Systematic
Review
Public Health
Kasmera 49(2):e49235056, Julio-Diciembre, 2021
P-ISSN 0075-5222 E-ISSN
2477-9628
https://doi.org/10.5281/zenodo.5546295
Treatment in Infections by Enterobacterales Producing
Extended Spectrum Betalactamase. Systematic Review
Tratamiento en
infecciones por Enterobacterales que producen betalactamasa de espectro
extendido. Revisión Sistemática
Aziz-Delgado Carli Samira (Corresponding
author). https://orcid.org/0000-0001-5096-114X.
Universidad de Los Andes. Facultad de Medicina. Extensión Valera.
Valera-Trujillo. Venezuela. Dirección Postal: Final Calle 6, Detrás del
Hospital Central “Dr. Pedro E. Carrillo” Valera-Estado Trujillo. Teléfono: +58
426 2743265. E-mail: samiraaziz16@gmail.com
Mendoza-Gaviria José Andrés. https://orcid.org/0000-0002-0269-5526.
Universidad de Los Andes. Facultad de Medicina. Cátedra de Microbiología.
Mérida-Mérida. Venezuela. E-mail: joseandres.mendozagaviria@gmail.com
https://www.researchgate.net/scientific-contributions/Jose-Andres-Mendoza-Gaviria-2028888336
Abstract
Extended
spectrum beta-lactamases producing Enterobacterales have become pandemic
worldwide representing a major public health threat due to poor outcomes and
high mortality associated with infections by these bacteria, consequently it is
essential to conduct a systematic review to document the antibiotic combination
used to fight infections, in order to categorize and sort the most widely used
treatments and determine the most effective ones. The electronic search was
conducted since June 2020 until August 2020. The databases used were PubMed,
Virtual Health Library, ScienceDirect and the Cochrane library; the following
Medical Subject Headings (MESH) were used: “Enterobacterales”,
“infection”, “beta-lactamase”, “beta-lactamase inhibitors”, “therapeutics”, “Enterobacteriaceae/enzymology”. The electronic search
resulted in 1.526 articles meeting the general criteria, 1.493 articles were
excluded; only 35 articles met all the inclusion criteria. there is
basically no tangible difference between treatment with beta-lactam antibiotics
(either combinations or carbapenem), fluoroquinolones, tetracyclines and Fosfomycin in patients without any
pre-existing antibiotic resistance. It is required developing antibiotics, with the
understanding that the microorganism will respond to them and resistance will
develop (an evolutionary fact). Therefore, efforts to develop antibiotics and
study mechanisms of resistance should be continuous, resilient, and steady.
Keywords: Enterobacterales, infection,
beta-lactamase, beta-lactamase inhibitors, Enterobacteriaceae/enzymology,
therapeutics.
Resumen
Palabras claves: Enterobacterales, infección,
betalactamasas, inhibidores de betalactamasas, Enterobacteriaceae/enzimología,
terapéutica.
Recibido: 31/01/2020 | Aceptado: 07/08/2021 | Publicado: 04/10/2021
How to Cite: Aziz-Delgado CS, Mendoza-Gaviria JA. Treatment in Infections by Enterobacterales Producing Extended Spectrum
Betalactamase. Kasmera. 2021;49(2):e49235056. doi:
10.5281/zenodo.5546295
Introduction
Extended spectrum beta-lactamases
(ESBL) producing Enterobacterales have become pandemic worldwide representing a
major public health threat due to poor outcomes and high mortality associated
with infections by these bacteria (1), consequently it is essential to conduct a systematic review to
document the treatment used to fight infections, in order to categorize and
sort the most widely used treatments and determine the most effective ones. New
therapies for the treatment of ESBL-producing bacteria during the last years
has been breathtaking; nevertheless, for one successful case there are others
that get complicated or the chemotherapy results unsuccessful because of the
indiscriminate use of antibiotics in early ages. Resistant bacteria could exist
in any environment, but its frequency is likely to rise when microorganisms
increase survival capacity under selective pressure (e.g. hospitals). While there
are many types of selective pressures, for the purpose of the current
discussion, we will assume that the evolution of antibiotic resistance is
driven primarily by the exposure to antibiotic drugs (2).
The cascade of resistance mechanisms is
responsible for preventing the action of antibiotics at each step of their
passage through the bacterial cell: bacteria can alter their cell wall
structure to deny entry of the drug or synthesize efflux pumps to expel it;
they can modify (and even destroy) compounds by producing enzymes such as
beta-lactamases or stop the production of enzymes necessary for antibiotic
activation; they can modify, hide or quantitatively adjust the intended drug
target; or, finally, they can activate alternative metabolic pathways to
circumvent the toxic action of the antibiotic (3).
During the last few decades, several bacterial
pathogens have evolved into multi-drugs resistance forms. Of particular concern
are multi-drugs resistance Gram-negative pathogens, such as Enterobacterales
Order (4). The differences between Gram-negative bacteria
(GNB) and Gram-positive bacteria lie in the cell wall structure: resulting in
differences in penetration and retention of chemical agents. GNB have a complex
envelope, consisting of three main layers: 1. an outer membrane, containing the
lipopolysaccharide/endotoxin (Gram-positive bacteria generally lack these); 2.
a thin cell wall consisting of peptidoglycan with peptide chains, partially
cross-linked; and 3. the cytoplasmic or inner membrane (5).
Beta-lactamases are enzymes produced by bacteria
that cleave the beta-lactam ring of some antibiotic compounds, rendering
otherwise effective antibiotics largely powerless6. ESBLs are
derived from point mutations in the genes that encode common beta-lactamases
such as TEM-1, TEM-2, or SHV-1 (5) and are found exclusively in gram negative bacteria, particularly the
Enterobacterales family members, including the common pathogens Escherichia coli and Klebsiella pneumoniae (6).
Methods
The objective of this review is focused on the
categorization of the different treatments used in the infections produced by
ESBL considering the pharmacological classification to which they belong;
emphasizing the antibiotic effectiveness; as well as establishing the worldwide
problem that exists around multi-resistant bacteria.
The electronic search was conducted since June
2020 until August 2020. The databases used were PubMed, ScienceDirect and the
Cochrane library; the following Medical Subject Headings (MESH) were used:
“Enterobacterales”, “infection”, “beta-lactamase”, “beta-lactamase inhibitors”, “Enterobacteriaceae/enzymology”, “therapeutics”. Filters used in PubMed: publication year “10 years”, species “human”,
article type “systematic review”, “meta-analysis”, “clinical trial”, “clinical
study” and “randomized controlled trial”. The descriptors used in the databases
were used and combined using the logical operators: "AND". No method
of exclusion was applied concerning age, sex or gender. We excluded all studies
conducted before 2010, that were not systematic reviews or that were not
clinical trials. An exhaustive search was carried out on the Internet following
the criteria mentioned above and then a compilation of the articles that
adapted to them, once the texts had been selected, a first reading was carried
out to classify them. After the collection, the articles were read in such a
way as to detail recurrent patterns in order to categorize the information and
report the results in a concise manner.
Result
The electronic search resulted in 1.526 articles meeting the general criteria, 1.495 articles were excluded; only 33 articles met all the inclusion criteria, Figure 1.
Drugs
used in the treatment of infections by extended spectrum
beta-lactamase-producing enterobacteria
Regarding the above evidence, it can be stated
that the infections produced by Extended spectrum beta-lactamases (ESBL)
producing Enterobacterales are not a rare occurrence, being the combinations of
several beta-lactam antibiotics the most effective ones in the treatment of
such infections, as well as of the fluorinated quinolones and tetracyclines,
the second most used in the treatment of these infections. The following is the
categorization of the results.
Beta-lactam
Antibiotics: the β-lactam antibiotics have a bactericidal action that disrupts
bacterial cell wall formation due to covalent binding to essential
penicillin-binding proteins (PBPs), which are involved in the terminal steps of
peptidoglycan cross-linking in both Gram-negative and Gram-positive bacteria (7). Their commonality is the ability to hydrolyze
chemical compounds containing a β-lactam ring;
Gram-negative bacteria, β-lactamases have
played a critical clinical role and have served as the primary resistance
mechanism for the β-lactam antibiotics (8). With a limited number of treatment options available
against multidrug-resistant Gram-negative bacteria, newer treatment strategies
are becoming increasingly important (9) (Table 1)
Table 1. Beta-lactam Antibiotics
|
Cite |
Year/Study type |
Authors |
Sample |
Results |
|
(2018) Original article |
Bush K. |
A later scheme classifies -lactamases according to
amino acid sequences, resulting in class A, B, C, and D enzymes. A more
recent nomenclature combines the molecular and biochemical classifications
into 17 functional groups. |
Lactamases, some of our oldest enzymes, have
emerged as perhaps the most studied, and most troublesome, of the antibiotic
resistance determinants. |
|
|
(2018) Critical Review |
Chastain DB, White BP, Cretella DA, Bland
CM. |
Data abstracted included empirical or
definitive therapy, patient population, dosing, source of infection and
severity, infectious etiology, and outcome. |
Completely sparing carbapenem therapy cannot
be justified among patients with ESBL BSIs. |
Carbapenem: have been recommended as the first-line antimicrobial agent to treat
infections caused by ESBL-producing Enterobacterales (10-12), because they are not affected by these resistance
mechanisms. In relation to definitive therapy, the overall mortality was lower
with carbapenem therapy than with non-carbapenem (RR 0.78, 95% CI 0.61–0.98,
I2"29%) or non-BL/BLI (RR 0.71, 95% CI 0.56–0.90, I2"22%) therapy. In
contrast, there were no significant differences with respect to the overall
mortality rates between the carbapenem groups and the BL/BLI (RR 0.67, 95% CI
0.37–1.20, I2"61%) (13).
An observational
prospective study suggests that patients with nosocomial
infections were also more frequently treated empirically with carbapenems
(79.41% vs. 57.8%; OR 2.8, 95% CI 1.1–7.8) (14).
In a meta-analysis,
a total of 25 observational studies describing 3842 patients were identified
1963 patients received empiric antibiotics and 1879 received definitive
antimicrobial therapy, the pooled odds ratio of BL-BLI versus carbapenems
mortality within 30 days for ESBL-producing Enterobacterales bloodstream
infections, from random effects meta-analysis, was 1.07 but it was not
clinically significant (95% CI, 0.81-1.41; P=0.63) (1).
In contrast to the
other carbapenems, ertapenem was as efficacious as any other carbapenem for the
treatment of bloodstream infections due to diverse ESBL-E from different
sources and in different clinical situations. In fact, a study indicates that de-escalation
therapy to ertapenem is non-inferior to continuation of group 2 carbapenems for
clinical cure rate (%Δ = 14.0 [95% CI:
-2.4 to 31.1]), microbiological eradication rate (%Δ = 4.1 [-5.0 to 13.4]), superimposed infection (%Δ = -16.5 [-38.4 to 5.3]), and 28-day mortality (%Δ = -20.0 [-39.3 to -0.8]) (11).
The current ‘gold standard’ treatment for
ESBL-producing Gram-negative bacteremia is carbapenem. However, only limited observational data exist regarding the clinical
outcome with carbapenem. Studies
addressing the clinical efficacy of ertapenem are exceedingly scarce. Nevertheless, recent reports suggest
favorable clinical responses after having used ertapenem against ESBL-producing
organism (15) (Table 2)
Table 2. Carbapenem
|
Cite |
Year/Study type |
Authors |
Sample |
Results |
|
(2012)
Systematic review and meta-analysis |
Vardakas
KZ, Tansarli GS, Rafailidis PI, Falagas ME. |
Twenty-one
articles, studying 1584 patients, were included. Escherichia coli and Klebsiella
pneumoniae were the most commonly studied bacteria. Delay in appropriate
treatment up to 6 days was reported. |
No
statistically significant differences in mortality were found between
carbapenems and BL/BLIs administered as definitive (RR 0.52, 95% 0.23-1.13)
or empirical (RR 0.91, 95% CI 0.66-1.25) treatment. BL/BLIs were not
associated with lower mortality than non-BL/BLIs administered either
definitively (RR 1.59, 95% 0.83-3.06) or empirically (RR 0.82, 95%
0.48-1.41). |
|
|
(2017) Open-label randomized controlled trial |
Rattanaumpawan P, Werarak P, Jitmuang A, Kiratisin P, Thamlikitkul V. |
Enterobacteriaceae infections who had received any group 2 carbapenem for less than 96
h. In the intervention group, the previously-prescribed group 2 carbapenem
was de-escalated to ertapenem. In the control group, the group 2 carbapenem
was continued. |
During June 2011-December 2014, 32 patients were randomized to the
de-escalation group and 34 to the control group. Most common sites of
infection were urinary tract infection (42%). Characteristics of both groups
were comparable. |
|
|
(2016) Multinational pre-registered
cohort study |
Gutiérrez-Gutiérrez B, Bonomo
RA, Carmeli Y, Paterson DL, Almirante B, Martínez-Martínez L, et al. |
The
empirical therapy cohort (ETC) and the targeted therapy cohort (TTC) included
195 and 509 patients, respectively. |
Cure/improvement
rates were 90.6% with ertapenem and 75.5% with other carbapenems (P¼0.06) in
the ETC and 89.8% and 82.6% (P¼0.02) in the TTC, respectively; 30-day
mortality rates were 3.1% and 23.3% (P¼0.01) in the ETC and 9.3% and 17.1%
(P¼0.01) in the TTC, respectively. Adjusted ORs (95% CI) cure/improvement
with empirical and targeted ertapenem were 1.87 (0.24-20.08; P¼0.58) and 1.04
(0.44-2.50; P¼0.92), respectively. |
|
|
(2018) Systematic review and meta-analysis |
Son SK, Lee NR, Ko JH, Choi JK, Moon SY, Joo EJ, et al. |
Thirty-five publications fulfilled the inclusion criteria. |
Regarding empirical therapy, there were no significant differences
between the groups that received carbapenems and those that received
non-carbapenems in relation to overall mortality. |
|
|
(2015)
Clinical trial |
Pilmis
B, Delory T, Groh M, Weiss E, Emirian A, Lecuyer H, et al. |
Seventy-nine
patients were included: 36 (45.6%) were children, 27 (34.1%) were hospitalized
in intensive care units, and 37 (47%) were immunocompromised. |
Antimicrobial
resistance (44.7%), infection relapse (26.9%), and clinical instability
(19.2%) were the most important reasons for not prescribing alternatives. E.
coli-related infections appeared to be a protective factor against
maintaining the carbapenem prescription (odds ratio 0.11, 95% confidence
interval 0.041-0.324; p = 0.0013). |
|
|
(2012) |
Wu UI, Chen WC, Yang CS, Wang JL, Hu FC, Chang SC, et al. |
This non-concurrent prospective study included adult patients with
ESBL-EC bacteremia during a 2.5-year period at a 2200-bed teaching hospital. |
Of 71 patients who met the study criteria, nine died within 3 days.
Among the 62 remaining patients who received definitive antimicrobial
therapy, 13 died within 30 days. |
Ceftazidime/Avibactam: is an antibacterial agent
that consists of an existing third-generation cephalosporin combined with a
novel β-lactamase inhibitor. The addition of avibactam
restores the activity of ceftazidime against gram-negative bacilli infections
caused by MDR gram-negative organisms such as ESBL- producing Enterobacterales,
MDR P. aeruginosa, and KPC K. pneumoniae (16).
A meta-analysis of three
studies including 1186 patients demonstrated that there was no significant
difference in the rate of clinical success between the two groups treated with
CAZ- AVI versus carbapenems (RD = 0.00, 95% CI –0.0 6 to 0.0 6; P = 0.99), Only
one study comprising 332 patients reported mortality and showed no
statistically significant difference between the two groups (RD = 0.00, 95% CI
–0.03 to 0.03; P = 0.98) (17).
Ceftazidime/avibactam at a 4:1 ratio (1 g or 2 g
of ceftazidime) was effective in suppressing the growth of eight strains of
ceftazidime-resistant Enterobacterales; unexpectedly, all strains were rapidly
killed with growth suppression for ≥10 h when ceftazidime was dosed as a continuous
infusion and avibactam was given as a single bolus dose (18).
In two identical prospective,
randomized, double-blind, comparative phase 3 non-inferiority studies in
patients with cIAI (RECLAIM; NCT01499290), ceftazidime-avibactam was found to
be highly active in vitro against baseline Enterobacterales isolates, with an
overall MIC90 of 0.25 mg/l (128-fold lower than that of ceftazidime alone) and
an MIC90 of ≤2 mg/l against each of the individual members of the
Enterobacterales family. These results agree with the clinical results of the
Phase 3 study, which showed that ceftazidime-avibactam plus metronidazole is
effective in patients with cIAI, with a clinical cure rate similar to that of
meropenem in patients with Gram-negative infection (19).
In a post hoc exploratory
analysis that evaluated the clinical activity of ceftazidime/avibactam against
MDR Enterobacterales and P. aeruginosa
isolates14 pooled from the ceftazidime/avibactam Phase III clinical trials,
included 2585 patients from countries across North and South America, Europe,
Asia and Africa, successfully demonstrated ceftazidime/avibactam to be a
suitable alternative to carbapenem-based therapies for certain serious
Gram-negative infections (20).
REPRISE was an international,
randomized, open-label, phase 3 trial that recruited patients from hospitals
worldwide. 33 patients were enrolled and randomized at 53 hospitals in 16
countries worldwide: 165 to ceftazidime-avibactam, and 168 to best available
therapy. The study showed that ceftazidime-avibactam and best available therapy
led to the same proportion of patients achieving an overall clinical cure at
the test-of- cure visit in the mMITT population (91% in both groups) (21). This agent replenishes the current candidate therapy for multidrug-resistant
GNB pathogens, particularly ESBL-producing organisms and CRE, which is likely
to be its principal role in therapy (22) (Table 3).
Table
3. Ceftazidime/Avibactam
|
Cite |
Year/Study type |
Authors |
Sample |
Results |
|
(2016) New Drug Review |
Sharma
R, Eun Park T, Moy S. |
Abstracts
from Infectious Disease Week (2014–2015), the Interscience Conference on
Antimicrobial Agents and Chemotherapy (2014–2015), and the European Congress
of Clinical Microbiology and Infectious Diseases were also searched. |
Ceftazidime,
a third-generation cephalosporin, when combined with avibactam has a
significant improvement in its activity against β-lactamase producing
gram-negative pathogens, including extended spectrum β-lactamases, AmpC
β-lactamases, Klebsiella pneumoniae carbapenemase-producing
Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa. |
|
|
(2019) Meta-analysis of randomized controlled trials |
Che H, Wang R, Wang J, Cai Y. |
Three RCTs (1186 patients) were included in the meta-analysis. |
The meta-analysis showed that there were no significant differences
between CAZ-AVI and carbapenems in clinical success [risk difference (RD) =
0.00, 95% confidence interval (CI) -0.06 to 0.06; P = 0.99], microbiological
success (RD = 0.07, 95% CI -0.04 to 0.18; P = 0.21) or AEs (RD = 0.00, 95% CI
-0.02 to 0.03; P = 0.81). SAEs with CAZ-AVI were numerically higher than with
carbapenems (RD = 0.02, 95% CI -0.00 to 0.04; P = 0.06). |
|
|
(2015)
Article original |
Bush K. |
Lactamase
inhibitors (BLIs) have played an important role in combatting -lactam
resistance in Gram-negative bacteria, but their effectiveness has diminished
with the evolution of diverse and deleterious varieties of -lactamases. |
Because
all of the inhibitor combinations are being developed as parenteral drugs, an
orally bioavailable combination would also be of interest. |
|
|
(2018) Clinical trial |
Stone GG, Newell P, Bradfordc PA. |
In vitro activity of ceftazidime-avibactam versus comparators was
evaluated against 1,440 clinical isolates obtained in a phase 3 clinical
trial in patients with complicated intra- abdominal infections (cIAI;
NCT01499290). Overall, in vitro activity was determined for 803
Enterobacteriaceae, 70 P. aeruginosa, 304 Gram-positive aerobes and 255
anaerobes isolated at baseline from 1,066 randomized patients. |
Ceftazidime-avibactam was highly active against isolates of Enterobacteriaceae,
with an overall MIC90 of 0.25 mg/l. In contrast, the MIC90 for ceftazidime
alone was 32 mg/l. The MIC90 value for ceftazidime-avibactam (4 mg/l) was one
dilution lower than that of ceftazidime alone (8 mg/l) against isolates of
Pseudomonas aeruginosa. |
|
|
(2018) Phase III clinical trial program |
Stone
GG, Newell P, Gasink LB, Broadhurst H, Wardman A, Yates K, et al. |
Baseline
isolates from five Phase III randomized controlled trials of ceftazidime/
avibactam versus predominantly carbapenem comparators in patients with cIAI
(RECLAIM 1 and 2; NCT01499290 and RECLAIM3;NCT01726023), cUTI (RECAPTURE 1
and 2; NCT01595438 and NCT01599806), NP including VAP (REPROVE;NCT01808092)
and cIAI or cUTI caused by ceftazidime-non-susceptible Gram-negative
pathogens (REPRISE; NCT01644643) were tested for MDR status and
susceptibility to ceftazidime/avibactam and carbapenem based comparators
using CLSI broth microdilution methodology. |
In the
pooled microbiologically modified ITT population, 1051 patients with MDR
Enterobacteriaceae and 95 patients with MDR P. aeruginosa isolates were
identified. Favorable microbiological response rates at TOC for all MDR
Enterobacteriaceae and MDR P. aeruginosa were 78.4% and 57.1%, respectively,
for ceftazidime/avibactam and 71.6% and 53.8%, respectively, for comparators. |
|
|
(2016) Randomized, pathogen-directed, phase 3 study |
Carmeli Y, Armstrong J, Laud PJ, Newell P, Stone G, Wardman A, et al. |
Between Jan 7, 2013, and Aug 29, 2014, 333 patients were randomly
assigned, 165 to ceftazidime-avibactam and 168 to best available therapy. |
Of these, 154 assigned to ceftazidime-avibactam (144 with complicated
urinary tract infection and ten with complicated intra-abdominal infection)
and 148 assigned to best available therapy (137 with complicated urinary
tract infection and 11 with complicated intra-abdominal infection) were
analyzed for the primary outcome. 163 (97%) of 168 patients in the best
available therapy group received a carbapenem, 161 (96%) as monotherapy. |
|
|
(2018)
Systematic review and meta-analysis |
Zhong H,
Zhao XY, Zhang ZL, Gu ZC, Zhang C, Gao Y, et al. |
Twelve
articles (4951 patients) were included, consisting of nine RCTs and three
observational studies comparing CAZ-AVI with other regimens, e.g. carbapenems
or colistin. |
No
significant differences were detected between groups in terms of mortality
and adverse events. In addition, subgroup analyses demonstrated that CAZ-AVI
improved clinical response (RR = 1.61; 95% CI: 1.13-2.29). |
Ceftolozane/Tazobactam: β-Lactam/β-lactamase
inhibitor combination antibiotics, have been considered a carbapenem-sparing
option for treatment of ESBL producers (23).
Ceftolozane/tazobactam consists of a novel cephalosporin and an established
β-lactamase inhibitor that is being developed to address antimicrobial
resistance in serious infections caused by gram-negative pathogens, including
complicated urinary tract infection/pyelonephritis (cUTI) and ventilated
nosocomial pneumonia (24). In vitro activity of
ceftolozane/tazobactam has been confirmed against ESBL-producing
Enterobacterales; in two identical multicenter, prospective, randomized,
double- blind, placebo-controlled trials; In total, 993 patients were
randomized to ceftolozane/tazobactam plus metronidazole (n = 487) or meropenem
(n = 506), and 806 (81.2%) qualified for the MITT population. In this study,
more than one- half of the ESBL-producing Enterobacterales isolated at baseline
were positive for CTX-M-14 or CTX-M-15–type enzymes. Ceftolozane/tazobactam
plus metronidazole maintained clinical efficacy against these highly resistant
strains (100%) (25).
In Forty-four hospitals, of the 2511
Enterobacterales collected, 442 (18%) of these isolates screened positive for
ESBL production, when considering only the Enterobacterales-confirmed
ESBL-positive isolates in the absence of detectable carbapenemases, the rank
order susceptibility of the conventional non-carbapenem agents was as follows:
C/T, 82% (26).
Another randomized (1:1 ratio),
double-blind, phase 3 non-inferiority trials study, clinical cure rates for
patients with ESBL-ENT (including CTX-M-14/ 15), the overall clinical cure rate
for ceftolozane/tazobactam against ESBL-ENT was 97.4%; clinical cure rates were
high regardless of the presence/absence of CTX-M-14/15-type ESBLs. In vitro
susceptibility testing showed that ceftolozane/tazobactam was at least 2-fold
more potent (MIC90 values) than most antibacterial tested against ESBL-ENT (27) (Table 4).
Table 4. Ceftolozane/Tazobactam
|
Cite |
Year/Study type |
Authors |
Sample |
Results |
|
(2018)
Randomized Clinical Trial |
Harris
PNA, Tambyah PA, Lye DC, Mo Y, Lee TH, Yilmaz M, et al. |
Included
hospitalized patients enrolled from 26 sites in 9 countries from February
2014 to July 2017.Of 1646 patients screened, 391 were included in the study. |
A total
of23 of187 patients (12.3%) randomized to piperacillin-tazobactam met the
primary outcome of mortality at 30days compared with 7of 191 (3.7%)
randomized to meropenem (risk difference, 8.6%[1-sided97.5%CI, to 14.5%];P = .90
for noninferiority) |
|
|
(2015)
Comparative study |
Liscio
JL, Mahoney M V., Hirsch EB. |
An
online literature search was performed using the MEDLINE database and the
search terms ‘ceftolozane’, ‘tazobactam’, ‘ceftazidime’, ‘avibactam’,
‘antibiotic resistance’, ‘beta-lactamase’ and ‘beta-lactamase inhibitor’.
English language studies from 2009 to 2015 were considered. |
Both
agents appear to be well tolerated and show promise in the treatment of MDR
Gram-negative infections. |
|
|
(2015) Randomized, Double-Blind, Phase 3 Trial (ASPECT-cIAI) |
Solomkin
J, Hershberger E, Miller B, Popejoy M, Friedland I, Steenbergen J, et al. |
993
patients were randomized to ceftolozane/tazobactam plus metronidazole (n =
487) or meropenem (n = 506), and 806 (81.2%) qualified for the MITT
population. |
Ceftolozane/tazobactam
plus metronidazole was noninferior to meropenem in the primary (83.0%
[323/389] vs 87.3% [364/417]; weighted difference, -4.2%; 95% confidence
interval [CI], -8.91 to .54) and secondary (94.2% [259/275] vs 94.7%
[304/321]; weighted difference, -1.0%; 95% CI, -4.52 to 2.59) endpoints,
meeting the prespecified noninferiority margin. |
|
|
(2015)
Systematic review |
Sutherland
CA, Nicolau DP. |
44
hospitals provided nonduplicate, nonurine isolates of E coli (n ¼ 1306), K
pneumoniae (n ¼ 1205), and P aeruginosa (n ¼ 1257) from adult inpatients.
MICs for C/T and 11 other antimicrobials were determined with broth microdilution
methods. |
The
carbapenems, C/T, and colistin displayed the highest percentage of
susceptibility and lowest MIC90 against the Enterobacteriaceae, followed by
piperacillin/tazobactam (TZP), cefepime, tobramycin, aztreonam, ceftriaxone,
and ciprofloxacin. |
|
|
(2017)
Clinical trial |
Popejoy
MW, Paterson DL, Cloutier D, Huntington JA, Miller B, Bliss CA, et al. |
Of 2076
patients randomized, 1346were included in the pooled ME population and 150
of1346 (11.1%) had ESBL-ENT at baseline. |
At US
FDA/EUCAST breakpoints of ≤2/≤1 mg/L, 81.8%/72.3% of ESBL-ENT
(ESBL- Escherichia coli, 95%/ 88.1%; ESBL-Klebsiella pneumoniae,
56.7%/ 36.7%) were susceptible to ceftolozane/tazobactam versus 25.3%/24.1%
susceptible to levofloxacin and 98.3%/ 98.3% susceptible to meropenem at
CLSI/ EUCAST breakpoints. Clinical cure rates for ME patients with ESBL-ENT
were 97.4% (76/78) for ceftolozane/tazobactam [ESBL-E. coli, 98.0% (49 of
50); ESBL-K. pneumoniae, 94.4% (17 of 18)], 82.6% (38 of 46) for levofloxacin
and 88.5% (23 of 26) for meropenem. |
Fluoroquinolone: quinolones
target two essential bacterial type II topoisomerase enzymes, DNA gyrase and
DNA topoisomerase IV. Both enzymes are heterotetramers with two subunits,
gyrase being constituted as GyrA2GyrB2 and topoisomerase IV as ParC2ParE2.
Quinolones inhibit enzyme function by blocking the resealing of the DNA
double-strand break, but, in addition, this process stabilizes a catalytic
intermediate covalent complex of enzyme and DNA that serves as a barrier to
movement of the DNA replication fork or transcription complexes and can be con-
verted to permanent double-strand DNA breaks, thereby functioning as
topoisomerase poisons (28).
The increased use of
carbapenems in response to ESBL and other resistant infections has led to the
emergence of carbapenem resistance. In order to preserve carbapenems, all
antibiotic options that may be available to treat ESBL- producing infections
should be considered (29). A systematic review and
meta-analysis compare patient outcomes, specifically recurrence of infection
and all-cause mortality, with the use of Fluoroquinolone or Trimethoprim-
Sulfamethoxazole vs ß-lactams as oral step-down treatment of GNR bacteremia; findings
suggest that mortality is not significantly different with use of FQ/TMP-SMX vs
ß-lactams in the step-down treatment of uncomplicated GNR bacteremia. It did
find, however, that overall recurrence of infection occurred more frequently
with ß-lactams when compared with FQs (30).
In a study of 716 participant’s fluoroquinolones were the only class of
antibiotics with sufficient variation in treatment duration to explore the
impact of duration on emergence of resistance. Of 76 patients receiving
fluoroquinolones, 33 (43%) and 43 (57%) received short and long treatment,
respectively; no epidemiologic risk factorswere identified for colonization by
ESBL-PE, nor was fluoroquinolone treatment significantly associated with an
increase in the prevalence of ESBL-PE colonization within 28 days: aPR at 1.36
(0.35−5.20) (31).
Multiple studies have analyzed
occurrence of co-resistance between fluoroquinolones and ESBL production mainly
in Enterobacterales. There is a high risk of fluoroquinolone resistance in
ESBL- producing Gram-negative bacilli. The qnr genes, commonly found on
ESBL-producing Enterobacterales, have not been linked to outright resistance,
but rather confer reduced susceptibility to fluoroquinolones. In such
situations, the minimum inhibitory concentration (MIC) should be taken into
consideration and it may be prudent to use increased doses of fluoroquinolones.
For infections at sites such as the urinary tract where ciprofloxacin and
levofloxacin concentrate, selection of these agents may be more appropriate. It
is important, nevertheless, to consider historical patterns of quinolone use
leading to QRDR and the potential for increased resistance with continued use.
Data regarding the use of fluoroquinolones, when reported as susceptible, in
the treatment of ESBL-producing organisms have conflicting results (29).
Sitafloxacin, a broad-spectrum
oral fluoroquinolone, is active against many gram-positive, gram-negative, and
anaerobic bacteria, including strains resistant to other fluoroquinolone. A
prospective, open-label, randomized, controlled trial was conducted at
Ramathibodi Hospital, a 1200-bed university hospital in Bangkok, Thailand.
Thirty-six patients with a presumptive diagnosis of acute pyelonephritis were
enrolled. They were randomized into either the sitafloxacin group (19 patients,
52.8%) or the ertapenem group (17 patients, 47.2%). Bacterial eradication was
84.2% and 75.0% in sitafloxacin and ertapenem groups, respectively ESBL-EC
infection (32).
Unfortunately, increasing in vitro resistance to
quinolones in isolates which are also ESBL producers will limit the role of
these antibiotics in the treatment of infections due to ESBL-producing
organisms in the future (33) (Table 5).
Table 5. Fluoroquinolones
|
Cite |
Year/Study type |
Authors |
Sample |
Results |
|
(2016)
Original article |
Hooper
DC, Jacoby GA. |
Resistance
mutations in one or both of the two drug target enzymes are commonly in a
localized domain of the gyrA and parC subunits of gyrase and
topoisomerase IV, respectively, and reduce drug binding to the enzyme–DNA
complex. |
Plasmids
with these mechanisms often encode additional antimicrobial resistance and
can transfer multidrug resistance that includes quinolones |
|
|
(2016) Literature
Review |
Wiener ES, Heil EL, Hynicka LM,
Kristie Johnson J. |
A total
of 18 studies that analyzed fluoroquinolone resistance and association to
ESBL producing bacteria from either molecular or clinical perspectives were
identified. |
Fluoroquinolone
resistance may be co-transmitted in ESBL-producing Enterobacteriaceae.
There are limited data on the efficacy for fluoroquinolones in the treatment
of ESBL-producing infections. |
|
|
(2019) Systematic Review and Meta-analysis |
Punjabi
C, Tien V, Meng L, Deresinski S, Holubar M. |
Eight
retrospective studies met inclusion criteria with data for 2289 patients, of
whom 65% were transitioned to oral FQs, 7.7% to TMP-SMX, and 27.2% to BLs.
Follow-up periods ranged from 21 to 90 days. |
All-cause
mortality was not significantly different between patients transitioned to
either FQ/TMP-SMX or BLs (odds ratio [OR], 1.13; 95% confidence interval
[CI], 0.69–1.87). Overall recurrence of infection, either bacteremia or the
primary site, occurred more frequently in patients transitioned to oral BLs
vs FQs (OR, 2.05; 95% CI, 1.17–3.61). Analysis limited to recurrent
bacteremia was similarly suggestive, although limited by small numbers (OR,
2.15; 95% CI, 0.93–4.99). |
|
|
(2018)
Multinational prospective cohort study |
Stewardson
AJ, Vervoort J, Adriaenssens N, Coenen S, Godycki-Cwirko M, Kowalczyk A, et
al. |
We
included 300 households (205 exposed, 95 non-exposed) with 716 participants. |
Most
exposed patients received nitrofurans (86 [42%]) or fluoroquinolones (76
[37%]). CIP-RE were identified in 16% (328/2033) of samples from 202 (28%)
participants. |
|
|
(2017) Pilot
study |
Malaisri
C, Phuphuakrat A, Wibulpolprasert A, Santanirand P, Kiertiburanakul S. |
A
prospective randomized controlled trial of patients with acute pyelonephritis
caused by ESBL-EC was performed as a pilot study. One of the carbapenems was
initially given to the patients. After day 3, patients were randomized to
receive either sitafloxacin or ertapenem. |
There
was no statistically significant difference in baseline characteristics
between the two groups except a lower proportion of previous urinary catheter
insertion in the sitafloxacin group (15.8% vs. 52.9%, p ¼ 0.018). |
|
|
(2000)
Article original |
Paterson
DL. |
In
vitro studies and observational studies strongly suggest that carbapenems
(imipenem or meropenem) should be regarded as drugs of choice for serious
infections due to ESBL-producing organisms. Other b-lactam antibiotics
(cefepime, b-lactam/b-lactamase inhibitor combinations) are not suitable as first-line
therapy. |
The
increasing frequency of the association between quinolone resistance and ESBL
production have greatly limited the role of this class of antibiotic against
ESBL producers. |
Tetracyclines: many studies have indicated
that the tetracyclines bind to the RNA component of bacterial ribosomes. More
specifically, they are believed to inhibit translation by binding to the 16S
rRNA and inhibiting the binding of aminoacyl-tRNA to the mRNA-ribosome complex.
A number of binding sites have been identified on the 16S rRNA through
photoaffinity labelling and chemical foot printing, indicating certain bases as
contributing to the binding pocket. Recently, another study has shown that the
tetracyclines bind to double stranded RNAs of random base sequence, indicating
that the double-stranded structures of RNAs may play a more important role in
their interaction with the tetracyclines than the specific base sequences (34).
Eravacycline is a novel, fully synthetic
antibiotic of the tetracycline class designed to be active against the 2 main
acquired tetracycline-specific resistance mechanisms: ribosomal protection and
active drug efflux. A randomized, double-blind, double-dummy, multicenter study
using a 2-arm, with a total of 541 patients, the difference in clinical cure
rates was −1.80% with a 2-sided 95% CI of −7.4% to 3.8%, meeting
the statistical criteria for noninferiority. The microbiologically evaluable
population also achieved statistical noninferiority, with clinical cure rates
of 91.4% (181 of198) for eravacycline and 95.0% (189of199) for ertapenem
(difference of −3.6%; 95% CI, −8.9% to 1.5%) (35).
Another trial compared eravacycline with
ertapenem (IGNITE1), and eravacycline with meropenem (IGNITE4). Both studies
were randomized, double-blind, double-dummy, multicenter, prospective studies.
A total of 1041 patients were randomly assigned to receive either eravacycline
or the carbapenem control drug. For the micro-ITT population, clinical cure
rates were virtually identical between treatment groups in both studies: 86.8%
for eravacycline versus and 87.6% for ertapenem; 90.8% for eravacycline versus
91.2% for meropenem, with overall cure rates of 88.7 and 89.3% for the pooled
eravacycline and comparator groups, respectively (36).
A clinical trial compared eravacycline (1 mg/kg
IV q12h) to meropenem (1 g IV q8h) for the management of complicated
intra-abdominal infections. The key finding was non-inferiority of eravacycline
to meropenem (37).
Eravacycline as monotherapy has demonstrated
broad antimicrobial activity in both in
vitro activity studies and in the two-Phase III trials completed
for cIAI, each using a broad-spectrum carbapenem as a comparator. This, coupled
with the improved pharmacokinetics and adverse event profile relative to older
members of the tetracycline class (35) (Table 6).
Table 6. Tetracyclines
|
Cite |
Year/Study type |
Authors |
Sample |
Results |
|
(2016) Article Original |
Chukwudi CU. |
Many studies have investigated the binding of the
tetracyclines to the 16S rRNA using the small ribosomal subunit of different
bacterial species, but there seem to be no agreement between various reports
on the exact binding site on the 16S rRNA. |
In the light of recent evidence that the
tetracyclines bind to various synthetic dsRNAs of random base sequences,
suggesting that the double-stranded structures may play a more important role
in the binding of the tetracyclines to RNA than the specific base pairs as
earlier speculated, it is imperative to consider possible alternative |
|
|
(2019) Review article |
Solomkin JS, Sway A, Lawrence K, Olesky M, Izmailyan
S, Tsai L. |
Clinical cure rates were 86.8% for eravacycline
versus 87.6% for ertapenem, and 90.8% for eravacycline versus 91.2% for
meropenem in the Intent to Treat (micro-ITT) populations, and 87.0% for
eravacycline versus 88.8% ertapenem, and 92.4 versus 91.6% for meropenem in
the Modified Intent to Treat (MITT) populations. |
Eravacycline is an effective new option for use in
complicated intra-abdominal infections, and in particular, for the treatment
of extended-spectrum β-lactamase- and carbapenem-resistant
Enterobacteriaceae-expressing organisms |
|
|
(2018) Expert review |
Sheu CC, Lin SY, Chang YT, Lee CY, Chen YH, Hsueh
PR. |
The clinical efficacy of piperacillin/tazobactam and
cefepime on in vitro-susceptible ESBL-producing Enterobacteriaceae remains a
concern. Many studies found an in vitro-in vivo discordance based on current
breakpoints. |
Recently, ceftolozane/ tazobactam and
ceftazidime/avibactam have been approved for the treatment of complicated
urinary tract infections and complicated intra-abdominal infections. The
introduction of these new β-lactam/β-lactamase inhibitor
combinations offer new carbapenem-sparing options for the treatment of ESBL
infections |
|
|
(2019) Comparative test |
Solomkin JS, Gardovskis J, Lawrence K, Montravers P,
Sway A, Evans D, et al. |
A sample size of approximately 466 randomized
subjects. |
Eravacycline was noninferior to meropenem in the
primary endpoint (177/195 [90.8%] vs 187/205 [91.2%]; difference –0.5%; 95% confidence
interval [CI] –6.3 to 5.3), exceeding the prespecified margin. |
Fosfomycin: previous surveys have shown
that fosfomycin, a phosphonic acid derivative that disrupts cell wall
synthesis, is active against 85–100% of multidrug-resistant uropathogens.
Fosfomycin is active against most ESBL-producing Enterobacterales according to
the current susceptibility breakpoints. Clinical and microbiological success
with fosfomycin and carbapenems was not significantly different (77.8% vs. 95
and 59.3% vs. 80%, respectively; P> 0.05) (36).
A systematic review conducted in 2010 with a
total of 21 studies, shows that fosfomycin has a high level of antimicrobial
activity against Enterobacterales isolates with advanced resistance to
antimicrobial drugs, such as the production of ESBLs (38).
Even though development of resistance to fosfomycin can occur during
treatment, it seems to be much less frequent in E. coli than in Klebsiella spp
or Pseudomonas aeruginosa, and specifically in UTI. In the same way fosfomycin trometamol is an oral formulation of fosfomycin reaching low
plasma concentrations but very high urinary concentrations; the results from
observational studies suggest that fosfomycin trometamol is useful for the
treatment of cystitis and complicated UTIs caused by ESBL-EC (39).
In an observational study of
patients with complicated UTIs due to ESBL-producing E. coli, oral fosfomycin was compared to carbapenem treatment.
Clinical and microbiological success with fosfomycin and carbapenems was not
significantly different (77.8% vs. 95 and 59.3% vs. 80%, respectively; P >
0.05) (36) (Table 7)
Table 7. Fosfomycin
|
Cite |
Year/Study type |
Authors |
Sample |
Results |
|
(2018) Expert review |
Sheu CC, Lin SY, Chang YT, Lee CY, Chen YH, Hsueh
PR. |
The clinical efficacy of piperacillin/tazobactam and
cefepime on in vitro-susceptible ESBL-producing Enterobacteriaceae remains a
concern. Many studies found an in vitro-in vivo discordance based on current
breakpoints. |
Recently, ceftolozane/ tazobactam and
ceftazidime/avibactam have been approved for the treatment of complicated
urinary tract infections and complicated intra-abdominal infections. The
introduction of these new β-lactam/β-lactamase inhibitor combinations
offer new carbapenem-sparing options for the treatment of ESBL infections |
|
|
(2010) Systematic review |
Falagas ME, Kastoris AC, Kapaskelis AM,
Karageorgopoulos DE. |
17 antimicrobial-susceptibility studies were found
and included in our Review, accounting for 5057 clinical isolates of
Enterobacteriaceae with advanced resistance to antimicrobial drugs (4448 were
producers of ESBL); 11 of the 17 studies reported that at least 90% of the
isolates were susceptible to fosfomycin. |
Initial clinical data support the use of fosfomycin
for the treatment of urinary tract infections caused by these pathogens,
although further research is needed. |
|
|
(2015) Research
protocol for a randomized controlled trial |
Rosso-Fernández
C, Sojo-Dorado J, Barriga A, Lavín-Alconero L, Palacios Z, López-Hernández I,
et al. |
Hospitalised adults (18 years of age or older) with
bacteraemic UTI caused by fosfomycin and meropenem susceptible ESBL-EC are
candidates to be included in the study. Eligible |
Data will be presented at international conferences
and published in peer-reviewed journals. |
Discussion
The introduction of antibiotics into clinical use was arguably the
greatest medical breakthrough of the 20th century. In addition to treating
infectious diseases, antibiotics made many modern medical procedures possible,
including cancer treatment, organ transplants and open-heart surgery (40). However, the fear of missing covering
empirical coverage is the main reason that leads clinicians to the
indiscriminate use of broad-spectrum antibiotics, with the consequent negative
effect on further rise in resistance rates; a systematic review shows that
there are a significant association between inappropriate empirical antibiotics
and the percentage of patients in the study with all resistance phenotypes
tested (41).
Thus, in most of these
studies, what is tested is the inappropriate prescription of antibiotics: if a
3GC is prescribed in patients with bacteria resistant to this antibiotic, they
are more likely to die than if the bacteria are susceptible. This does not mean
that mortality is higher with these bacteria but simply that the prescription
of antibiotics was inappropriate, which is indeed more likely to occur in the
case of MDR bacteria (42), but the long-time misuse
and overuse of antibiotics have resulted in the widespread dissemination of
antibiotics as well as antibiotic resistance genes all over the environment,
not only in sewage and wastewater treatment plants, hospital effluents,
aquaculture, agricultural and slaughterhouse waste, but also in surface waters,
soils, and so on (43).
This research determined what antibiotics have
been used in the last ten years in the treatment of infections by
Enterobacteria producing extended-spectrum beta-lactamase, as well as their
effectiveness by performing a systematic review of the literature; the efficacy
rates achieved by Carbapenemics6 are significantly higher
compared to other beta-lactams or antibiotics belonging to another
classification; also combination therapy is advisable in patients from whom an
isolate with a low carbapenem minimum inhibitory concentration (8 mg/L) is
recovered, a combination regimen including high dose carbapenem is associated
with better outcome (44).
β-Lactam antibiotics inhibit bacterial growth by inhibiting cell wall
synthesis via binding to a series of enzymes, penicillin-binding proteins
(PBPs) that synthesize and remodel peptidoglycan, they are broad spectrum and
highly effective antibiotics (45) but the persistent exposure of bacterial strains to a multitude of β-lactams has induced dynamic and continuous production and mutation of β-lactamases in these bacteria, expanding their activity even against the
newly developed β-lactam antibiotics (46), the downside of modifying known chemical structures is that, usually,
multiple mechanisms of resistance exist for every class of antibiotics and not
all relevant resistance mechanisms can be addressed by chemical modification (47).
The most effective combinations registered in that research are
Ceftacidime/Avibactam and Ceftolozane/Tazobactam, which demonstrate that the
use of other compounds to potentiate the antimicrobial effects of beta-lactam
inhibitors is a useful option to resort to in the treatment of a patient.
It is impossible to ignore
the fact that many of the previously used antibiotics have ceased to be
effective due to the resistance developed by the bacteria; antibiotics such as
Fluoroquinolones are rarely used for fear of developing resistance, but are
considered in patients without previous exposure (29); at the same time, specific treatments such as
Eravacicline have been created to counteract specific resistances that have a
high degree of effectiveness (35); Fosfomycin in turn
demonstrated great capacity for success against infections produced by
Enterobacterales ESBLs (38); there is basically no
tangible difference between treatment with beta-lactam antibiotics (either
combinations or carbapenem), fluoroquinolones, tetracyclines and fosfomycins in patients without any
pre-existing antibiotic resistance.
The implementation of molecular methods for rapid detection of
resistance mechanisms is generating an improvement in the treatment and control
of infections produced by multi-resistant bacteria (48); furthermore, understanding local epidemiology
is essential in optimizing targeted appropriate empiric therapy and strategies
such as combination antibiograms offer significant promise as tools that can be
used to optimize empiric therapy regimens. However, it is important that
individual patient scenarios and previous antibiotic exposures are taken into
account and appropriate diagnostics are performed (49).
It is required developing antibiotics, with the
understanding that the microorganism will respond to them and resistance will
develop (an evolutionary fact). Therefore, efforts to develop antibiotics and
study mechanisms of resistance should be continuous, resilient, and steady (50).
The use of various antibiotic treatments to
counteract infections by extended spectrum beta-lactamase-producing
enterobacteria is losing effectiveness today; it is increasingly common to
announce a new compound to be used to try to win the race against antibiotic
resistance, however, the root of the problem that lies between poor clinical
management of the patient and the indiscriminate use of antibiotics by them is not
being addressed. However, using all the
necessary tools at the time of diagnosis can counteract most antibiotic
resistances, the use of antibiotics when the causative agent of infections is
suspected, as well as combined antibiotic therapy are the mainstay in the fight
against these infections.
Conflict of Relations and Activities
The authors
declare that they have no conflicts of relationships and activities during the
development of this research.
Funding
The research was
carried out with the researchers' own funds; therefore, it was self-financed.
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Authors' Contribution
ADCS: conceptualization,
methodology, software, formal analysis, investigation, resources, data
curation, drafting-preparation of the original draft, writing-review and
editing, visualization, supervision, planning and execution, project
administration. MGJA: conceptualization, software, investigation,
resources, drafting-preparation of the original draft, writing-review and
editing, visualization, supervision, planning and execution, project
administration
©2021. The Authors. Kasmera. Publication of the Department of Infectious and
Tropical Diseases of the Faculty of Medicine. University of Zulia.
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