Postgraduate Medicine

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ipgm20

Treatment of urinary tract infections in the era of

antimicrobial resistance and new antimicrobial
agents

Mazen S. Bader, Mark Loeb, Daniela Leto & Annie A. Brooks

To cite this article: Mazen S. Bader, Mark Loeb, Daniela Leto & Annie A. Brooks (2020) Treatment
of urinary tract infections in the era of antimicrobial resistance and new antimicrobial agents,
Postgraduate Medicine, 132:3, 234-250, DOI: 10.1080/00325481.2019.1680052

To link to this article: https://doi.org/10.1080/00325481.2019.1680052

Published online: 24 Oct 2019.

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POSTGRADUATE MEDICINE
2020, VOL. 132, NO. 3, 234–250
https://doi.org/10.1080/00325481.2019.1680052

CLINICAL FOCUS: GASTROENTEROLOGY, HEPATOLOGY & NEPHROLOGY

REVIEW

Treatment of urinary tract infections in the era of antimicrobial resistance and new
antimicrobial agents
Mazen S. Badera, Mark Loebb, Daniela Letoc and Annie A. Brooksd
a
Staff Physician, Department of Medicine, Hamilton Health Sciences, Juravinski hospital and Cancer Centre, Hamilton, Ontario, Canada; bDepartments of
Pathology & Molecular Medicine and Clinical, Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada; cDepartment of Medicine
and Pathology and Molecular Medicine, McMaster University, Hamilton Health Sciences, Juravinski Hospital and Cancer Centre, Hamilton, Ontario,
Canada; dDepartment of Pharmacy, Hamilton Health Sciences, Juravinski hospital and Cancer Centre, Hamilton, Ontario, Canada

ABSTRACT ARTICLE HISTORY

Urinary tract infections (UTIs) caused by antibiotic-resistant Gram-negative bacteria are a growing concern due Received 22 June 2019
to limited treatment options. Knowledge of the common uropathogens in addition to local susceptibility Accepted 10 October 2019
patterns is essential in determining appropriate empiric antibiotic therapy of UTIs. The recommended first-line KEYWORDS
empiric antibiotic therapy for acute uncomplicated bacterial cystitis in otherwise healthy adult nonpregnant Antibiotic resistance; cystitis;
females is a 5-day course of nitrofurantoin, a 3-g single dose of fosfomycin tromethamine, or a 5-day course of enterobacteriales; gram-
pivmecillinam. High rates of resistance for trimethoprim-sulfamethoxazole and ciprofloxacin preclude their negative bacteria;
use as empiric treatment of UTIs in several communities, particularly if patients who were recently exposed to pyelonephritis; urinary tract
them or in patients who are at risk of infections with extended-spectrum β-lactamases (ESBLs)-producing infections
Enterobacteriales. Second-line options include oral cephalosporins such as cephalexin or cefixime, fluoroqui-
nolones and β-lactams, such as amoxicillin-clavulanate. Current treatment options for UTIs due to AmpC- β -
lactamase-producing Enterobacteriales include nitrofurantoin, fosfomycin, pivmecillinam, fluoroquinolones,
cefepime, piperacillin–tazobactam and carbapenems. Treatment oral options for UTIs due to ESBLs-E coli
include nitrofurantoin, fosfomycin, pivmecillinam, amoxicillin-clavulanate, finafloxacin, and sitafloxacin while
pivmecillinam, fosfomycin, finafloxacin, and sitafloxacin are treatment oral options for ESBLs- Klebsiella
pneumoniae. Parenteral treatment options for UTIs due to ESBLs–producing Enterobacteriales include piper-
acillin-tazobactam (for ESBL-E coli only), carbapenems including meropenem/vaborbactam, imipenem/cilas-
tatin-relebactam, and sulopenem, ceftazidime-avibactam, ceftolozane-tazobactam, aminoglycosides
including plazomicin, cefiderocol, fosfomycin, sitafloxacin, and finafloxacin. Ceftazidime-avibactam, merope-
nem/vaborbactam, imipenem/cilastatin-relebactam, colistin, fosfomycin, aztreonam and ceftazidime-
avibactam, aztreonam and amoxicillin-clavulanate, aminoglycosides including plazomicin, cefiderocol, tigecy-
cline are treatment options for UTIs caused by carbapenem-resistant Enterobacteriales (CRE). Treatment
options for UTIs caused by multidrug resistant (MDR)-Pseudomonas spp. include fluoroquinolones, ceftazi-
dime, cefepime, piperacillin-tazobactam, carbapenems including imipenem-cilastatin/relebactam, merope-
nem, and fosfomycin, ceftolozane-tazobactam, ceftazidime-avibactam, aminoglycosides including plazomicin,
aztreonam and ceftazidime-avibactam, cefiderocol, and colistin. It is important to use the new antimicrobials
wisely for treatment of UTIs caused by MDR-organisms to avoid resistance development.

Introduction Management of UTIs requires a systematic approach to

confirm the presence of infection and its type (site and either
Urinary tract infections (UTIs) are one of the most common
complicated or uncomplicated), assess risk factors of infection
bacterial infections encountered by clinicians [1]. UTIs are classi-
with antibiotic-resistant organisms, and to select the optimal
fied according to the site of infection into upper (pyelonephritis)
dose, route and duration of the empiric antibiotic regimen
and lower UTIs (urethritis, cystitis, prostatitis) [2,3]. UTIs are
based on a local antibiogram [2,5].
further classified into complicated or uncomplicated infections
This review is an update of our previously published article
according to the presence of certain risk factors [2,3].
on this topic [6]. It will focus on the role of both old and new
Gram-negative bacteria, specifically Enterobacteriales, are com-
antimicrobial agents in the treatment of UTIs.
mon causes of UTIs [1]. UTIs due to antibiotic-resistant Gram-
negative bacilli are a challenge due to increasing prevalence and
limited oral treatment options. Examples of these organisms
Uncomplicated cystitis
include AmpC- β -lactamase- and extended-spectrum β-
lactamases (ESBLs)-producing Enterobacteriales, carbapenem- An uncomplicated lower UTI is usually defined as acute
resistant Enterobacteriales (CRE), multidrug-resistant (MDR) and cystitis occurring in a healthy, premenopausal, nonpregnant
Pseudomonas aeruginosa [4]. female with no known structural urological abnormalities

CONTACT Mazen S. Bader msbader1@gmail.com Department of Medicine, Juravinski Hospital and Cancer Centre, 711 Concession Street, Hamilton, Ontario L8V1C3
© 2019 Informa UK Limited, trading as Taylor & Francis Group

[2]. Uncomplicated UTIs are responsible for a large propor-
tion of all antibiotic prescriptions and pathogen resistance is
increasing worldwide which requires a responsible and wise
antibiotic prescription across all health-care professions
[2,5,6]. Urine culture and antimicrobial susceptibility testing
for patients with uncomplicated acute cystitis are not
recommended by current guidelines because of lack of
management impact [5,6]. Acute uncomplicated cystitis is
most commonly due to Enterobacteriales, enterococci and
Staphylococcus saprophyticus. The most commonly isolated
Enterobacteriales spp are Escherichia coli, Klebsiella spp, and
Proteus spp., which are responsible for over 80% of uncom-
plicated UTIs [7,8].
The first-line empiric antibiotics for treating acute bacterial
cystitis in otherwise healthy adult non-pregnant females that are
recommended by the Infectious Diseases Society of America
(IDSA) includes 5 days of nitrofurantoin, a three-day course of
double-strength trimethoprim-sulfamethoxazole in settings
where the prevalence of trimethoprim-sulfamethoxazole resis-
tance to E coli is <20%, or a 3 g single dose of fosfomycin
trometamol. Fluoroquinolones and oral β-lactams (e.g., amoxicil-
lin-clavulanate, cephalexin) are second-line therapies (Table 1)
[2]. However, selection of empirical antimicrobial agent should
be based on local or regional susceptibility data and it is recom-
mended to choose the most appropriate and narrowest effective
antibiotic to combat the rise in resistance due to inappropriate
use of broad-spectrum antibiotics [2,5].
Nitrofurantoin, fosfomycin, and pivmecillinam are the most
active antimicrobial agents in vitro against E. coli, including
multi-drug resistant (MDR) isolates such as ESBL- and AmpC- β
-lactamase-producing E coli, isolated among outpatients with
acute cystitis. Furthermore, the resistance rates to these anti-
biotics are relatively stable over time [7,9,10].
Meta-analysis of 27 controlled trials including 4807 patients
found similar clinical cure rates, but nonsignificant lower
microbiological efficacy, in patients with UTI treated with
either nitrofurantoin or other antibiotics such as trimetho-
prim/sulfamethoxazole, ciprofloxacin and amoxicillin [11].
However, nitrofurantoin is favored over fluoroquinolones
because it is primarily used for treatment of UTIs, narrow
spectrum, and safety profile (Table 1) [12].
Fosfomycin tromethamine, a soluble salt of fosfomycin is
approved as single-dose oral therapy for uncomplicated UTIs
in women caused by E. coli and Enterococcus faecalis (Table 1)
[2]. Fosfomycin is not approved for the treatment of UTIs due
to Klebsiella spp. Although it is active against other antibiotic-
resistant gram-negative organisms, data supporting its efficacy
for treatment of MDR-uropathogens or complicated urinary
tract infections (cUTIs) are limited and there is a concern of
increasing resistance with its widespread use [13–19].
The interpretation of fosfomycin susceptibility varies world-
wide, with different sensitivity thresholds proposed by labora-
tory regulatory bodies and variation between susceptibility
testing methods. Fosfomycin susceptibility testing has low
sensitivity for the detection of resistant isolates and is highly
method dependent on low agreement rate for K. pneumoniae
[20]. Finally, Wijma et al. found a considerable inter-individual
pharmacokinetic variability in the urinary concentrations after
POSTGRADUATE MEDICINE 235
a 3-g fosfomycin trometamol dose administered to 40 healthy
women with normal renal function [21].
In an open-label randomized trial of 513 women with
uncomplicated lower UTIs, nitrofurantoin (100 mg thrice
daily for 5 days) was found to be superior to fosfomycin (a
single 3-g dose) clinically (symptoms resolution at 2 weeks
75% vs. 66%, P= 0.03 and at 4 weeks 70% vs. 58%, P= 0.004)
and microbiologically (cure at 4 weeks 74% vs. 63%. P= 0.04),
even in UTIs due to E coli [22].
Therefore, until there is further data, nitrofurantoin should
be used as first-line option for treatment of acute cystitis
except in case of resistance, allergy or kidney dysfunction
(creatinine clearance <30 mL/min) then fosfomycin can be
used as alternative while monitoring for clinical failure.
Trimethoprim-sulfamethoxazole is no longer recommended
as empiric treatment option for uncomplicated cystitis in sev-
eral geographical locations due to high resistance rates of
urinary E. coli which in excess of 20% particularly in large
urban areas (Table 1). However, regional difference in antibio-
tic resistance patterns should be considered [7,9,10,23].
Trimethoprim-sulfamethoxazole can be used as empiric or
definitive treatment of uncomplicated cystitis in case of resis-
tance and allergy to first-line antibiotics (nitrofurantoin and
fosfomycin), UTIs due to Enterobacteriales other than E coli
(Enterobacter sp, klebsiella pneumoniae, proteus mirabilis, serra-
tia marcescens) and stenotrophomonas maltophila [8]. It should
be used with caution in elderly patients due to risk of acute
kidney injury and hyperkalemia [24].
Fluoroquinolones are not recommended for treatment of
uncomplicated cystitis due to increasing resistance rates, par-
ticularly among E coli, and safety issues (Table 1) [25].
Resistance rates of urinary E. coli to fluoroquinolones are
increasing over time and can reach up in excess of 20%
[7,9,10,23]. However, fluoroquinolones can be used as empiric
or definitive treatment of uncomplicated cystitis in case of
resistance and allergy to first-line antibiotics (nitrofurantoin
and fosfomycin), kidney dysfunction (creatinine clearance
<30 mL/min), UTIs due to Enterobacteriales other than E coli
(Enterobacter sp, klebsiella pneumoniae, proteus mirabilis, pro-
videncia sp, serratia marcescens), pseudomonas aeruginosa, and
stenotrophomonas maltophila [8].
Oral cephalosporins (cephalexin, cefpodoxime, ceftibuten,
cefadroxil, cefixime) are the fourth most active antimicrobial
agents, after nitrofurantoin, fosfomycin, and pivmecillinam,
against E. coli (Table 1) [7,8,26–28]. However, cephalexin is
among the broad-spectrum antibiotics that are associated with
increased rates of drug-related adverse events and antibiotic-
associated diarrhea [29]. For unclear reasons, elderly patients
with UTIs who were prescribed cephalexin had greater risk of
hospitalization due to sepsis and death [30]. The outcome was
not adjusted for the severity of infection and patients who
received cephalexin might have more severe infection than
patients who received nitrofurantoin. However, oral cephalos-
porins can be used as empiric or definitive treatment of uncom-
plicated cystitis in case of resistance and allergy to first-line
antibiotics (nitrofurantoin and fosfomycin), kidney dysfunction
(creatinine clearance <30 mL/min), UTIs due to Enterobacteriales
other than E coli (Klebsiella pneumoniae, proteus mirabilis) [8].

Table 1. First- and second-line oral treatment options for uncomplicated cystitis.
Anti-infective Dosing Advantages
Nitrofurantoin 100 mg twice daily with Active against common urinary
monohydrate food for 5 days pathogens including Staphylococcus
macrocrystals saprophyticus, Enterococcus including
VRE, Escherichia coli, Klebsiella
pneumonia, Citrobacter spp, and
AmpC- β -lactamase and ESBLs-
producing Gram-negative organisms
High urinary concentration
Low rates of resistance
Low risk of Clostridium difficile infection
Pregnancy Category B
Fosfomycin 3 g sachet as a single dose Active against common urinary
tromethamine. pathogens including Enterococci
including VRE, Escherichia coli,
Klebsiella pneumonia, Proteus mirabilis,
Pseudomonas aeruginosa,
AmpC- β -lactamase and ESBLs-
producing Gram-negative organisms
and KPC- and MBLs-producing CRE
Low rates of resistance and no cross
resistance with other antimicrobial
classes
High urine concentration
Good safety profile
Improved compliance
Low risk of Clostridium difficile infection
Pregnancy Category B
Pivmecillinam 400 mg twice daily for 5 Active against Escherichia coli including Poor activity against
days ESBLs- producing strains, K pneumonia
including ESBLs and carbapenemase-
producing strains, K. oxytoca, Proteus
mirabilis, Enterobacter spp, Citrobacter
spp
Trimethoprim- 160 mg/800 mg twice Active against Staphylococcus
sulfamethoxazole daily for 3 days saprophyticus, Escherichia coli,
(females) and for 7 days Klebsiella pneumonia, Proteus mirabilis Increasing resistance to common
(males) Short course therapy
Indicated for both
uncomplicated cystitis and
uncomplicated pyelonephritis
High urine concentration
Low risk of Clostridium difficile infection Potential drug- drug interactions:
Disadvantages
Lacks activity against Serratia marcescens,
Morganella spp, Proteus mirabilis,
Providencia spp, Pseudomonas
aeruginosa, Stenotrophomonas
maltophila, Acinetobacter spp, and CRE
High rates of resistance to Klebsiella
pneumonia and Enterobacter spp,
Not recommended for CrCl<30ml/min
High failure rate with short course
therapy (3 days)
Contraindicated for pyelonephritis due to
low plasma concentrations
Lacks activity against Morganella spp,
Acinetobacter spp., Stenotrophomonas
maltophilia and Staphylococcus
saprophyticus
Increasing resistance of ESBLs- Klebsiella
pneumonia and ESBLs 025b/B2 E. coli
strains
High clinical failure with Pseudomonas
aeruginosa
Oral formulation contraindicated for
pyelonephritis due to low plasma
concentrations
P. vulgaris and M. morganii
Lacks activity against Enterococci spp,
Pseudomonas aeruginosa, and CRE
uropathogens such as Escherichia coli
and AmpC- β -lactamase and ESBLs-
producing Gram-negative organisms
Not recommended in pregnancy (avoid
in 1st trimester and last 6 weeks)
warfarin, phenytoin and sulfonylureas
Requires dose adjustment in renal
impairment
236
Adverse effects Comments
Nausea First line for acute uncomplicated
Headache cystitis
Cough Not recommended for empiric
Dyspnea treatment of hospital-acquired
Rare side effects include acute allergic UTIs or acute pyelonephritis
pneumonitis, bone marrow suppression,
M. S. BADER ET AL.
and hepatotoxicity
Risk of hemolysis in patients with glucose-
6-phosphate dehydrogenase deficiency,
neuropathy in patients with chronic kidney
disease
Alters methotrexate clearance
Diarrhea Single dose therapy is not
Nausea, vomiting recommended in males
Dyspepsia Off label use: cUTIs dose: 3 g once
Headache daily for 3–5 days or every
Vaginitis 48–72 h for 3–5 doses
Esophageal discomfort Not recommended for empiric
Transient elevation of liver enzymes treatment of hospital-acquired
UTIs
Rash and gastrointestinal upset, including
nausea and vomiting
Vulvovaginal candidiasis
Carnitine deficiency with long term or
frequent use
Avoid concomitant use with valproate
products
Nausea Not recommended for empiric
Vomiting treatment of pyelonephritis
Hypersensitivity reactions such as fever, rash, Not recommended as empiric use
urticarial, and Stevens–Johnson syndrome for cystitis if E coli resistance
Bone marrow suppression rate in the community is >20%
Acute kidney injury Avoid co-administration with
Hyperkalemia, hyponatremia spironolactone, angiotensin
Hemolysis in patients with glucose- converting – enzyme inhibitors
6-phosphate dehydrogenase deficiency or angiotensin-receptor blockers
due to increased potential risk
of hyperkalemia and sudden
death
(Continued )
Table 1. (Continued).

Anti-infective Dosing Advantages Disadvantages Adverse effects Comments

Trimethoprim 100-200 mg twice daily for Active against Staphylococcus No activity against Enterococci, Nausea and vomiting Not recommended for empiric
3–5 days saprophyticus, Escherichia coli, Pseudomonas aeruginosa and CRE Rash treatment of cystitis if E coli
Klebsiella pneumonia, Proteus mirabilis Increasing resistance to common Hyperkalemia, hyponatremia resistance rate in the
High urine concentration uropathogens such as Escherichia coli, Bone marrow suppression community is >20%
Low risk of Clostridium difficile infection AmpC- β -lactamase and ESBLs- Megaloblastic anemia
producing Gram-negative organisms Methemoglobinemia
Not indicated for pyelonephritis Acute kidney injury
Drug-drug interaction: dapsone,
methotrexate phenytoin
Not recommended in first trimester of
pregnancy
Requires dose adjustment in renal
impairment
Cephalosporins Cephalexin Active against E. coli, Klebsiella spp, and Lacks activity against Enterococcus Headaches
250–500 mg orally every Proteus mirabilis species, AmpC- β -lactamase and Diarrhea
6–8 h for 7 days Indicated for acute prostatitis ESBLs-producing Gram-negative Nausea
Cefixime Pregnancy Category B organisms, Morganella spp, Vomiting
400 mg daily for 7 days Acinetobacter spp., Stenotrophomonas Allergic reactions: rash, urticarial, or
maltophilia and Pseudomonas anaphylactic reaction (<2% risk cross
Dose adjustment required in renal reactivity in patients with IgE mediated
dysfunction penicillin allergy)
Risk of Clostridium difficile infection Vaginitis
May result in elevated INR
Fluoroquinolones Ciprofloxacin: 250–500 mg Active against Staphylococcus Lacks activity against Enterococci and Nausea For patients who cannot tolerate
twice daily for 3 days saprophyticus, Enterobacterales spp CRE. Vomiting oral therapy give first dose IV
(females) OR for 7 days including E. coli, Klebsiella spp, and Increasing resistance to common Diarrhea If local resistance of E coli against
(males) OR Levofloxacin: Proteus mirabilis uropathogens including Escherichia Headache fluoroquinolones exceeds 10%,
250-500 mg daily for 3 , Pseudomonas aeruginosa coli, AmpC- β -lactamase, ESBLs- Drowsiness use other treatment options for
days (female) OR for 7 Definitive oral therapy for susceptible producing Gram-negative organisms, Insomnia pyelonephritis
days (male) OR AmpC- β -lactamase and ESBLs- Pseudomonas aeruginosa, and Dizziness Not recommended for empiric
Norfloxacin 400 mg producing Gram-negative organisms Acinetobacter spp. Photosensitivity/phototoxicity treatment of hospital-acquired
twice daily for 3 days Indicated for both uncomplicated cystitis High risk of Clostridium difficile infection Vaginitis UTIs
(female) OR for 7 days and uncomplicated pyelonephritis Pregnancy category C (Contraindicated in Nausea, vomiting, and diarrhea Norfloxacin has no known cardiac
(male) OR Ofloxacin Short course therapy – lower cost, and pregnancy and breastfeeding) QTc prolongation effects or interactions with
200-400 mg twice daily improved compliance Drug Drug interactions: cations (antacids Tendinitis and tendon rupture spironolactone and is not
Short course definitive therapy for and vitamins), warfarin, theophylline Central nervous system adverse events such associated with sudden death
uncomplicated pyelonephritis (monitor) as encephalopathy, delirium, and seizures
High urine concentration Require dose adjustment in renal
impairment
Penicillins Amoxicillin Active against, Enterococcus faecalis, Lacks activity against Staphylococcus Diarrhea Not recommended for empiric
500 mg every 8 h for 5–7 Escherichia coli, Proteus mirabilis saprophyticus, Klebsiella pneumonia, Nausea treatment of cystitis
days Pregnancy Category B Pseudomonas aeruginosa, Morganella Vomiting
morganii, Providencia stuartii, AmpC- β Allergic reactions: rash, urticarial, or
-lactamase and ESBLs-producing anaphylactic reaction
Gram-negative organisms and CRE. Vaginitis
Generally inferior to fluoroquinolones Headaches
Low urine concentration
High risk of Clostridium difficile infection
POSTGRADUATE MEDICINE

Requires dose adjustment in renal

impairment

(Continued )
237
238 M. S. BADER ET AL.

Pevmecillinam is oral synthetic penicillin marketed in sev-

VRE: vancomycin resistant Enterococci; N/A: not applicable; ESBLs: extended-spectrum β-lactamases; CRE: carbapenem-resistant Enterobacteriaceae; CrCl: creatinine clearance; UTIs: urinary tract infections; IV; intravenous; MBLs:
concentration used by EUCAST
eral European countries (Table 1) [9,31]. However, there is

susceptibility testing results,

pyelonephritis and hospital-

Not recommended for empiric
and CLSI results in variable

particularly among ESBLs-

a poor correlation between pivmecillinam MIC and clinical

Variation in the clavulanate

producing E. coli isolate

outcome and treatment failure in mecillinam – susceptible

Comments

treatment of acute
ESBLs-E. coli has been observed in some cases [32,33].
The prevalence of outpatient UTIs due to ESBLs-

acquired UTIs
Enterobacteriales is increasing [7–9]. Risk factors for UTIs due
to ESBLs-Enterobacterales include age, comorbid condition,
recent antibiotic exposure, recent hospitalization, and long-
term facility residency [34]. Oral treatment options for ESBLs-
E coli include nitrofurantoin, fosfomycin, pivmecillinam, amox-
icillin-clavulanate, and sitafloxacin. Treatment oral options for
ESBL- Klebsiella pneumoniae include pivmecillinam and fosfo-
Allergic reactions: rash, urticarial, or

mycin [5,6]. Unfortunately, the level of resistance of ESBLs

Adverse effects

Enterobacteriales to trimethoprim-sulfamethoxazole and fluor-

oquinolones is very high and they have very limited role in the
anaphylactic reaction

treatment of UTIs due to these organisms [7,35,36]. The role of

amoxicillin/clavulanic acid in the treatment of UTIs due to
ESBL-Enterobacteriales is very limited due to increasing rates
of resistance, limited evidence for its clinical efficacy, and
Headaches
Vomiting

Vaginitis
Diarrhea

Metallo-β-lactamases; EUCAST: The European Committee on Antimicrobial Susceptibility Testing; CLSI: clinical and laboratory standards institute.

increased rates of drug-related adverse events and antibiotic-

Nausea

associated diarrhea [6,7,29]. However, a combination aztreo-

nam, active on Metallo-β-Lactamase (MBLs) alone, with amox-
lactamase and ESBLs-producing Gram-

High risk of Clostridium difficile infection

icillin/clavulanic acid, inhibiting ESBLs if present, is an effective

aeruginosa, Morganella morganii,

therapeutic option to treat infections caused by MBLs-

Longer treatment courses required

including susceptible organisms

Requires dose adjustment in renal

Lacks activity versus Pseudomonas

Providencia stuartii, AmpC- β -

High rates of relapse and failure

producing Gram-negative bacteria [37].

negative organisms and CRE
Disadvantages

Low urine concentration

Complicated UTIs and acute pyelonephritis

Complicated UTIs are associated with an underlying condition
impairment

that increases the risk of recurrent infections or treatment

failure due to functional or anatomic abnormalities of the
urinary tract [5,6]. All patients with complicated UTIs and
acute pyelonephritis require urine culture and antimicrobial
susceptibility testing due to the wide diversity of potential
saprophyticus, Enterococci, Escherichia

pathogens, risk of antimicrobial resistance, and risk of compli-

coli, Klebsiella pneumonia, Proteus

Definitive treatment for susceptible

ESBLs-producing Gram-negative

cations [2,5]. Recurrent infection, instrumentation and repeat

Active against Staphylococcus

courses of antimicrobial therapy increase the risk of antibiotic-

Advantages

resistant organisms causing cUTIs [2,5,6].

Pregnancy Category B

Management of cUTIs and acute pyelonephritis caused by

Enterobacteriales continues to pose a challenge for clinicians
due to the lack of viable traditional oral antibiotic options,
organisms
mirabilis

such as amoxicillin-clavulanate, cephalosporins, trimethoprim-

sulfamethoxazole, and fluoroquinolones [5,6]. As a result,
managing cUTIs and acute pyelonephritis often requires intra-
venous empiric broad-spectrum antibiotics [6]. However, once
twice daily for 5–7 days
125 mg twice daily for

CrCl<30 ml/min 500 mg

there is a response to initial therapy and the result antimicro-

CrCl > 30 ml/min 875/
Amoxicillin-clavulanate

bial susceptibility testing is available, a step down to oral

Dosing

antibiotic that the isolated organisms are susceptible is recom-

mended to complete the total duration of therapy even in
5–7 days

patients with bacteremia [38].

Cephalosporines
Table 1. (Continued).

Ceftriaxone is the first recommended empiric treatment of acute

Anti-infective

pyelonephritis in the absence of risk factors for resistance organ-

isms such as ESBLs-Enterobacteriales, Pseudomonas aeruginosa,
or Enterococci (Table 2) [2,5,39]. Risk factors of UTIs due to
extended-spectrum cephalosporin resistance (ESC-R) include
Table 2. Treatment options for acute pyelonephritis and complicated urinary tract infections.

Anti-infective Dosing Advantages Disadvantages Adverse effects Comments

Cephalosporins Ceftriaxone 1–2 g IV every 24 h
Ceftazidime 1–2 g IV every 8 h
Cefepime 1–2 g IV every 8 h or 2 Active against many common urinary
g IV every 12 h
Active against Escherichia coli, Klebsiella
pneumonia, Proteus mirabilis, Enterobacter
spp, Serratia, Citrobacter spp, and Morganella
spp., and Providencia stuartii
No dose adjustment required in renal
dysfunction
Administered once daily
Pregnancy category B
Active against Escherichia coli, Klebsiella
pneumonia, Proteus mirabilis, Proteus vulgaris,
Enterobacter, Serratia, Citrobacter, and
Morganella spp., Providencia stuartii,
Pseudomonas aeruginosa including some
MDR Pseudomonas strains
High urinary concentration
Pregnancy category B
pathogens including Staphylococcus
saprophyticus, Escherichia coli, Klebsiella
pneumonia, AmpC- β -lactamase – producing
Gram-negative organisms and Pseudomonas Increased resistance of Pseudomonas
aeruginosa
High urinary concentration
Pregnancy category B
Lacks activity against Enterococci,
Pseudomonas aeruginosa, AmpC- β -
lactamase and ESBL-producing Gram-
negative organisms and CRE
Reduced activity versus Staphylococcus
saprophyticus
Low urine concentration
Increased risk of Clostridium difficile
infection
Lacks activity against Enterococci,
Staphylococcus saprophyticus
and CRE
High resistance rates in AmpC- β -
lactamase and ESBLs-producing Gram- Nausea
negative organisms and Acinetobacter Vomiting
baumannii
Increased resistance of Pseudomonas
aeruginosa
Increased risk of Clostridium difficile
infection
Requires dose adjustment in renal
impairment
Lacks activity against Enterococci and CRE Encephalopathy associated Indicated for the treatment of suspected
High resistance rates in ESBLs-producing
Gram-negative organisms and
Acinetobacter baumannii
aeruginosa
Risk of cross reactivity with penicillins
High risk of Clostridium difficile infection Vomiting
Requires dose adjustment in renal
impairment
Diarrhea First line empiric option for acute
Thrombocytopenia, pyelonephritis in patients without risk
Thrombocytosis, factors for antibiotic-resistant
Leukopenia organisms such as ESBLs producing
Biliary pseudolithiasis organisms or Pseudomonas aeruginosa
Allergic reactions: rash,
urticarial, or anaphylactic
reaction(<2% risk cross
reactivity in patients with
IgE mediated penicillin
allergy)
Seizures Indicated for the treatment of suspected
Encephalopathy or proven cUTIs or acute pyelonephritis
Local infusion related due to Pseudomonas aeruginosa
effects
Diarrhea
Allergic reactions: rash,
urticarial, or anaphylactic
reaction(<2% risk cross
reactivity in patients with
IgE mediated penicillin
allergy)
Avoid in patients with
history of cephalosporin-
associated hemolytic
anemia
with higher doses in or proven cUTIs or acute pyelonephritis
setting of renal due to AmpC- β -lactamase –
dysfunction producing Gram-negative organisms
Rash and Pseudomonas aeruginosa
Diarrhea
Nausea
Allergic reactions: rash,
urticarial, or anaphylactic
reaction(<2% risk cross
reactivity in patients with
IgE mediated penicillin
allergy)
Avoid in patients with
history of cephalosporin-
associated hemolytic
anemia
POSTGRADUATE MEDICINE

(Continued )
239
 240

Table 2. (Continued).

Anti-infective Dosing Advantages Disadvantages Adverse effects Comments

Ceftazidime-avibactam 2.5 g IV Activity comparable to ceftazidime with Lacks activity against Enterococci, Gastrointestinal such as Indicated for the treatment of suspected
every 8 h additional activity against AmpC- β - Staphylococcus saprophyticus, class nausea, vomiting, or proven cUTIs or acute pyelonephritis
M. S. BADER ET AL.

lactamase and ESBLs-producing Gram- B metallo- β -lactamases (eg, NDM, constipation, and due to CRE or MDR-Pseudomonas
negative organisms, CRE, and MDR- VIM, IMP, VEB, PER) and Acinetobacter elevated liver enzymes. aeruginosa
Pseudomonas aeruginosa baumannii, ceftazidime-resistant Cough
High urine concentration Stenotrophomonas Dizziness
Pregnancy category B Emergence of resistance during therapy Headache
particularly among KPC- K pneumonia Insomnia
Reduced efficacy in patients with Seizures
moderate renal impairment Myoclonus
Risk of cross reactivity with penicillins Encephalopathy
Requires dose adjustment in renal Avoid in patients with
impairment history of cephalosporin-
Risk of Clostridium difficile infection associated hemolytic
Limited data for the use in the elderly anemia
population
Ceftolozane-tazobactam 1.5 g IV Active against common urinary pathogens Lacks activity against Enterococci CRE, Nausea Indicated for the treatment of suspected
every 8 h including Escherichia coli, Klebsiella S. maltophilia, ESBLs-, KPC-, or MBLs- Diarrhea or proven cUTIs or acute pyelonephritis
pneumonia, AmpC- β -lactamase and ESBLs producing P. aeruginosa Headaches due to MDR- Pseudomonas aeruginosa
producing-Enterobacteriales, and MDR- Reduced activity against Staphylococci Pyrexia
Pseudomonas aeruginosa saprophyticus Avoid in patients with
High urine concentration Reduced activity against ESBLs- history of cephalosporin-
Pregnancy category B K pneumonia associated hemolytic
Variable activity against AmpC- producing anemia
Enterobacteriales
Reduced efficacy in patients with
moderate renal impairment
Risk of cross reactivity with penicillins
Requires dose adjustment in renal
impairment
Risk of Clostridium difficile infection
Piperacillin – 3.375–4.5 g IV every 6–8 h Active against common urinary pathogens such Lacks activity against most ESBLs- Rash Indicated for the treatment of suspected
tazobactam as Staphylococcus saprophyticus, Enterococci, producing Gram-negative organisms, Nausea or proven cUTIs or acute pyelonephritis
Escherichia coli, Klebsiella pneumonia, AmpC- CRE, and S. maltophilia. Diarrhea due to AmpC- β -lactamase –
β -lactamase- and ESBLs- producing Gram- Increasing resistance rates for Neutropenia producing Gram-negative organisms
negative organisms, and Pseudomonas Pseudomonas aeruginosa Hypokalemia and Pseudomonas aeruginosa
aeruginosa Requires dose adjustment in renal Prolonged prothrombin
High urine concentration impairment time (specifically in renal
Pregnancy category B Moderate risk of Clostridium difficile failure)
infection

(Continued )
Table 2. (Continued).
Anti-infective Dosing
Carbapenems Ertapenem 1 g IV daily
Meropenem 500 mg every 6 h up
to 1 g IV every 8 h
Doripenem 500 mg IV every 8 h
Imipenem/cilastatin 500 mg IV
every 6 h
Meropenem-vaborbactam 4
g every 8 h
Aminoglycosides Gentamicin 5 mg/kg IV once daily Active against common urinary pathogens
Tobramycin 5 mg/kg IV once daily
Amikacin 15 mg/kg IV once daily
Plazomicin 15 mg/kg once daily
Advantages
Active against common urinary pathogens such
as Staphylococcus saprophyticus, Enterococci,
Escherichia coli, Klebsiella pneumonia, AmpC-
β -lactamase, ESBLs-producing Gram-
negative organisms, Pseudomonas
aeruginosa, and Acinetobacter baumannii
High urinary concentration
Pregnancy category B
(Meropenem, ertapenem, doripenem)
Low risk of cross reactivity for IgE- mediated
hypersensitivity to penicillins
Activity comparable to meropenem with
additional activity against KPC-producing
CRE.
Higher barrier for developing resistance in
comparison to ceftazidime–avibactam for
CRE
including Escherichia coli, Klebsiella
pneumonia, AmpC- β -lactamase, ESBLs-
producing Enterobacteriales, MDR-
Pseudomonas aeruginosa, CRE, and
Acinetobacter baumannii
High urine concentration
Once daily dosing
Low risk of Clostridium difficile infection
Plazomicin has activity similar to other
aminoglycosides but displays additional
activity against aminoglycoside-resistant
Enterobacteriales containing aminoglycoside-
modifying enzymes, colistin-resistant
Enterobacteriales (including those expressing
the mcr-1 gene), gram positive bacteria such
Staphylococcus aureus including MRSA and
Staphylococcus saprophyticus.
Disadvantages
Lacks activity against E. faecium,
S. maltophilia, and CRE.
Ertapenem has no activity against
Enterococci, Pseudomonas aeruginosa,
and Acinetobacter baumannii
Increasing resistance rates of ESBLs-
producing Gram-negative organisms
(particularly K. pneumonia and Proteus
mirabilis), Pseudomonas aeruginosa
, and Acinetobacter baumannii
Require dose adjustment in renal
impairment (all carbapenems)
Pregnancy category C for imipenem
Moderate risk of Clostridium difficile
infection
Lacks activity against meropenem-
resistant Acinetobacter baumannii,
Pseudomonas aeruginosa, or
Stenotrophomonas maltophilia
Lacks activity against Ambler class B and
D carbapenemases (MBLs including
NDM and OXA-like beta-lactamases,
respectively)
Lacks activity against Staphylococcus
saprophyticus, Enterococci
Increasing resistance rates of ESBLs-
producing Gram-negative organisms,
Pseudomonas aeruginosa, and
Acinetobacter baumannii
All aminoglycosides lack activity against
NDM-1-producing Enterobacteriales
Require dose adjustment in renal
impairment
Require Therapeutic Drug Monitoring
Pregnancy category D
Plazomicin has no activity against
Enterococci, NDM-producing CRE,
High MIC Proteus mirabilis and indole-
positive Proteeae, and morganella
Adverse effects Comments
Seizures Carbapenems are considered first line
Diarrhea treatment options for the treatment of
Nausea suspected or proven cUTIs or acute
Rash pyelonephritis due to ESBLs- producing
Headache Gram-negative organisms
Hypokalemia Meropenem/vaborbactam is indicated for
Elevted liver enzymes the treatment of suspected or proven
cUTIs or acute pyelonephritis due to
KPC-CRE
Meropenem is favored over imipenem in
patients with a history of seizures,
pregnancy or impaired renal function
Nephrotoxicity Dosing based on ideal body weight
Vestibulocochlear toxicity Amikacin is preferred over gentamicin
Neurotoxicity when used for empiric treatment due
Edema to antibiotic-resistant Gram-negative
organisms such ESBLs-producing
Enterobacteriales or MDR-
Pseudomonas aeruginosa
Combination therapy is recommended
(e.g. with ampicillin) when used as
empiric treatment
Monotherapy is acceptable if used as
definitive therapy
Plazomicin is indicated for the treatment
of cUTIs or acute pyelonephritis due to
gram-negative organisms in patients
who have limited or no alternative
treatment options.
Dizziness, Somnolence,
Nausea
Transient hypotension or
hypertension
Neuromuscular blockade
POSTGRADUATE MEDICINE
(Continued )
241

Table 2. (Continued).
Anti-infective Dosing
Polymixins Polymixin B 15,000–25,000 Units/ Active against common urinary pathogens such Lacks activity against Staphylococcus
kg/day IV every q12
h (Maximum daily dose
2 million units)
Polymixin E (colistin) 2.5–5 mg
CBA/kg/day in 2–4 divided
doses
Monobactams Aztreonam
0.5–2 g IV every 6–8 h
Fluoroquinolones **Refer to Table 1
Fosfomycin 4–6 g iv every 6–8 h
MDR: multi-drug resistant; ESBLs: extended-spectrum β-lactamases; CRE: carbapenem-resistant Enterobacteriaceae; MBLs: Metallo-β-lactamases; UTIs: urinary tract infections; IV; intravenous; CBA: colistin base activity; VRE:
vancomycin-resistant enterococci.
242
Advantages Disadvantages Adverse effects Comments
Nephrotoxicity Dosing based on ideal body weight
M. S. BADER ET AL.
as Escherichia coli, Klebsiella pneumonia, saprophyticus, Enterococci, Proteus spp., Neurotoxicity Colistin (polymixin E) is preferred over
AmpC- β -lactamase, ESBLs-producing Gram- Providencia spp., Serratia marcescens, Neuromuscular blockade polymixin B due to higher urinary
negative organisms, MDR-Pseudomonas Morganella morganii Respiratory arrest concentrations
aeruginosa, CRE, and Acinetobacter baumannii Colistin resistance is emerging in Colistin is indicated for the treatment of
Bladder irrigation considered in those who Acinetobacter baumannii and K. suspected or proven cUTIs or acute
cannot tolerate intravenous pneumonia, MDR- Pseudomonas pyelonephritis due to MDR- gram
Low resistance rates aeruginosa, and E.coli negative organisms in patients who
High urine concentration for polymixin E Decreased urine concentration for have limited or no alternative
Low risk of Clostridium difficile infection Polymixin B treatment options.
Narrow therapeutic window & requires
dose adjustment in renal impairment
Safety in pregnancy has not been
established for polymixin B
Polymixin E is Pregnancy Category C
Active against common urinary pathogens such Lacks activity against Staphylococcus Neutropenia Indicated for the treatment of suspected
as Escherichia coli, Klebsiella pneumonia, MBLs saprophyticus, Enterococci, AmpC β - Increased serum or proven cUTIs or acute pyelonephritis
and OXA-48-like carbapenemases- producing lactamase, ESBLs and KPC-producing transaminases due to gram negative bacteria in
Enterobacteriales and Pseudomonas Enterobacteriales Rash patients with beta-lactam allergy as
aeruginosa. High level of resistance among Diarrhea cross reactivity rare
P aeruginosa Nausea
Vomiting
Active against common urinary pathogens Lacks activity against Morganella spp, Headache
including Enterococci including VRE, Acinetobacter spp., S. maltophilia, NDM- Dizziness
Escherichia coli, Klebsiella pneumonia, Proteus producing CRE, Rash
mirabilis, Pseudomonas aeruginosa, and Staphylococcus saprophyticus. Diarrhea
AmpC- β -lactamase and ESBLs-producing Increasing resistance of ESBLs- Klebsiella Nausea
Gram-negative organisms and KPC- and pneumonia and ESBLs 025b/B2 E. coli Dyspepsia
MBLs-producing CRE strains Vaginitis
Low rates of resistance and no cross resistance High clinical failure with Pseudomonas Infusion related reaction,
with other antimicrobial classes aeruginosa Hypokalemia,
High urine concentration Sodium overload that might
Low risk of Clostridium difficile infection lead heart failure
Pregnancy Category B Hypertension
Elevated serum
aminotransferases

older age, nursing home residence, previous antimicrobial ther-
apy, trimethoprim-sulfamethoxazole exposure in the prior 6
months, hospitalization, malignancy, diabetes mellitus, and
recurrent UTIs [17,40].
Although the resistance rate of E coli to oral cephalosporins is
<10% in several regions, it should not be used as empiric treat-
ment of uncomplicated acute pyelonephritis due to lack of clinical
evidence [7,8]. However, oral cephalosporins can be used as a step
down treatment from parenteral therapy if the isolated organisms
are susceptible or an empiric treatment of mild acute pyelone-
phritis when the resistance rate is very low [41–43].
Avibactam, a non-β-lactam β-lactamases inhibitor (BLI),
restores the activity of ceftazidime against Ambler class
A (e.g. ESBL and KPC), class C (e.g. AmpC), and some class D β-
lactamase–producing bacteria (OXA-48-like). It is approved for
the treatment of cUTIs and acute pyelonephritis and for gram-
negative infections such as bacteremia with limited treatment
options (Table 2) [44]. In vitro studies of ceftazidime/avibac-
tam have demonstrated inhibition against >99.9% of
Enterobacterales and 99.4% of P. aeruginosa isolates that
were resistant to meropenem, ceftazidime and piperacillin/
tazobactam and 100% of KPC and OXA-48 producers [45–48].
Although clinical improvement can be seen in some patients
infected with MBLs-producing pathogens, persistence of cau-
sative pathogen may occur and therefore ceftazidime-
avibactam monotherapy should be avoided in treating infec-
tions due to MBLs-producing isolates [49]. However,
a combination aztreonam with ceftazidime-avibactam is an
effective therapeutic option to treat infections caused by
MBLs-producing Gram-negative bacteria [37].
Several Phase 2 and 3 trials showed that ceftazidime-
avibactam was non- inferior to carbapenems for the co-
primary endpoints of clinical (symptom resolution) and com-
bined clinical/microbiological but superior for the microbiolo-
gical endpoint for the treatment of cUTIs and acute
pyelonephritis [50–52]. Serious adverse events, gastrointestinal
adverse events, and creatinine increase were significantly
more common with ceftazidime/avibactam than carbapenems
[53]. Furthermore, for unclear reasons the clinical cure rates of
ceftazidime-avibactam were lower than carbapenems for
AmpC- β -lactamase-Enterobacteriales and pseudomonas aer-
uginosa. However, the number of cases is too small to allow
for firm conclusions [49,54]. Finally, there is a concern of
resistance development to ceftazidime-avibactam during ther-
apy particularly among K. pneumoniae bacteria harboring var-
iant KPC-3 enzymes [55].
Wagenlehner et al. reported at least a fourfold increase in MIC
of ceftazidime-avibactam at test of cure in 2% of isolates [50].
Ceftolozane/tazobactam is a combination of ceftolozane,
a novel oxyimino – aminothiazolyl cephalosporin that resem-
bles ceftazidime, and the β-lactamase inhibitor tazobactam. It
is approved for cUTIs and acute pyelonephritis (Table 2) [56]. It
demonstrates remarkable stability against the numerous resis-
tance mechanisms employed by P. aeruginosa, including over-
expression of AmpC, efflux pumps and loss of porin channels
but not against ESBLs, KPC, or MBLs [57].
In a randomized, double-blind, phase III trial, ceftolozane/
tazobactam was superior to high dose levofloxacin for com-
posite clinical and microbiological cure in patients with cUTIs
POSTGRADUATE MEDICINE 243
and acute pyelonephritis [58]. Although randomized trial data
have demonstrated high clinical cure rates with ceftolozane/
tazobactam for the treatment of cUTIs caused by ESBLs-
Enterobacteriales, there was a high rate of resistance particu-
larly among ESBLs-Klebsiella pneumoniae [35,57,59,60].
Therefore, ceftolozane/tazobactam should be used an alterna-
tive, and not a primary choice, to carbapenems for the treat-
ment of infections caused by ESBLs-Enterobacteriales.
Cefiderocol is a novel cephalosporin, siderophore antibio-
tic, that forms a chelating complex with iron and is then
actively transported into bacterial cells via iron transporters.
Cefiderocol is released in the periplasmic space and binds to
penicillin binding proteins (PBPs), primarily to PBP3, and inhi-
bits peptidoglycan synthesis, causing cell death [61]. It has
significant antimicrobial activity against Enterobacterales,
Ambler class A, B, C and D β-lactamases, P. aeruginosa,
A. baumannii, S. maltophilia and Burkholderia cepacia [62,63].
A randomized, double-blind, phase II trial comparing cefi-
derocol with imipenem/cilastatin for cUTIs due to gram-
negative organism, 25-29% had acute pyelonephritis, in hos-
pitalized patients demonstrated superiority of cefiderocol for
the composite clinical and microbiological outcome, primarily
due to higher microbiological eradication. The composite
microbiological and clinical responses at test of cure for cefi-
derocol and imipenem/cilastatin were 72.6% and 54.6%,
respectively, a difference of 18.58 (95% CI 8.23–28.92) [64]. It
is still not approved for treatment of cUTIs.
Fluoroquinolones
Fluoroquinolones are no longer recommended as an empiric
treatment of acute pyelonephritis since the rate of fluoroqui-
nolones-resistant E coli is in excess of 10% in several regions
and countries [7–9,23,65]. Furthermore, they cannot be used
as empiric treatment of cUTIs or acute pyelonephritis in
patients with risk factors for ESBLs-Enterobacteriales because
of high rates of resistance [7,35].
However, fluoroquinolones can be used as a step-down
treatment from parenteral therapy if the isolated organisms
are susceptible [38,66].
Finafloxacin is an investigational intravenous and oral fluor-
oquinolone that is highly excreted in the urine and has higher
potency at acidic pH in contrast to ciprofloxacin and levoflox-
acin. It is effective against fluoroquinolones-resistant E coli and
ESBLs- Enterobacteriales (Table 1) [67,68].
In a phase II trial, a total of 225 patients with cUTIs and or
acute pyelonephritis were randomized 1.1:1 to treatment of
finafloxacin 800 mg intravenous/oral daily for 5 days, finaflox-
acin 800 mg intravenous/oral daily for 10 days, and ciproflox-
acin (intravenous 400 mg and oral 500 mg twice daily) for 10
days. Both short and long course of finafloxacin resulted in
comparable clinical and microbiological response rates as well
as composite response rates at the test of cure visit (TOC)
on day 17 and both showed higher treatment success rates
than ciprofloxacin. The treatment success rates (combined
clinical and microbiological response) at the TOC visit on day
17 were 70.3% (95% CI, 57.6% to 81.1%) for the 5-days fina-
floxacin group, 67.6% (95% CI, 55.2% to 78.5%) for the 10-days
244 M. S. BADER ET AL.
finafloxacin group, and 57.4% (95% CI, 44.1% to 70.0%) for the
ciprofloxacin group [69].
Carbapenems
Carbapenems are considered the antimicrobial agents of choice
for treatment of cUTIs and acute pyelonephritis, particularly
severe infections, due to ESBLs-Enterobacteriales (Table 2).
Ertapenem is the preferred carbapenem to treat cUTIs and
acute pyelonephritis due to ESBLs- Enterobacteriales due to its
efficacy, convenience for outpatient therapy, and narrower
spectrum comparing to other carbapenems (Table 2) [70,71].
Ertapenem remains highly active against Enterobacteriales
including ESBLs strains from UTIs. Resistance to ertapenem is
increasingly reported in parts of the world other than US/
Canada particularly among Enterobacter cloacae, k pneumonia,
ESBL- Enterobacteriales, and hospital-acquired infections
[72,73].
The role of (β-lactam/β- lactamase inhibitor) BLBLIs (piper-
acillin-tazobactam) in the treatment of UTIs caused by ESBL-
Enterobacteriales is still controversial. Piperacillin/ tazobactam
still has retained good in vitro activity against ESBLs-
Enterobacteriales, particularly ESBLs- E coli, but its clinical effi-
cacy remains controversial (Table 2) [74–80].
A small randomized study of hospitalized adult patients
with healthcare-associated UTI due to ESBLs-E coli were ran-
domized to 10–14 days treatment with piperacillin-
tazobactam (33 patients), cefepime (6 patients), and ertape-
nem (33 patients). The clinical and microbiological response to
piperacillin-tazobactam and ertapenem treatment was 94%
and 97%, respectively, but significantly lower for cefepime
(33.3%) [81].
A retrospective study revealed that treatment failure,
defined as a composite of in-hospital mortality, change of
initial antibiotic regimen and microbiological eradication fail-
ure, of patients with acute pyelonephritis caused by ESBLs-
E coli susceptible to piperacillin-tazobactam was not signifi-
cantly different for piperacillin-tazobactam and ertapenem
(20.6 vs. 23.2%, respectively,
P = 0.704) [76].
In a noninferiority, parallel group, randomized clinical trial
of hospitalized adult patients with bloodstream infection
caused by ceftriaxone-nonsusceptible E coli (266) or
K pneumoniae (40) were randomly assigned 1:1 to intravenous
piperacillin-tazobactam, 4.5 g every 6 h, (n = 188 participants)
or meropenem, 1 g every 8 h, (n = 191 participants) for
a minimum of 4 days, up to a maximum of 14 days.
A urinary tract source for blood stream infection was 67% of
meropenem and 55% in piperacillin-tazobactam group.
Phenotypic ESBLs production was confirmed in 86.0% of iso-
lates (85.0%of E coli and 92.5% of K pneumoniae). All-cause
mortality at 30 days, primary outcome, occurred in 12.3% (23
of 187) and 3.7% (7 of 191) patients who randomized to
piperacillin-tazobactam and meropenem, respectively (risk dif-
ference, 8.6% [one-sided 97.5% CI, -∞ to 14.5%]; P = .90 for
noninferiority), demonstrating that piperacillin-tazobactam did
not meet criteria for noninferiority [82].
It is reasonable to continue piperacillin-tazobactam for
definitive monotherapy for cUTIs or acute pyelonephritis due
to ESBLs-E. coli after the susceptibility results showed those
isolates to have lower MICs and there is a clinical response to
the empiric Piperacillin-tazobactam therapy. Optimizing the
dosing of piperacillin-tazobactam to achieve the drug target
attainment is necessary by a continuous infusion (4.5 g infused
over 4 h every 6–8 h) [83,84].
The role of cefepime in the treatment of UTIs due to ESBLs-
Enterobacteriales is fading because of the very limited evi-
dence of its efficacy (Table 2) [85]. Several studies showed
high clinical failure rates with the use of cefepime to treat
infections caused by ESBL-Enterobacterales [81,86–88].
Vaborbactam (formerly named RPX7009) is a cyclic boronic
acid β-lactamase inhibitor that has activity against Ambler
class A (including KPC, CTX-M, SHV, TEM) and C enzymes
(P99, MIR, FOX). Vaborbactam does not inhibit class D or
class B carbapenemases. Meropenem–vaborbactam is four
times more potent than ceftazidime–avibactam against KPC-
producing isolates [89]. The FDA has approved a fixed-dose
combination of meropenem and vaborbactam for treatment
of adults with cUTIs and acute pyelonephritis (Table 2) [90].
TANGO I is a multicenter, randomized, double-blinded, con-
trolled trial comparing meropenem–vaborbactam (2g/2g over 3
h every 8 h; n = 274) to piperacillin–tazobactam (4 g/0.5 g over 30
min every 8 h; n = 276) for the treatment of adults with cUTIs or
acute pyelonephritis (59%). For the primary end point (compo-
site clinical cure and microbiological eradication at end of intra-
venous treatment), overall success occurred in 189 of 192 (98.4%)
with meropenem-vaborbactam vs 171 of 182 (94.0%) with piper-
acillin-tazobactam (difference, 4.5%[95%CI, 0.7%to 9.1%]; P <
.001 for noninferiority, but superiority since the lower limit of
the 95% CI (0.7%) exceeded 0 (P = .01).) [91].
TANGO II was a phase III, open-label, multicenter, rando-
mized controlled trial designed to assess the effectiveness of
meropenem–vaborbactam versus best available therapy for
documented or suspected CRE infections. Among 47 patients
with CRE infections (34% had cUTIs and acute pyelonephritis),
monotherapy with meropenem-vaborbactam was associated
with increased clinical cure at test of cure (59.4% vs. 26.7%,
95% CI of difference 4.6–60.8, p = 0.02), decreased 28 days
mortality (15.6% vs. 33.3%, 95% CI of difference −44.7 to 9.3,
p = 0.2), and reduced nephrotoxicity compared with best-
available therapy (mono/combination therapy with polymix-
ins, carbapenems, aminoglycosides, tigecycline; or ceftazi-
dime-avibactam alone) [92].
Among 25 patients harboring KPC-Enterobacteriales treated
with meropenem–vaborbactam, only one had a subsequent
isolate recovered with a ≥ fourfold increase in MIC (0.25–1 μg/
mL) while two out four patients treated with ceftazidime –
avibactam had subsequent K. pneumoniae isolates recovered
with a ≥ fourfold MIC increases to ceftazidime–avibactam and
one evolved into full resistance during therapy [93,94].
Relebactam (formerly named MK-7655) is a diazabicyclooctanes
non β- lactam β-lactamase inhibitor that has activity similar to
vaborbactam in addition to improving the activity of imipenem
against Pseudomonas aeruginosa. It is not active against imipenem-
resistant Enterobacteriales expressing IMPs, VIMs, NDM, or MBLs,
A. baumannii, or IMP- or VIM-producing P. aeruginosa [95].
A randomized, double-blind, Phase 2 study comparing effi-
cacy and safety of imipenem/cilastatin plus Relebactam (either

125 mg or 250 mg intravenous every 6 h) with imipenem/cilas-
tatin alone in patients with cUTIs and acute pyelonephritis
showed non-inferiority of both imipenem/cilastatin + relebactam
doses to imipenem/cilastatin alone for both clinical (97.1%,
98.7% and 98.8%, respectively) and microbiological response
(95.5%, 98.6% and 98.7%, respectively) [96].
Sulopenem is a new broad-spectrum carbapenem in devel-
opment in both oral and intravenous formulations for the
treatment of uncomplicated and cUTIs. It has antimicrobial
activity similar to other carbapenems except it has no activity
against P. aeruginosa [97].
Aminoglycosides
Despite being not widely used because of concerns of toxicity,
aminoglycosides are still an important therapeutic option for
treatment of infections caused by MDR organisms for which
treatment options are limited (Table 2) [98]. However, most of
these MDR organisms carry plasmids that often harbor ami-
noglycoside-modifying enzymes (AMEs)-encoding genes able
to modify the clinically available aminoglycosides [99,100].
Plazomicin is a new aminoglycoside derivative of sisomicin
that is resilient to the activity of all clinically relevant AMEs, the
primary mechanism of aminoglycoside resistance [99–101]. It is
approved by FDA for adults with cUTIs and acute pyelonephritis,
caused by certain Enterobacteriales in patients who have limited
or no alternative treatment options (Table 2) [102].
A multicenter, randomized, double-blind, phase 2 study
comparing plazomicin with Levofloxacin showed that plazo-
micin (10 or 15 mg/kg) given once daily for 5 days achieved
microbiological eradication and clinical cure in 85% and 80%
of patients with cUTIs and acute pyelonephritis, respec-
tively [103].
In a multinational, randomized, double-blind, non-
inferiority phase III study, 609 patients with cUTIs, including
acute pyelonephritis (40-44%), were randomized in to receive
intravenous plazomicin (15 mg per kilogram of body weight
once daily) or meropenem (1 g every 8 h) for a total of 7 to 10
days of therapy [103]. Among the 382 patients with
Enterobacteriales in the microbiologic modified intention-to-
treat population, 28.0%, 30.1%, and 26.4% had uropathogens
with an ESBLs phenotype, multidrug-resistant uropathogens,
and uropathogens that were not susceptible to other amino-
glycosides, respectively. The primary end point (composite
clinical cure and microbiologic eradication) at test of cure for
plazomicin vs. meropenem was 81.7% vs. 70.1% (difference
11.6%, 95%CI 2.7–20.3%). Plazomicin achieved higher micro-
biological eradication than meropenem (89.5% vs. 74.6%, dif-
ference 14.9%, 95% CI 7.0–22.7%) including eradication of
Enterobacteriales that were not susceptible to aminoglyco-
sides (78.8% vs. 68.6%) and ESBLs-Enterobacterales (82.4% vs.
75.0%). It was not associated with increased risk of nephro-
toxicity or vestibular toxicity [104].
Other antimicrobial agents
Fosfomycin in its intravenous formulation (fosfomycin diso-
dium) is being developed for treatment of cUTIs and acute
pyelonephritis due to MDR-organisms in the United States,
POSTGRADUATE MEDICINE 245
recently approved in Canada, despite being available for sev-
eral years in Europe. Fosfomycin has a broad spectrum of
activity against a variety of clinically important MDR Gram-
negative pathogens such as ESBLs- and CRE-Enterobacteriales
and Gram-positive pathogens such as vancomycin-resistant
enterococci (Table 2) [105].
In a multicenter, phase II/III; randomized noninferiority
study of hospitalized adults with suspected or microbiologi-
cally confirmed cUTIs and acute pyelonephritis (54%), 233 and
231 were treated with intravenous fosfomycin (6 g every 8 h)
and piperacillin/tazobactam (4.5 g every 8 h), respectively.
Fosfomycin was not inferior to piperacillin/tazobactam in
the overall response (primary endpoint: clinical cure and
microbiologic eradication at test of cure) (64.7% [119/184] vs.
54.5% [97/178], respectively, with a difference of 10.2% [95%
CI −0.4, 20.8]). The clinical and microbiological cure rates were
similar between the groups: 90.8% (167/184) for fosfomycin
versus 91.6% (163/178) for piperacillin/tazobactam and 66%
(127/184) for fosfomycin and 57.3% (102/178) for piperacillin/
tazobactam, respectively [106].
The major concerns of fosfomycin are the development of
resistance during treatment and clinical failure with infections
due to P aeruginosa particularly when used as monotherapy.
Therefore, it should be combined with other antibiotics for the
treatment of infections due to MDR pathogens [107–110].
Eravacycline is a novel synthetic tigecycline analogue with
broad-spectrum antibacterial activity against gram-negative
organisms including ESBLs-Enterobacteriales, CRE, acinetobacter
baumannii, and polymixin resistant strains and against Gram-
positive pathogens, such as methicillin-susceptible and -resistant
staphylococci, vancomycin-susceptible and -resistant enterococci.
It has no activity against Pseudomonas aeruginosa [111].
A phase 3 study evaluating eravacycline (1.5 mg/kg daily)
versus ertapenem (1 g daily) for a minimum of 5 days with an
oral stepdown for the treatment of cUTIs and acute pyelone-
phritis (IGNITE2) did not demonstrate noninferiority. The co-
primary endpoints of responder rates at test of cure were
68.5% and 74.9% for eravacycline and ertapenem, respectively
(−6.5% CI: −12.6%, −0.3%) [112]. Despite its broad antibacterial
activity and high urine concentration, it should not be used for
the treatment of cUTIs or acute pyelonephritis till further
studies demonstrating its efficacy.
Omadacycline is a semisynthetic tetracycline derivative that
exhibits activity against Gram-positive and Gram-negative
aerobes, anaerobes, and atypical bacteria. Its use in treatment
of UTIs is in its preliminary stage [113].
Aztreonam is a β-lactam antibiotic and the only clinically
available member of its monobactam class. Aztreonam remains
an option for treating infections due to MBLs) producing gram-
negative organisms that test susceptible to this agent. However,
these carbapenemase-producing bacteria are often coupled with
additional resistance mechanisms, such as ESBLs and AmpC-type
enzymes, which confer resistance to aztreonam (Table 2) [104].
Therefore, aztreonam should not be used as empiric monother-
apy for cUTIs or acute pyelonephritis due to high resistance and
failure rate [114]. Combing aztreonam with other antibiotics
(ceftazidime-avibactam, amoxicillin-clavulanic acid) or β -lactam
inhibitors (avibactam, zidebactam, nacubactam, and WCK 5153)
enhances activity against these resistant organisms [37,115–118].
246 M. S. BADER ET AL.
Temocillin is a 6-α-methoxy derivative of ticarcillin that
shows in vitro activity against AmpC-, ESBLs-, and KPC-
producing Enterobacteriales with minimal risk of Clostridium
difficile infection [119]. It can be used for treatment UTIs as
carbapenem-sparing antibiotic. Current recommended regi-
mens are 2 g q12h or 2 g q8h depending on infection severity
and strain susceptibility [118]. However, there is very limited
data on its clinical efficacy in the treatment of UTIs and debate
on its susceptibility breakpoints [120].
Conclusion
There are recently new antimicrobial agents (ceftolozane/
tazobactam, ceftazidime/avibactam, meropenem/vaborbac-
tam, plazomicin) that are approved for the treatment of
cUTIs and acute pyelonephritis due to MDR-organisms. It is
crucial to use these new antimicrobials only as last-resort
treatments when UTIs caused by MDR-organisms that resis-
tant to old antimicrobial options are confirmed or strongly
suspected to safe-guard these antibiotics from resistance
development. It is also strongly recommended to use old
existing antimicrobial agents wisely in the treatment of UTIs
according to local antimicrobial susceptibility information,
clinical settings, and patient’s risk factor for antimicrobial
resistance. Nitrofurantoin is the first recommended empiric
antibiotic therapy for uncomplicated cystitis due to its high
activity against E. coli, safety profile, and limited impact on
the intestinal microbiota [2,5]. Oral cephalosporins can be
used as empiric treatment of uncomplicated cystitis, if
neither nitrofurantoin nor fosfomycin can be used, and as
a step down treatment from parenteral therapy of acute
pyelonephritis if the isolated organisms are susceptible
[7,41,42].
Fluoroquinolones and trimethoprim-sulfamethoxazole are
not recommended for empiric treatment of uncomplicated
cystitis, cUTIs with risk of fluoroquinolones resistance or
ESBLs- Enterobacteriales, acute pyelonephritis, and hospital-
acquired UTIs [7,9,23,25]. The prevalence of UTIs due to
ESBLs Enterobacteriales even in outpatient settings is
increasing [7–9]. Carbapenems remain the antibiotic of
choice with proven efficacy for patients with cUTIs and
acute pyelonephritis, particularly severe infections, due to
ESBL-Enterobacteirales [70,82]. Piperacillin-tazobactam might
have a role in the treatment of mild-moderate UTIs caused
by susceptible ESBL-E coli or when the MIC is low while
cefepime should not be used for this indication [80].
Although ceftolozane/tazobactam and ceftazidime/avibac-
tam provide carbapenem-sparing options for the treatment
of ESBLs infections, they should be reserved for the treat-
ment of cUTIs and acute pyelonephritis due to MDR-
P aeruginosa (both) and CRE (ceftazidime/avibactam only)
[44,56]. Meropenem–vaborbactam is the preferred therapy
for cUTIs and acute pyelonephritis due to KPC-producing
Enterobacteriales because of efficacy and potential barrier
for resistance development [89,90,92]. Consultation with an
infectious diseases specialist, microbiologist, or antimicrobial
stewardship team for the management and treatment of
UTIs due to resistant organisms is highly recommended.
Declaration of interest
The contents of the paper and the opinions expressed within are those of
the authors, and it was the decision of the authors to submit the manu-
script for publication.
None of the authors has any conflict of interest.
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
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