-producing Enterobacteriaceae

MIC (mg/L)

MIC reduction

Downloaded from https://academic.oup.com/jac/advance-article-

Organism and b-lactamase References cefdinir cefixime ceftibuten cefpodoxime with clavulanate?

102, 103

E. coli ! AmpC >64 >64 >256 16 to >64 no

12, 36, 82, 103

E. coli ! CTX-M-1 8 4–16 1–8 1–64 yes

12, 82

E. coli ! CTX-M-9 1 0.5–1 yes

30, 102–106

E. coli ! TEM-1 0.5 0.25–0.5 0.12–1 0.5–1 yes

103, 105, 106

E. coli ! TEM-2 0.12 0.06–0.12 0.12 yes

30, 105, 106

E. coli ! OXA-1 0.5 0.1–0.25 0.25 0.5 yes

102, 105, 106

E. coli ! OXA-2 0.25 0.25–0.5 0.5 0.5 yes

36

K. pneumoniae ! CTX-M-1 NA 8 0.25 32 yes

36

K. pneumoniae ! AmpC NA >64 >64 >64 no

30

K. pneumoniae ! SHV-1 NA NA NA 0.25 yes

102, 105, 106

K. pneumoniae ! K14 30, 102, 105, 106 4 0.25 0.06 8 yes

K. pneumoniae ! hyperexpressed K1 30, 35, 102, 106, 107 4 0.25 0.06 0.25–8 yes
Enterobacter ! basal AmpC 0.12 to >128 4 to >32 0.5 to >32 2 to >128 no

NA, data not available.

MICs determined by BMD lie within the susceptible distribution
significantly reduce the MIC50/90 against organisms producing
range for cephalosporins alone.
N
spe-cific ESBLs (CTX-M, TEM or SHV-1) with little activity
o
against AmpC producers (Table 4).
v
e
Limitations of in vitro oral cephalosporin/b-
l
lactamase inhibitor susceptibility data
interpretation b
In the current literature, cephalosporin/b-lactamase inhibitor -
susceptibility testing (as with other BLBLI combinations) appears to
l
be frequently performed by non-standardized methods and exhibits
great heterogeneity in methodology. Methods to deter-mine a
antimicrobial susceptibility and synergy in oral cephalo-sporin/b- c
lactamase inhibitor combinations have included disc diffusion, broth t
microdilution (BMD), Etest, disc approximation and disc a
73,75–77
replacement. In addition, different concentra-tions of b- m
lactamase inhibitors are often used amongst testing strategies. With
regard to clavulanic acid, either fixed concentra-tions of 2 mg/L or 4
a
mg/L have been used, or ratios of 2:1 (cepha-losporin:clavulanate) s
have been reported. Despite having standardized and accepted e
clinical breakpoints for both EUCAST and CLSI for many oral
cephalosporins, when assessing them in combination with i
clavulanate, interpretation can be problematic as the two differ with
regard to methodology (fixed 2 mg/L for EUCAST and 2:1 ratio for
n
83
CLSI). Many reported studies used fixed combinations of 4 mg/L,
h
not complying with either EUCAST or CLSI. The spectrum of testing i
performed highlights a need for further research towards a unified b
approach. Ultimately, BMD and disc diffusion MIC distributions are i
required to determine ap-propriate breakpoints but, similarly to other
t
BLBLIs currently available, it would seem prudent to assess activity
for cephalo-sporin/clavulanate combinations based on whether the
o
rs in combination with ceftibuten or

abstract/doi/10.1093/jac/dkaa183/5842233 by Uppsala Universitetsbibliotek user on 23 May 2020

cefpodoxime
There has been a recent drive to develop new oral antimicrobials
that are active against ESBL-producing uropathogens. QPX7728 is
a next-generation cyclic boronic acid b-lactamase inhibitor that is
orally bioavailable and inhibits all clinically important b-lacta-
84
mases. It has been shown to restore the activity of cefpodoxime
and ceftibuten on ESBL producers, with MIC 50/90 values of 0.5/4 and
85
0.06/1 mg/L, respectively. ETX0282 is an oral prodrug that
is hydrolysed in vivo to release ETX1317, another novel b-lacta-
mase inhibitor that is orally bioavailable and inhibits Class A and C
86
b-lactamases. When paired with cefpodoxime it was able to sig-
nificantly reduce bacterial titres in kidney, bladder and urine in a
86
murine ESBL-producing E. coli UTI model. ETX1317 was able to
restore the activity of cefpodoxime in 1875 global
Enterobacteriaceae UTI isolates, with MIC50/90 values of 0.06/ 0.12
87
mg/L. It demonstrated similar potency against AmpC pro-ducers.
VNRX7145 is another b-lactamase inhibitor that undergoes
biotransformation to the active VNRX5236 with potent activity
against Class A, B and C enzymes. Among 100 isolates of
Enterobacteriaceae, ceftibuten/VNRX5236 maintained an MIC 90 of 1
mg/L across all enzyme subgroups tested (ESBL, KPC, AmpC and
88
OXA-48). Moreover, VNRX5236 was able to reduce the MIC
values of ceftibuten for a similar profile of susceptible isolates com-
pared with ceftazidime/avibactam and meropenem against ESBL
88
producers. Of 50 ESBL-producing isolates tested, MIC50/90 values
were 0.06/0.12 mg/L, with 98% susceptible by EUCAST criteria for
89
ceftibuten. Ceftibuten/VNRX5236 has also demonstrated in vivo
efficacy in a neutropenic thigh infection model against serine b-
lactamase-producing Enterobacteriaceae, achieving a mean re-
90
duction in bacterial burden of #0.2 log10 cfu/thigh. Ceftibuten/
clavulanate is another novel BLBLI combination that also has po-
tential utility in the management of UTIs caused by ESBL pro-
ducers. It exhibited promising activity in four ESBL-producing

6 of 10
Review
isolates.91 It has also shown favourable in vivo activity against
ESBL-producing Enterobacteriaceae in murine thigh model
planned.92
studies and human clinical trials are
Pharmacodynamic studies have been helpful in designing
potential dosage regimens for this combination molecule.91
A Phase 1 clinical trial to establish the safety and
pharmacokin-etics of ETX0282 is registered and underway. 93
Clinical trials involv-ing these other new agents are expected to
be registered in the near future.
Conclusions
The increase in frequency of ESBL-producing
Enterobacteriaceae as causes of UTI worldwide is a concern.
More alarming still is the limited number of oral antibiotic options
currently available to clinicians to treat these infections. Recent
enthusiasm and drug development directed towards
cephalosporin/b-lactamase inhibitor combinations with good oral
bioavailability has pro-vided some much-needed optimism.
Novel oral b-lactamase in-hibitor compounds QPX7728,
ETX0282 and VNRX5236, when paired with the oral third-
generation cephalosporins ceftibuten and cefpodoxime were
able to demonstrate good in vitro activity against MDR Gram-
negative uropathogens. However, analysis of their potency is
significantly limited by non-standardized testing methods and
limited consensus regarding application of clinical breakpoints.
Moreover, the combination of two established com-pounds,
ceftibuten and clavulanate, has also demonstrated encouraging
efficacy. A clinical trial assessing the safety and effi-cacy of
cefpodoxime/ETX0282 is currently underway. Well-designed
studies assessing the pharmacokinetic/pharmacody-namic
profile of both new and old antimicrobials used to treat ESBL-
producing UTI continue to be important. Orally adminis-tered
carbapenems (e.g. tebipenem) are being developed and it
remains to be seen how their efficacy compares with orally
administered BLBLI combinations. Given the rising incidence of
carbapenem-resistant organisms worldwide, the search to find a
suitable ‘carbapenem-sparing’ agent has become a top priority.
Transparency declarations
P.N.A.H. has received funding from Pfizer, Merck Sharpe & Dohme
(MSD), and Shionogi. D.L.P. has received funding from AstraZeneca,
Leo Pharmaceuticals, Bayer, GlaxoSmithKline (GSK), Cubist, Venatorx
and Accelerate; reports board membership from Entasis, Qpex, Merck,
Shionogi, Achaogen, AstraZeneca, Leo Pharmaceuticals, Bayer, GSK,
Cubist, Venatorx, and Accelerate; reports grants/grants pending from
Shionogi and Merck; and has received payment for lectures including
service on speaker’s bureaus from Pfizer, outside the submitted work.
All other authors: none to declare.
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