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Expert Opinion on Drug Safety

ISSN: 1474-0338 (Print) 1744-764X (Online) Journal homepage: http://www.tandfonline.com/loi/ieds20

Antimicrobial resistance and treatment: an unmetclinical safety need

Matteo Bassetti, Alessandro Russo, Alessia Carnelutti, Alessandro La Rosa &Elda Righi

To cite this article: Matteo Bassetti, Alessandro Russo, Alessia Carnelutti, Alessandro La Rosa& Elda Righi (2018): Antimicrobial resistance and treatment: an unmet clinical safety need, ExpertOpinion on Drug Safety, DOI: 10.1080/14740338.2018.1488962

To link to this article: https://doi.org/10.1080/14740338.2018.1488962

Accepted author version posted online: 13Jun 2018.

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Publisher: Taylor & Francis

Journal: Expert Opinion on Drug Safety

DOI: 10.1080/14740338.2018.1488962

Antimicrobial resistance: an unmet clinical safety need

Matteo Bassetti1,*, Alessandro Russo1, Alessia Carnelutti1, Alessandro La Rosa1, Elda Righi1

Affiliations

1Infectious Diseases Division, Santa Maria Misericordia Hospital, Udine, Italy

*Corresponding author:

Phone +39 0432 559355 ; Fax +39 0432 559360 ; Email: mattba@tin.it

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Abstract

Introduction Infections due to multidrug-resistant (MDR) bacteria are burdened by high

mortality rates. The development of new compounds to face the global threat of resistance is

urgently needed. Combination regimens including “old” high-dose antimicrobials are

currently limited by the risk of toxicity, resistance selection, and reduced efficacy.

Following the Infectious Diseases Society of America call to develop 10 new antibacterials

by 2020, new molecules are currently under development or have become available for use

in clinical practice.

Areas covered We have reviewed safety characteristics and tolerability of old

antimicrobials that are currently employed in combination regimens as well as new

antimicrobials, including beta-lactams/beta-lactamase inhibitors, new cephalosporins,

quinolones, and aminoglycosides.

Expert opinion

The availability of new compounds that show in vitro efficacy against MDR represents a

unique opportunity to face the threat of resistance and to optimize the current use of

antimicrobials, potentially reducing toxicity. Among agents that are potentially active

against MDR Gram-negatives are ceftozolane/tazobactam, new carbapenems and

cephalosporins, the combination of avibactam with ceftazidime, and plazomicin. Further

data from clinical trials and post-marketing studies for drugs targeting MDR pathogens are

crucial to confirm their efficacy and safety.

Keywords: multidrug-resistant Gram-negative infections, drug toxicity, colistin, tigecycline,

fosfomycin, new antibiotics

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Article highlights

• The use of increased doses and prolonged regimens in to overcome resistance to Gram-

negative bacteria has been associated over the years with reports of relevant adverse

effects

• Among old antibiotics, regimens including aminoglycosides and high-dose colistin have

been associated by increased rates of nephrotoxicity

• New antimicrobials that are currently used in clinical practice (e.g.,

ceftolozane/tazobactam, ceftazidime/avibactam) are usually well tolerated

• Novel antimicrobials that are currently under development showed favorable safety

profiles in clinical trials, but real-world studies are needed to confirm their efficacy and

safety

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1. Introduction

The emergence of multidrug-resistant (MDR) Gram-negative bacteria (GNB) has led to a

global public health emergency [1]. Severe infections due to MDR GNB pose a great threat

due to their high mortality and associated prolonged hospitalizations [2]. In 2017, the World

Health Organization (WHO) published a list of pathogens presenting relevant resistance

issues, highlighting as a priority the research and development of new antibiotics targeting

carbapenem-resistant Acinetobacter, Pseudomonas, and Enterobacteriaceae species [3]. In

the past decades, the emergence of MDR strains of Pseudomonas aeruginosa and extended-

spectrum-beta-lactamases (ESBLs)-producing Enterobacteriaceae has greatly limited the

choices for an adequate antimicrobial regimen, affecting patients’ outcome [4]. Furthermore,

until recently the increase in MDR bacteria was not compensated by the development of

new molecules targeting carbapenem resistance [5]. Newer compounds that are now

available in clinical practice, such as ceftolozane/tazobactam and ceftazidime/avibactam,

have demonstrated high in vitro efficacy against selected MDR GNB and good tolerability

in clinical trials and preliminary post-marketing reports (Table 1) [6].

While awaiting the availability of newer compounds, clinicians aiming to target severe

infections had to rediscover the use of “old” drugs that retain in vitro activity against MDR

GNB, such as fosfomycin or polymixins [7]. High doses of broad-spectrum antimicrobials,

such as carbapenems or tigecycline, have been used in combination regimens including two

or three antimicrobials, to attain pharmacokinetics (PK)/pharmacodynamics (PD) targets,

showing therapeutic benefit in observational studies [8-10]. These strategies, however, have

been correlated to an increase in drug-related toxicity and present negative implications for

antimicrobial stewardship.

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Here we discuss the safety and tolerability of “old” and new compounds used for the

treatment of MDR GNB, including molecules that are under development and are

completing Phase 3 clinical trials.

2. Safety profiles of “old” antibiotics for MDR Gram-negative infections

2.1 Polymixins: colistin

Polymyxins are “old” polypeptide antibiotics commonly used in the 1950s for the treatment

of complicated urinary tract infections (cUTIs) [11]. This class exerts its antibacterial

activity through the interaction of a polycationic peptide ring with the lipid A of the

lipopolysaccharides (LPS), causing disorganization and loss of the membrane integrity and

bacterial cell death [11, 12]. Due to frequent reports of neurotoxicity and nephrotoxicity

associated with their use, polymyxin use was limited in the past years [13-15]. Attempts to

generate polymyxin derivatives that are less toxic have been made, but they all lacked a

significant antibacterial effect [16].

Recently, due to the spread of carbapenem-resistant GNB that showed in vitro sensitivity to

polymyxins, this class has been resumed as part of combination treatments, especially for

severe infections due to carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) [6,

17]. Despite their widespread use over the years, polymyxins retain in vitro activity against

carbapenemase-producing strains of Enterobacteriaceae, MDR Pseudomonas aeruginosa

and Acinetobacter spp., including most of the pandrug-resistant (PDR) strains [18]. Two

polymyxins are currently available for use, polymyxin B and colistin (polymyxin E).

Polymyxin B is currently used in North and South America while colistin is frequently used

in Europe. Colistimethate sodium (CMS) represents colistin’s inactive prodrug and is

available for parenteral use or for nebulization [19]. Since CMS is rapidly degraded to its

active form, the PK of colistin remains only partially understood, especially in difficult-to-

treat populations such as critically ill patients [20, 21]. Furthermore, there are different

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dosages and potency definitions associated with colistin according to different marketed

products, leading to a lack of universally adopted dose recommendations [22,23]. Based on

recent studies, however, higher dosages than those previously reported (e.g., a loading dose

of 9 MIU of CMS followed by a maintenance dose of 4.5 MIU every 12 h) have been

proposed in order to timely achieve a PK target [24]. Adjustments based on patient’s renal

function are suggested, although studies in patients on continuous hemodiafiltration have

shown that colistin dose should not be reduced [21]. Overall, a correct dose regimen and the

use of polymyxins only as part of combination regiments for the treatment of carbapenem-

resistant (CR) Enterobacteriaceae are recommended to limit the emergence of antimicrobial

resistance [8, 25].

Early reports associated total cumulative colistin dose and longer treatments with kidney

damage [26-28]. Studies performed after the reintroduction of colistin reported rates of mild

reversible nephrotoxicity in the range of 0–40%, without confirming the high levels of

toxicity reported in the 1970s [29]. Other adverse events (AEs), such as neurotoxicity or

bronchospasm following colistin nebulization for respiratory infections, were also extremely

rare [30].

A meta-analysis including 6 controlled studies and 14 single arm studies Florescu et al.

aimed to assess the efficacy and safety of colistin in the treatment of ventilator-associated

pneumonia (VAP). Data from controlled trials did not confirm a cumulative toxicity of

colistin [30]. Overall nephrotoxicity from 5 studies encompassing 344 patients did not differ

significantly between colistin and comparators (OR, 1.14, 95% CI, 0.59–2.20, P =0.69) [31-

35]. Neurotoxicity, assessed in 3 studies involving 183 patients was similar between groups

(OR, 1.39 [95% CI, .17–11.61; P = .76) [31,32,35].

Recent studies analyzing colistin-associated AEs following the use of higher daily doses

compared to the previous recommended ones have shown higher incidence of

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nephrotoxicity, usually appearing within the first week of treatment [36-38].

Specifically, results from PK and observational studies analyzing colistin safety highlighted

that particular attention to the patient’s actual bodyweight is important to reduce

nephrotoxicity, and showed frequent overdosing associated with obesity [21, 28]. Overall,

data from single studies and meta-analyses have highlighted how neurotoxicity does not

seem to be an issue during colistin treatment regimens, although higher occurrence has been

reported in patients with renal impairment [26, 27, 30]. The use of aerosolized CMS has

been associated with possible AEs, including bronchospasm, chest tightness and apnea, but

they are considered rare [30]. Patients with a history of pre-existing bronchial hyper-

reactivity or chronic obstructive pulmonary disease (COPD) are more subject to

bronchospasm that can be prevented but inhalation of beta2-agonists before the use of

aerosolized colistin [39].

In conclusion, colistin-associated nephrotoxicity represents an independent predictor or

treatment failure and mortality in severe MDR infections. For these reasons, factors that may

enhance colistin nephrotoxicity (i.e., shock, hypoalbuminemia, concomitant use of

nephrotoxic drugs such as aminoglycosides) should be limited whenever possible [37].

Renal function should be closely monitored during colistin treatment and dose adjustments

should be performed in case of renal impairment.

2.2 Fosfomycin

Fosfomycin belongs, similarly to colistin, to the group of “old” antibiotics that were

employed in clinical practice decades ago to treat various infections, especially UTIs. An

oral formulation of fosfomycin is also available for the treatment of cystitis. Fosfomycin

retains, despite the widespread use over the years, good activity against Gram-positive

bacteria (GPB) and multidrug-resistant GNB, especially those involved in UTIs [40].

Fosfomycin mechanism of action regards the inhibition of an early step in the bacterial cell

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wall synthesis involving phosphoenolpyruvate synthetase [41]. Fosfomycin in vitro activity

includes PDR strains of K. pneumoniae, while its activity remains moderate against P.

aeruginosa [40].

Fosfomycin has a hydrophilic character and is eliminated almost entirely by glomerular

filtration. For this reason, intensive care unit (ICU) patients with difficult-to-predict blood

concentrations due to augmented renal clearance may present fosfomycin subtherapeutic

concentrations that can affect clinical outcomes and/or promote selection of resistance [42].

Clinical studies employing fosfomycin as part of combination regimens to treat MDR Gram-

negative infections have not raised safety concerns so far. In a prospective study of 11

patients receiving fosfomycin as a part of combination regimens, no AEs were reported [43].

A multicenter prospective study involving 11 Greek ICUs included 68 fosfomycin-treated

patients with bacteremia and VAP due to MDR pathogens [44]. Successful clinical outcome

was observed in 54.2% of patients and bacterial eradication in 56.3% No major AEs were

noted, while among minor events the most common was the occurrence of reversible

hypokalemia. Various studies have evidenced the efficacy along with excellent tolerability

of oral fosfomycin in less serious infections, including the treatment of recurrent cystitis in

pregnant and non-pregnant women [45-48]. A recent review of the literature aiming at

characterizing the AEs associated with fosfomycin use showed a prevalence of AEs

consistent with its safety profile. In the study, a total of 23 trials (8 comparative and 15 non-

comparative trials) of intra-venous (IV) fosfomycin were selected, including 1242 patients.

For oral fosfomycin, 28 prospective comparative trials in 2743 patients were included. The

most frequent AEs associated with parenteral fosfomycin were rash, peripheral phlebitis,

hypokalemia, and gastrointestinal disorders. Serious AEs such as aplastic anemia,

anaphylaxis, and liver toxicities were reported infrequently. Gastrointestinal disorders were

the most common AEs associated with oral fosfomycin [49]. Overall, the oral formulation of

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fosfomycin is considered to have a favorable safety profile with gastrointestinal disturbances

being the most commonly associated AE. These comprise mainly transient and mild

symptoms, including diarrhea (10%), nausea (5%), abdominal pain (2%), and dyspepsia (1–

2%) [50]. Other AEs reported were headache, dizziness, back pain, and weakness. The IV

formulation of fosfomycin, fosfomycin disodium, is associated with a high sodium intake

(e.g., 1 g of intravenous fosfomycin corresponds to 0.33 g or 14.4 mEq of sodium) that has

to be taken into consideration when treating patients with heart failure or on hemodialysis

[41]. Other rare AEs associated with IV fosfomycin include nausea, neutropenia,

hypereosinophilia, and local phlebitis [51, 52] Recently, Florent et al. reported as mild and

transient AEs associated with IV fosfomycin among 72 patients the occurrence of

hypokalemia (26%), injection-site reaction (4%) and hypertension (3%) [53].

2.3 Tigecycline

Tigecycline belongs to the semisynthetic tetracycline derivative class of the glycylcyclines,

and acts inhibiting the bacterial protein synthesis [54]. Tigecycline use has been commonly

associated with presentation of mild AEs, mainly including nausea (ranging from 30 to

55%) and vomiting (ranging from 18 to 28%) [55]. Apart from gastrointestinal disturbances,

tigecycline is well tolerated and does not require dose adjustments for renal impairment or

mild-to-moderate hepatic failure (Child–Pugh scores B and C) [56, 57]. Compared to older

tetracyclines, tigecycline presents a wider spectrum of activity including Staphylococcus

aureus, vancomycin-resistant Enterococcus, tetracycline-resistant Escherichia coli and

certain ESBL-producing strains [58]. Tigecycline has also in vitro activity against

Clostridium difficile [59]. No activity has been reported, instead, against P. aeruginosa,

Proteus spp. and Providencia spp. Tygecycline has bacteriostatic activity and its use as

monotherapy in severe infections has been discussed. Specifically, an increased risk of

mortality associated with tigecycline use in the treatment of serious infections was reported

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by the Food and Drug Administration (FDA) in 2010 [60]. Data supporting this hypothesis

included the analysis of a pooled group of randomized clinical trials including various

infections. Despite the warning, tigecycline’s microbiological profile has supported its use

as part of combination treatments in severely ill patients with MDR GNB, especially KPC-

Kp mediated infections [61].

Clinically significant organ toxicity has not been reported in clinical trials employing

tigecycline. In Phase 1 studies, no relevant AEs were observed [55,62], although transient

elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and

alkaline phosphatase (ALP) levels occurred in some test subjects. In a Phase 2 clinical trial

encompassing 160 hospitalized patients, one case of paresthesia and one case of mild skin

reaction were associated with tigecycline use [63]. In a larger Phase 3 study, 1383 patients

received tigecycline for skin and skin-structure infections (SSTIs). No hematologic or

laboratory abnormalities were associated with use of tigecycline [64], although activated

partial thromboplastin or prothrombin time was prolonged in 3% of patients. In a study

analyzing the efficacy of tigecycline among patients with cIAI, only few changes in

hematologic or serum chemistry test results, vital signs, or electrocardiogram data were

associated with tigecycline treatment [65].

Nausea and vomiting, especially in younger subjects and women, remain the most common

AEs associated with tigecycline use and appears improved by the use of antiemetics at the

time of administration [55, 62]. Nausea usually occurs in the first two days of treatment and

is often mild and transient. In a clinical trial, overall discontinuation rate during tigecycline

treatment was 5% and was most frequently associated with nausea (1.3%) and vomiting

(1.0%). Diarrhea was reported in a significant number of patients (13%) in Phase 3 clinical

trials, but no patient treated with tigecycline tested positive for C. difficile toxin [66].

Various studies support the use of high-dose tigecycline (200 mg initially, and then 100 mg

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twice daily compared to 100 mg loading dose followed by 50 mg every 12 hours) to achieve

higher cure rates [67-70]. No major issues of toxicity have been reported at high doses so

far, although the tolerability of high-dose tigecycline has only been assessed in small trials

3. Safety profiles of new compounds for the treatment of MDR Gram-negative

infections

3.1 Ceftazidime/avibactam

Ceftazidime is a third-generation cephalosporin binding a variety of penicillin binding

proteins (PBPs) including the PBP3 of GNB such as Pseudomonas aeruginosa. Conversely,

avibactam is a semi-synthetic, non-beta-lactam, beta-lactamase inhibitor (BLI) and differs

from other BLI, such as clavulanic acid, sulbactam and tazobactam, in three aspects,

including structure, mechanism of inhibition, and spectrum of inhibition [71]. Avibactam in

vitro inhibits the activity of Ambler class A (ESBL and KPC), class C (AmpC) and some

class D (OXA-48) enzymes, but it is not active against metallo-beta-lactamases (NDM,

VIM, IMP), or against Acinetobacter OXA-type carbapenemases [72].

The emergence of resistance during treatment with ceftazidime/avibactam has been reported.

In a preliminary, real-world study including 37 patients, three patients developed resistance

early during treatment for KPC-producing K. pneumoniae [73]. For this reason, the use of

ceftazidime/avibactam in combination with other antimicrobials has been advocated and

often reported in subsequent studies [73-76]. The efficacy of ceftazidime/avibactam

monotherapy compared to combination therapies, however, has not been assessed yet and

larger studies are needed to give clear direction to clinicians on this point.

Data about the safety of ceftazidime/avibactam include experience from Phase 1 and Phase 2

trials, and recent Phase 3 trials. In the Phase 2 studies, AEs were similar between both

ceftazidime/avibactam and comparators (Table 3). Overall, ceftazidime/avibactam was well

tolerated and no differences were reported in the study conducted in patients with cUTI in

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terms of AEs between ceftazidime/avibactam and imipenem/cilastatin [77]. Most common

laboratory findings were increases in ALP, ALT and AST. Most of these AEs were mild to

moderate and some of these could be attributable to other patients’ comorbidities or

concomitant metronidazole therapy [78].

The clinical indications for ceftazidime/avibactam, based on Phase 3 non-inferiority trials,

are in the setting of cUTI, cIAI, and hospital acquired pneumonia (HAP), including VAP.

In Phase 3 clinical trials, adverse events were similar between ceftazidime/avibactam and

comparators (Table 3). The RECLAIM study, comparing ceftazidime/avibactam with

meropenem in cIAI showed a similar number of adverse events between groups. Most

common AEs for ceftazidime/avibactam included diarrehea (7.6%), nausea (6.8%), vomiting

(4.5%(, and pyrexia (4.5%) [79]. In the RECAPTURE clinical trial showing non-inferiority

of ceftazidime/avibactam compared to doripenem in the treatment of cUTI, ceftazidime-

avibactam had a safety profile consistent with that of ceftazidime alone. Headache and GI

disorders were the most commonly reported AEs [80] In the REPROVE study, adverse

events occurred in 75% of patients in patients with HAP/VAP in the ceftazidime-avibactam

compared to 74% in the meropenem group and were mostly mild or moderate in intensity

and mainly unrelated to study treatment [81].

In a recent study in UTIs, ceftazidime-avibactam showed 100% of susceptibility in KPC and

OXA-48 producers, and rates of susceptibility in carbapenemase-producing

Enterobacteriaceae non-susceptible to ceftazidime or meropenem were 92.1% and 96.9%,

respectively [82]. Overall, the efficacy of ceftazidime/avibactam in severe infections due to

carbapenem-resistant Enterobacteriaceae (CRE) in real world studies appeared promising

and superior compared to colistin and other combination treatments, especially for KPC-

producing strains [73-76]. Ceftazidime-avibactam currently represents a reasonable choice

in the treatment of K. pneumoniae carbapenemase-producing infections, including patients

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with documented bacteremia. No concerns regarding clinical safety have emerged from real-

world studies, although the number of patients treated with ceftazidime/avibactam is still

limited and more data is awaited to confirm its tolerability in clinical practice.

3.2 Ceftolozane/tazobactam

Ceftolozane/tazobactam is a beta-lactam/beta-lactamase inhibitor combination that exhibits

bactericidal activity through inhibition of bacterial cell wall biosynthesis, mediated through

PBPs. Ceftolozane is highly active against P. aeruginosa, showing lower MICs than

ceftazidime and retaining activity for MDR strains, including major route of resistance such

as de-repressed AmpC or upregulated efflux pumps [83]. The addition of tazobactam

provides enhanced activity against ESBL-producing Enterobacteriaceae and anaerobic

organisms [84].

Based on data from clinical trials, AEs due to ceftolozane/tazobactam do not differ

considerably from other cephalosporins, being the most common nausea, diarrhea,

headache, and pyrexia. In a Phase 2 cUTI study, AEs in the ceftolozane vs. comparator arms

were similar and included mainly constipation, sleep disorder, and diarrhea [85]. Of

importance, in patients with moderate renal failure (creatinine clearance, 30–50 mL/minute),

a numerically lower cure rate was noted in the Phase 3 intra-abdominal infection trial: 11 of

23 (48%) in the ceftolozane/tazobactam plus metronidazole arm vs. 9 of 13 (69.2%) in the

meropenem arm. The decreased cure rate among patients aged ≥65 years (69% vs. 82%) was

also thought to be secondary to changes in renal clearance. On this basis, FDA included a

warning in the package insert of ceftolozane/tazobactam to monitor renal function at least

daily in patients with changing renal function and to change ceftolozane/tazobactam dosing

as needed. Reported AEs included hypokalemia (2.9%), headache (2.5%), and increased

ALT (2.5%) and AST (1.6%) levels [86].

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Ceftolozane/tazobactam is a beta-lactam/beta-lactamase inhibitor combination that is

currently approved for the treatment of cIAI and cUTI. However, considering the specific

action against MDR Pseudomonas aeruginosa was explored its possible role in severe

infections caused by MDR and extensively drug-resistant (XDR) P. aeruginosa [87, 88], and

the cure of pulmonary exacerbation in patients with cystic fibrosis, also for its good profile

of tolerability [89].

Finally, a recent study reported the role of ceftolozane/tazobactam in the treatment of

osteomyelitis and skin and soft tissue infections (SSTIs) due to P. aeruginosa strains [90].

3.3. Imipenem/relebactam

Relebactam, formerly known as MK-7655 is a IV, class A – and class C - beta-lactamase

inhibitor and is currently under evaluation in combination with imipenem/cilastatin for the

treatment of resistant GNB infections [91]. In vitro studies have demonstrated relebactam to

restore imipenem’s activity against KPC-producing carbapenem-resistant

Enterobacteriacae, including K. pneumoniae, and to lower imipenem minimal inhibitory

concentrations (MICs) in P.aeruginosa, particularly in strains with depressed OprD

expression and increased AmpC expression [92]. Conversely, the addiction of relebactam to

imipenem seems not to provide any adjunctive benefit against A.baumanii and S.maltophilia

[93].

Safety and efficacy of imipenem/relebactam have been evaluated in two Phase 2 trials in the

setting of cIAI and cUTI (NCT01506271 and NCT01505634) (Table 3).

In a double-blind, Phase 2 study, 351 patients with cIAIs were randomized to receive either

relabactam 250 mg, relabactam 125 mg, or placebo, each given intravenously in

combination with imipenem 500 mg every 6 hours for 4 to 14 days. Diarrhea, nausea and

vomiting were the most commonly reported AEs and occurred in 6.0%, 6.8% and 6.0% in

relabactam 250 mg + imipenem treatment arm, 6.0%, 7.8% and 7.8% in relabactam 125 mg

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+ imipenem treatment arm and in 4.4%, 7.0% and 2.6% in placebo + imipenem treatment

arm, respectively [94].

In a similar Phase 2 study, imipenem/ relabactam was evaluated for the treatment of adult

patients with cUTI or acute pyelonephritis. The most common adverse events were

represented by headache, diarrhea and nausea, and occurred with no significant differences

in incidence rates across the three groups. Particularly, haeadache, diarrhea and nausea

occurred in 7.1%, 5.1% and 4.0% in relabactam 250 mg + imipenem treatment arm, 3.0%,

2.0% and 6.1% in relabactam 125 mg + imipenem treatment arm and in 4.0%, 4.0% and

4.0% in placebo + imipenem treatment arm, respectively [95].

A Phase 3 study evaluating the efficacy and safety of imipenem/relabactam (200/100 mg to

500/250 mg depending on renal function) compared to CMS for the treatment of IMI-

resistant bacterial infections, including HAP, VAP, cIAI and cUTI, has recently been

completed (NCT02452047).

A non-inferiority, Phase 3 trial evaluating the efficacy and safety of imipenem/relabactam

compared to piperacillin/tazobactam for the treatment of HAP and VAP (NCT02493764)

and a Phase 3 trials evaluating the efficacy and safety of imipenem/relabactam in Japanese

patients with cIAI or cUTI (NCT03293485) are currently ongoing.

3.4 Meropenem/vaborbactam

Vaborbactam, formerly known as RPX7009, is a novel class A - and class C - beta-

lactamase inhibitor and is currently in Phase 3 clinical development in combination with

meropenem for the treatment of infections due to MDR GNB [96]. Vaborbactam is a cyclic

boronic acid pharmacophore and is a potent inhibitor of serine beta-lactamases due to the

high affinity between the serine-based active sites of beta-lactamases and boronates, leading

to the formation of a covalent complex and inhibition of beta-lactamases enzymes [97].

Particularly, vaborbactam was found to be effective in lowering the meropenem MIC50 from

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32 to 0.06 μg/ml and the MIC90 from 32 to 1 μg/ml in a study encompassing 991 isolates of

KPC-producing Enterobacteriaceae collected in 2014 and 2015 [97, 98].

A Phase 1 study investigated safety, tolerability and PK of vaborbactam following single

and multiple ascending doses in healthy adult subjects (NCT01751269). Overall,

vaborbactam was well tolerated and no serious safety concerns were identified. Most

commonly reported AEs were headache and catheter site complications (i.e., infusion site

phlebitis, catheter site pain, catheter site hematoma and catheter site phlebitis), with similar

incidence in subjects who received treatment and in patients who received placebo.

Moreover, no correlation between administered vaborbactam dose and AEs incidence was

found. Mild lethargy was described only among patients receiving high vaborbactam doses

(1000 mg or 2000 mg) [99].

Meropenem/vaborbactam has recently been approved by FDA on August 2017 for the

treatment of cUTI, based on the results of the TANGO1 trial, showing the superiority of

MER/VAB (2g/2g every 8 hours) compared with piperacillin/tazobactam (4g/0.5g every 8

hours) for the treatment of cUTI and acute pyelonephritis in adult patients (NCT02166476).

MER/VAB was well tolerated and headache, diarrhea and infusion site phlebitis were the

most frequently reported adverse events, occurring in 8.8%, 3.3% and 2.2% of cases,

respectively. Discontinuations from study drug due to an AE occurred in 7 (2.6%) patients

in the MER/VAB arm and 14 (5.1%) receiving piperacillin/tazobactam.

A Phase 3 study evaluating efficacy, safety and tolerability of meropenem/vaborbactam

compared to best available therapy for the treatment of infections due to carbapenem-

resistant Enterobacteriacae has recently been completed and results are pending

(NCT02168946).

3.5 Plazomycin

Plazomicin is a new generation aminoglycoside that is not affected by most clinically

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relevant aminoglycoside-modifying enzymes and is currently under investigation for the

treatment of MDR Gram-negative infections. Plazomycin demonstrated in vitro activity

against MDR Enterobacteriaceae, including aminoglycoside-resistant isolates, ESBL-

producing bacteria and CRE [100].

In a randomized double-blind Phase 2 study IV plazomicin (administered as 10 or 15 mg/kg)

efficacy and safety were compared to IV levofloxacin (750 mg once daily) in the treatment

of cUTI including acute pyelonephritis [101]. Treatment duration was 5 days and 145

patients were included in the study. Microbiological eradication and clinical cure were

comparable between the groups.

In the plazomicin 10 mg/kg, 15 mg/kg, and levofloxacin groups, respectively, AEs were

reported in 31.8%, 35.1%, and 47.7% of patients. Serum creatinine values were stable over

the course of the study. No sensorineural, conductive, or mixed hearing loss at audiometry

was documented among plazomicin-treated patients.

In the CARE study [102] 17 patients were treated with plazomicin (15 mg/kg once daily)

and compared with 20 patients treated with colistin in combination with adjunctive therapy

of meropenem or tigecycline� in the treatment of BSI or HAP/VAP due to CRE. Primary

endpoints included all cause mortality at 28 days or significant disease-related

complications, such as worsening acute respiratory distress syndrome (ARDS), new lung

abscess or empyema, new-onset septic shock, persistence or new-onset bacteremia. All

cause mortality or related complications appeared lower in the plazomicin arm (23.5% vs.

50%, difference 26.5%, range -0.7 to 51.2). Drug-related AEs were 42.9 vs. 27.8 in the

colistin vs. plazomycin group, respectively. Higher serious adverse events (SAE) were also

more common in the colistin compared to plazomycin arm (19 vs. 5.6 respectively). Serum

creatinine increase ≥0.5 mg/dL while on IV therapy was 37.5% and 8.3% in patients treated

with colistin vs. plazomycin, respectively. Overall, more favorable safety profile was

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reported for plazomicin-treated patients compared with colistin when used as part of a

combination regimen for the treatment of life-threatening infections due to CRE.

A recent FDA briefing document on plazomicin has supported its role in cUTI based on

efficacy and safety data, but did not recognize substantial evidence for recommending

plazomicin use in BSI for patients with limited or no treatment options [103].

3.6 Cefiderocol

Cefiderocol is an investigational siderophore new cephalosporin antibiotic with activity

against CR organisms, including metallo-beta-lactamases producing strains. Cefiderocol

demonstrated a favorable side effect profile in clinical trials [104].

Cefiderocol has promising activity against GNB, including MDR Pseudomonas aeruginosa,

Acinetobacter baumannii, and Klebsiella pneumoniae [105]. The PK, safety, and tolerability

of cefiderocol after single and multiple dosing by IV infusion over 60 min in healthy adult

subjects were assessed in a Phase 1 trial [106]. Single-ascending doses of 100, 250, 500,

1000, and 2000 mg were administered in 40 healthy Japanese males and females (6 active

and 2 placebo per cohort). A multiple-ascending-dose study at doses of 1000 (two groups),

and 2000 mg every 8 h (q8h) was conducted in 30 healthy Japanese and Caucasian males (8

active and 2 placebo per cohort). There were no serious or clinically significant AEs

observed in either study. A single subject receiving 1000 mg cefiderocol withdrew from the

study due to AEs. In the single-dose study, 9 AEs in the cefiderocol groups were considered

potentially related to study treatment, including diarrhea, rash, abdominal pain, blood

present in urine, leukocytosis, and leukocyturia. In the multiple-dose study, 16 AEs reported

by 7 subjects in the cefiderocol 1000 mg group were considered possibly or probably related

to the study treatment, most common being rash (n=5 events), increased blood thyroid-

stimulating hormone (TSH) (n=3), and pyrexia (n=2). In the cefiderocol 1000 mg 2 and

2000 mg groups, 22 AEs were reported by 12 subjects. All of the AEs were mild in

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intensity, except for one, pyrexia, considered moderate. No deaths, SAEs, abnormal

electrocardiogram (ECG) findings were reported. Overall, there was no dose-related

association in the incidence of AEs. In a Phase 1 study encompassing 38 subjects,

cefiderocol were studied in patients with renal impairment (including various degree of renal

impairment and end�stage renal disease, ESRD, requiring hemodialysis) compared with

healthy controls following a single 1000 mg IV infusion [107]. Approximately 60% of

cefiderocol was removed by hemodialysis. The incidence of AEs did not correlate with the

degree of renal impairment and single 1000 mg intravenous doses of cefiderocol were

generally well tolerated in subjects with impaired renal function. No deaths or SAEs were

reported during the study. One subject from the moderate renal impairment cohort presented

with urticaria during administration, which led to discontinuation of the study medication

and was considered related to the study drug. Only nausea was reported as an AE by more

than one subject per cohort. AEs in various groups included 4 subjects (50%) in the

moderate impairment cohort, 3 (37.5%) in the ESRD cohort (predialysis, period 1), 2 (25%)

in the mild and severe impairment cohorts, and 1 (12.5%) each in the healthy and ESRD

cohorts.

3.7 Eravacycline

Eravacycline is a novel fluorocycline similar to tigecycline but not affected by resistance

mechanisms that cause tetracycline resistance, such as efflux pumps and ribosomal

protection proteins [108]. Eravacycline is characterized by a broad-spectrum activity against

both Gram-positive and Gram-negative bacteria, including MRSA, vancomycin-resistant

Enterococci, multidrug resistant Enterobacteriacae (e.g., ESBL, KPC and OXA) and

A.baumanii [109]. Eravacycline is in Phase 3 of clinical development for cIAI and cUTI and

showed efficacy of both intravenous and oral formulations, representing an attractive option

for step-down therapy in patients with infections due to MDR Gram-negative bacteria [110].

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A randomized, double-blind, multicenter study demonstrated eravacycline non-inferiority

compared to ertapenem in cIAI [111]. A Phase 1 study in 20 healthy adult volunteers

showed that eravacycline was well tolerated, with no serious adverse events and no

treatment discontinuations [112]. In the cIAI trial, eravacycline demonstrated an overall

favorable profile. Compared to ertapenem, patients in the eravacycline arm had higher

number of episodes of nausea and phlebitis (8.1% vs. 0.7% and 3% vs. 0.4%, respectively).

The number of patients who experienced treatment-emergent adverse events such as

vomiting, anemia, pyrexia, and diarrhea as well as the number of SAE was similar in the two

groups (n = 13) [111].

3.8 Omadacycline

Omadacycline is the first aminomethylcycline, a class of semisynthetic antibiotics related to

the tetracycline [113]. Similar to eravacycline, the chemical structure of omadacycline

allows to overcome the mechanisms of tetracycline resistance. Omadacycline is effective

against Gram-positive aerobes, including methicillin-resistant strains and Gram-negative

aerobes [114]. A Phase 3 trial comparing the efficacy and safety of intravenous and oral

omadacycline to moxifloxacin in patients with community-acquired pneumonia confirmed

omadacycline non-inferiority [115]. Omadacyline was generally safe and well tolerated with

overall safety profiles similar to that of moxifloxacin, but with low incidence of diarrhea and

no reported cases of C. difficile.

4. Conclusions

We have reviewed the most common AEs associated with “old” and newer molecules used

in the treatment of MDR GNB infection reported by clinical trials and real-world data.

Combination regimens based on “old” antibiotics appear limited by increased toxicity,

potential selection of further resistance, and suboptimal PK/PD. New compounds present

favorable safety data and promising efficacy in the treatment of MDR GNB infections,

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although definitive data is awaited.

5. Expert opinion

The increase in drug resistance among GNB represents a challenge for clinicians due to the

high mortality associated with these infections and the high risk of treatment failure. Recent

studies support the use of combination regimens, often including high-dose carbapenems or

nephrotoxic drugs such as colistin and/or gentamycin. The potential toxicity associated with

double or triple antimicrobial regimens along with limited safety data from real-world

studies on new compounds constitute an unmet clinical safety need.

Although colistin nephrotoxicity appeared less relevant than initially described, recent

reports of higher doses regimens used for PK/PD optimization (9 MIU followed by 4.5 MIU

every 12 hours compared to 3 MIU every 12 hours) have been associated with reduced CrCl.

Patients receiving high-dose colistin, especially if associated with other nephrotoxic drugs,

such as diuretics or aminoglycosides, require strict follow up, drug adjustments, and

aminoglycosides therapeutic drug monitoring (TDM). Furthermore, careful clinician’s

judgment is required to avoid treatment failure due to nephrotoxicity but also occurrence of

resistance or limited clinical response associated with colistin reduced or inappropriate

dosing. Fosfomycin appears well tolerated without relevant associated AEs. Tigecycline has

been classically associated with occurrence of nausea and vomiting that often require co-

administration of antiemetic drugs, but other relevant AEs are uncommon and no dose

adjustments are required in case of renal or hepatic impairment (Table 2). The use of

increased tigecycline doses (e.g., 100 mg every 12 hours instead of 50 mg every 12 hours) in

combination regimens against KPC-Kp infections has not been associated with a higher

occurrence of AEs. New compounds are now available for use in the treatment of infections

caused by MDR resistant P. aeruginosa (e.g., ceftolozane/tazobactam) and KPC-Kp (e.g.,

ceftazidime/avibactam), although not all resistant strains, in particular metallo-beta-

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lactamase-producing bacteria are not covered by these compounds. Safety and tolerability

data of new drugs from clinical trials appeared favorable or similar to comparators. Most

common adverse events reported among patients receiving ceftazidime/avibactam were

headache, gastrointestinal symptoms (e.g., abdominal pain, vomiting, nausea and

constipation), and infusion-site reactions. Recent reports analyzing ceftazidime/avibactam

efficacy among patients with KPC-Kp infections have reported the occurrence of early onset

of resistance to ceftazidime/avibactam during antimicrobial treatment. For this reason,

ceftazidime/avibactam has been often used in association with other “old” drugs with in

vitro activity against MDR GNB (e.g., carbapenems, aminoglyscosides, tigecycline), thus

posing a new concern of potential toxicity associated with combination therapies.

Ceftolozane/tazobactam AEs did not significantly differ from other cephalosporins,

including mainly nausea, diarrhea, headache, and pyrexia. A careful monitoring of creatinine

serum levels is recommended in patients receiving ceftolozane/tazobactam with renal

function changes during treatment. Other beta-lactams or beta-lactams/beta-lactamase

inhibitors (e.g., cefiderocol, imipenem/relebactam, meropenem/vaborbactam) did not

present significant tolerability concerns in clinical trials.

Plazomycin, a new aminoglycoside, appeared less nephrotoxic than colistin in recent trials.

Safety and tolerability of new compounds, however, need to be confirmed in future trials

and large real-world studies.

Funding

This paper has not been funded.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or

entity with a financial interest in or financial conflict with the subject matter or materials

discussed in the manuscript. This includes employment, consultancies, honoraria, stock

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ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to

disclose.

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Table 1. Recently developed molecules with activity against multidrug-resistant Gram-

negative bacteria approved for clinical use or in late stage of development [5,16].

Molecule Class Spectrum Clinical indication

Ceftolozane/ Tazobactam*

BLBLI

Enterobacteriaceae ESBL-producers, MDR P.

aeruginosa (no MBLs)

cIAI (in association with metronidazole),

cUTI

Ceftazidime/ Avibactam*

BLBLI

Carbapenem-resistant Enterobacteriaceae and

P. aeruginosa (no MBLs)

cIAI, cUTI, HAP, VAP

Cefiderocol Cephalosporin

Carbapenem-resistant (including MBLs),

Enterobacteriaceae, P. aeruginosa, MDR A.

baumannii

cIAI, cUTI, HAP, VAP

Imipenem/ relebactam

BLBLI Carbapenem-resistant Enterobacteriaceae (no

MBLs)

cIAI, cUTI, HAP, VAP

Meropenem/ Vaborbactam

* BLBLI

Carbapenem-resistant Enterobacteriaceae (no

MBLs) cUTI

Plazomycin Aminoglycosid

es

Carbapenem-resistant Enterobacteriaceae (no

MBLs)

cUTI, VAP and HAP (as

combination therapy)

BLBLI= beta-lactam/beta-lactamse inhibitor, MDR= multidrug resistant, ESBL= extended-spectrum beta-lactamases, MBLs= metallo-beta-lactamases, c=complicated, IAI= intra-abdominal infections, UTI= urinary tract infections, HAP= hospital acquired pneumonia, VAP= ventilator-associated pneumonia

* FDA approved

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Table 2. Adverse effects associated with old antimicrobials used for multidrug-resistant

Gram-negative infections and suggested management

Drug Reported adverse effects (incidence)

Characteristics Management References

Colistin • Neprotoxicity (mild, reversible 0-40%)

• Neurotoxicity (rare) • Bronchospasm

(inhaled, rare)

• Associated with high doses (4.5 MU q12h)

• Increased by concomitant causes of nephrotoxicity

• Dose adjustments • Renal function

monitoring • Avoid other causes of

nephrotoxicity (aminoglycosides, shock, hypoalbuminemia)

[26,27, 30,39]

Fosfomycin • IV formulation: reversible hyperkalemia (26%); increased Na intake

• Oral formulation: diarrhea (10%), nausea (5%), abdominal pain (2%), and dyspepsia (1–2%)

• Usually reversible and mild

• Na and K monitoring • Caution in patients

with cardiac failure and hemodialysis

[50,53]

Tigecycline • Nausea (30 to 55%) and vomiting (18 to 28%)

• Mild • Clinical monitoring • Concomitant

antiemetic medications

• Slow IV administration (>1 hour)

[55, 64-67]

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Table 3. Common adverse events and serious adverse events reported during relevant

clinical trials of new compounds used in the treatment of multidrug-resistant Gram-

negative infections

Drug Study type Common adverse

effects SAE (%) Reference

Plazomycin

Phase 3 randomized trial for BSI, HAP/VAP due to CRE vs. colistin (CARE)

Total AE (88.9 vs. 100) Renal-related (27.8 vs. 42.9)

Total 5.6 vs. 19 Renal 11.1 vs. 28.6

[101]

Cefiderocol

Phase 1 ascending single doses in healthy subjects Phase 1 ascending multiple doses in healthy subjects

Any (20), diarrhea (7), abdominal pain (3), rash (7) Any (75), diarrhea (12.5), abdominal pain (6), pyrexia (12.5), headache (6), rash (12.5)

None [106,107]

Ceftolozane/

tazobactam

Phase 3 CT/TAZ 1000/500 mg iv q8h vs. levofloxacin in cUTI (ASPECT-cUTI) Phase 3 CT/TAZ 1000/500 mg plus metronidazole vs. MER in cIAI (ASPECT-cIAI)

75 CAZ/AVI vs. 74 levofloxacin 44 CT/TAZ vs. 42.7 MER

19 CT/TAZ vs. 13 levofloxacin 8.1 CT/TAZ vs. 7.2 MER

[85,86]

Ceftazidime/

Avibactam

(CAZ/AVI)

Phase 2 CAZ/AVI 500/125 mg q8h vs. IMI/cilastatin in cUTI/pyelonephritis Phase 2 CAZ/AVI 2000/500 mg q8h + metronidazole vs. MER in cIAI Phase 3 CAZ/AVI 2000/500 mg iv q8h vs. MER (REPROVE) in HAP/VAP Phase 3 CAZ/AVI 2000/500 mg iv q8h

67.6 CAZ/AVI vs. 76.1 IMI 64.4 CAZ/AVI vs. 57.8 MER 75 CAZ/AVI vs. 74 MER 45.9 CAZ/AVI vs. 42.9 MER

8.8 CAZ/AVI vs. 3 IMI 8.9 CAZ/AVI vs. 10.8 MER 19.0 CAZ/AVI vs. 13.0 MER 7.9 CAZ/AVI vs. 7.6 MER

[77-81]

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vs. MER (RECLAIM) in cIAI Phase 3 CAZ/AVI 2000/500 mg iv q8h vs. MER (RECAPTURE) in cUTI

36.2 CAZ/AVI vs. 31.0 DOR

4.1 CAZ/AVI vs. 2.4 MER

Imipenem/

Relebactam

(IMI/REL)

Phase 2 REL 250 mg vs. 125 mg vs. placebo in cUTI Phase 2 (REL 250 mg vs. 125 mg vs. placebo in cIAI

28.3 REL 250 mg vs. 29.3 REL 125 mg vs. 30.0 placebo 48.7 REL 250 mg vs. 47.4 REL 125 mg vs. 41.2 placebo

N/A 3.4 REL 250 mg vs. 9.5 REL125 mg vs. 7.0 placebo

[94,95]

Meropenem/vaborb

actam (MER/VA

B)

Phase 3 MER/VAB (2g/2g) iv every 8h ± levofloxacin 500 mg every 24h vs. piperacillin/tazobactam (± levofloxacin 500 mg every 24h (TANGO1) in cUTI

39 MER/VAB vs. 35.5% levofloxacin

4.0 MER/VAB vs. 4.4 levofloxacin

[116]

AE= adverse events; SEA=serious adverse effects CAZ/AVI= ceftazidime/avibactam; CT/TAZ= ceftolozane/tazobactam; cUTI= complicated urinary tract infections; cIAI= complicated intra-abdominal infection; VAP= ventilator-associated pneumonia; cUTI= complicated urinary tract infections; IMI/REL= imipenem/relebactam MER/VAB= meropenem/vaborbactam

Acknowledgements: none

Conflict of interest: In the past five years MB has participated in advisory boards and/or received speaker honoraria from Achaogen, Angelini, Astellas, AstraZeneca, Bayer, Basilea, Cidara, Gilead, Melinta, Menarini, MSD, Nabriva, Paratek, Pfizer, Roche, The Medicine Company, Shionogi, Tetraphase, VenatoRX, and Vifor. The remaining authors have no conflicts of interest.

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