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Review

Resistance in Pseudomonas aeruginosa: A Narrative Review of Antibiogram Interpretation and Emerging Treatments

by
Federico Giovagnorio
1,
Andrea De Vito
2,*,
Giordano Madeddu
2,
Saverio Giuseppe Parisi
1 and
Nicholas Geremia
3,4,*
1
Department of Molecular Medicine, University of Padua, 35121 Padua, Italy
2
Unit of Infectious Diseases, Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy
3
Unit of Infectious Diseases, Department of Clinical Medicine, Ospedale “dell’Angelo”, 30174 Venice, Italy
4
Unit of Infectious Diseases, Department of Clinical Medicine, Ospedale Civile “S.S. Giovanni e Paolo”, 30122 Venice, Italy
*
Authors to whom correspondence should be addressed.
Antibiotics 2023, 12(11), 1621; https://doi.org/10.3390/antibiotics12111621
Submission received: 15 October 2023 / Revised: 2 November 2023 / Accepted: 10 November 2023 / Published: 12 November 2023
(This article belongs to the Special Issue Emerging Treatment Options for Multidrug-Resistant Bacterial and Fungal Infections)
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Abstract

:
Pseudomonas aeruginosa is a ubiquitous Gram-negative bacterium renowned for its resilience and adaptability across diverse environments, including clinical settings, where it emerges as a formidable pathogen. Notorious for causing nosocomial infections, P. aeruginosa presents a significant challenge due to its intrinsic and acquired resistance mechanisms. This comprehensive review aims to delve into the intricate resistance mechanisms employed by P. aeruginosa and to discern how these mechanisms can be inferred by analyzing sensitivity patterns displayed in antibiograms, emphasizing the complexities encountered in clinical management. Traditional monotherapies are increasingly overshadowed by the emergence of multidrug-resistant strains, necessitating a paradigm shift towards innovative combination therapies and the exploration of novel antibiotics. The review accentuates the critical role of accurate antibiogram interpretation in guiding judicious antibiotic use, optimizing therapeutic outcomes, and mitigating the propagation of antibiotic resistance. Misinterpretations, it cautions, can inadvertently foster resistance, jeopardizing patient health and amplifying global antibiotic resistance challenges. This paper advocates for enhanced clinician proficiency in interpreting antibiograms, facilitating informed and strategic antibiotic deployment, thereby improving patient prognosis and contributing to global antibiotic stewardship efforts.

1. Introduction

Pseudomonas aeruginosa, a ubiquitous Gram-negative bacterium from the Pseudomonadaceae family, has garnered considerable attention for its resilience and adaptability in many environments. Notably, it bears a relatively larger genome, ranging from 5.5 to 7 Mbp, giving it a remarkable metabolic versatility and enabling it to thrive and adapt to diverse environmental shifts, thereby contributing to its survival in varied habitats, including water, soil, and associations with animals [1,2]. Furthermore, the bacteria’s widespread presence in water sources, such as tap water and hand soap dispensers, has been associated with hospital outbreaks, indicating a pressing need for stringent hygiene measures and environmental control [3,4]. P. aeruginosa genotypes analysis has identified household environments, such as sinks and nebulizers, as potential sources of infection, necessitating vigilant monitoring and sanitation [3,4].
While P. aeruginosa’s environmental tenacity is noteworthy, its role as an opportunistic pathogen has raised significant concerns, particularly in hospital settings [5]. It is notorious for causing nosocomial infections and ventilator-associated pneumonia, primarily affecting immunocompromised individuals, severe burn victims, and patients with underlying health conditions such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) [6,7,8,9,10]. In particular, P. aeruginosa’s ability to form biofilms, coupled with its intrinsic, acquired, and adaptive resistance mechanisms, has rendered it a formidable adversary in the clinical setting [11,12,13,14]. It exhibits resistance to many antibiotics, including aminoglycosides, fluoroquinolones, and β-lactams, through mechanisms such as low outer membrane permeability, the expression of efflux pumps, and the production of antibiotic-inactivating enzymes [11,15,16,17]. Acquired resistance through horizontal gene transfer and mutations, along with adaptive resistance exemplified by biofilm formation and the emergence of persister cells, further complicate its treatment landscape [18].
Globally, the incidence of multidrug-resistant (MDR.) P. aeruginosa has exhibited an alarming upswing, posing considerable challenges to public health and clinical treatment [19,20]. The European Centre for Disease Prevention and Control (ECDC) has reported a varying prevalence of MDR P. aeruginosa, with some regions witnessing a heightened occurrence, underscoring the geographical disparity and the necessity for region-specific interventions [21]. The global landscape is similarly marked by a heterogeneous distribution of MDR strains, emphasizing the criticality of continuous surveillance and adaptive strategies to curb the spread of resistance [22]. The escalating challenge posed by P. aeruginosa has been accentuated by the World Health Organization (WHO), which has categorized carbapenem-resistant strains as being in critical need of new antibiotics [23]. The emergence of these strains has been associated with elevated morbidity and mortality, amplifying the urgency for innovative and effective therapeutic approaches [24]. These strategies include novel antibiotics and non-antibiotic therapeutic options, including phage therapy, nanoparticle application, and quorum sensing inhibition [25,26,27,28,29,30,31]. These strategies aim to augment or substitute conventional antibiotic treatments in addressing the rising tide of antibiotic resistance.
In prescribing antibiotics, it has become fundamental to discern the potential resistance mechanisms inherent in P. aeruginosa, enabling clinicians to determine the most effective antibiotic treatment for this type of infection. A pivotal tool in this endeavor is the analysis of antibiograms, as they reveal the sensitivity patterns of the bacteria, providing invaluable insights into the underlying resistance mechanisms. By meticulously examining these patterns, clinicians can infer the probable resistance strategies employed by P. aeruginosa, thereby guiding a more informed and targeted approach to antibiotic therapy, optimizing antibiotic stewardship, and improving patient outcomes.

2. Materials and Methods

A comprehensive literature search was conducted to identify relevant studies concerning the principal mechanisms of resistance in P. aeruginosa. The search strategy was implemented using online databases (Pubmed/MEDLINE), books written by experts in the fields of microbiology, infectious diseases, and ICU, and antibiograms collected from real-life cases. The search was not restricted by language or publication date and covered articles up to the cutoff date of October 2023. The following keywords and MeSH terms were used: “Pseudomonas aeruginosa AND mechanisms of resistance”, “Therapy strategies AND Pseudomonas aeruginosa”, “Antibiotic resistance AND Pseudomonas aeruginosa”, “Efflux pumps”, “Systematic review AND Pseudomonas aeruginosa”. Studies were included in this narrative review if they met the following criteria: studies reporting the in vitro activity of antibiotics active against P. aeruginosa; reviews reporting the mechanism of resistance of P. aeruginosa; studies reporting the prevalence of susceptibility and resistance to certain classes of antibiotics.
The search strategy had no time limits or language restrictions. We screened the articles by title, abstract, and full text. After an initial screening of titles and abstracts of published articles, the reviewers evaluated full articles to assess eligibility for each study’s inclusion in this narrative review. A study was included if it was likely to provide valid and valuable information according to the review’s objective.

3. Mechanisms of Resistance

3.1. Porins

The mechanisms of resistance in P. aeruginosa are various, with one of the most crucial being related to the permeability of the outer membrane and the efflux systems [32]. The P. aeruginosa outer membrane is highly restrictive, and this is due to its lower folder [33,34] and the regulated expression of specific outer membrane porins. One of those porins, OprF, exists in two conformations: the most frequent form, where the dominant structures of the porin are closed, and one where OprF exhibits open channels, which account for about 5% of this protein [35]. This system is unbalanced in favor of reduced permeability. Additionally, the loss of OprF is associated with biofilm formation [36], which gives bacteria a reduced susceptibility to antimicrobial agents, even without mechanisms such as enzymes or efflux pumps [37].
Another significant porin in P. aeruginosa is OprD, which plays a role in antibiotic uptake due to the carbapenem binding site, thereby increasing antibiotic resistance (Table 1) [38]. Specifically, gene mutations lead to a down-regulation in the expression of OprD, which typically gives resistance to imipenem (IMP) [39]. The susceptibility of meropenem (MEM) is variable, depending on the type of OprD gene mutations [40]. Furthermore, strains of P. aeruginosa with mutations in the OprD gene may exhibit elevated cefiderocol (FDC) minimum inhibitor concentration (MIC) [41].
P. aeruginosa can also express other porins, like OprH, the smallest produced. Its overexpression is linked to Mg2+ starvation, which confers modification and stabilization of the lipopolysaccharide (LPS) and ultimately confers resistance to Polymyxin B and Gentamicin (GM) [42,43].
Table 1. Phenotypic antibiogram of clinical strain P. aeruginosa, showing an OprD loss of function/downregulation.
Table 1. Phenotypic antibiogram of clinical strain P. aeruginosa, showing an OprD loss of function/downregulation.
P. aeruginosaBlood Culture
AntibioticMICSIR *
Meropenem/Vaborbactam=4/4S
Imipenem/Relebactam=2/2S
Amikacin=8.0S
Cefepime=4.0I
Ceftazidime=4.0I
Ceftazidime/Avibactam=2.0S
Ceftolozane/Tazobactam=1.0S
Ciprofloxacin=0.125I
Colistin=1.0S
Imipenem>8R
Meropenem=4I
Piperacillin/Tazobactam=8.0I
MIC = minimum inhibitory concentration; SIR = Susceptible (S), Susceptible, Iincreased Eexposure (I), and Resistant (R). * Breakpoint sec. Clinical breakpoints (v 13.1) [44]. Comment: phenotype resistance to imipenem, increased MIC of meropenem, and main-tained susceptibility to others common β-lactams. The phenotype could be compatible with OprD loss of functions/down-regulation.

3.2. Efflux Pump Systems

The efflux systems of P. aeruginosa play a pivotal role, representing a significant resistance mechanism. Six families of efflux pumps have been described in the literature: the small multidrug resistance (SMR) family; the major facilitator superfamily (MFS); the resistance/nodulation/cell division (RND) family; the ATP-binding cassette (ABC) superfamily; the multidrug and toxic compound extrusion (MATE) family [45,46]; and the proteobacterial antimicrobial compound efflux (PACE) family [47]. The co-expression of multiple pumps can lead to the MDR phenotype. In particular, the proteins belonging to the RND family are the most important for antibiotic resistance in P. aeruginosa [48]. These are called multidrug efflux (Mex) pumps, including MexXY, MexAB-OprM, MexCD-OprJ, and MexEF-OprN, all genetically encoded [49].
The Mex are composed of three distinct proteins: a periplasmatic adaptor protein, such as MexA, MexX, MexC, or MexE; a resistant-nodulation-cell division transporter (RNDt), like MexB, MexY, MexD, or MexF; and a channel-forming outer membrane factor (OMF), such as OprM, OprJ, or OprN (Table 2) [50]. Wild-type (WT) P. aeruginosa strains constitutively express MexAB-OprM, and its overexpression is correlated with resistance to various antibiotic classes, resulting in numerous phenotypes, including carbapenem-resistant P. aeruginosa (CRP) [51].
MexAB-OprM displays the broadest substrate profile among the efflux pump systems and, when overexpressed, can export fluoroquinolones (FQ) and almost all β-lactams (BL) (except IMP), including MEM (Table 3) [50,52,53,54].
Other antibiotics affected by MexAB-OprM are macrolides, tetracyclines, lincomycin, and chloramphenicol (14). Moreover, it has been shown that the overexpression of MexAB-OprM and AmpC, a chromosomally encoded C β-lactamase, has synergistic effects on the resistance of P. aeruginosa to most antipseudomonal BL, except for ceftolozane/tazobactam (TOL-TZB), IMP, and imipenem/elebactam (IMP-REL) [55]. It is also known that the overexpression of MexAB-OprM could contribute to FDC resistance [41]. The overexpression of MexAB-OprM and the downregulation of OprD are among of the most relevant causes of clinical resistance to MEM [54].
The MexXY efflux pump is the only one in P. aeruginosa that does not contain a coding sequence for an outer membrane factor, but usually forms a multidrug efflux pump with the OprM of the MexAB complex [56]. Its expression is inducible by antimicrobials, and it is regulated mainly by two regulatory systems [51]. Its role in antibiotic resistance is well known, especially for aminoglycosides [57]. MexXY overexpression is commonly paired with the expression of aminoglycoside-modifying enzymes (AMEs). These two mechanisms synergize, ultimately providing resistance to aminoglycosides (AMG) [58]. MexXY is also associated with resistance to most antipseudomonal antibiotics [53]. Furthermore, mutations occurring in the MexY are linked to resistance to FQ, AMG, and cefepime (FEP) [59].
The overexpression of MexAB-OprM and MexXY is frequent among clinical strains, accounting for up to 30% of cases (Table 4) [54]. MexCD-OprJ is a multidrug efflux pump encoded by an operon, typically silent or expressed at a low level in P. aeruginosa [60]. Several mutations can trigger the overexpression of this pump, generating multiple antibiotic resistance actions [61]. In this scenario, the main antibiotics affected are Penems and FQ, such as Ciprofloxacin and Levofloxacin [59,61]. Other antipseudomonal BL, like FEP, may also be impacted [62].
It is essential to highlight that mutations that occur in MexD can change the substrate of the efflux pump, resulting in resistance to carbenicillin [63] and ceftazidime-avibactam (CAZ-AVI) [64]. TOL-TZB is an important option against MDR P. aeruginosa and is typically unaffected by the efflux system’s substrate [64]. However, in the case of MexD mutation, TOL-TZB susceptibility may also be compromised [64].
MexEF-OprN, like MexCD-OprJ, is usually inactive, but in some circumstances, gene mutations can overexpress this efflux pump system. Its overexpression is associated with resistance to chloramphenicol, FQ, and trimethoprim [65]. However, the MexEF-OprN alone is not particularly relevant to confer an MDR profile to P. aeruginosa. Its overexpression is linked to genes that are involved in the downregulation of OprD [65], granting resistance to carbapenems [66,67] and Colistin (COL) [68].
Table 2. Efflux pump systems and their activity versus antibiotics.
Table 2. Efflux pump systems and their activity versus antibiotics.
Efflux SystemAntibiotics Affected by Altered Expression
MexAB-OprMAztreonam, β-lactams a, macrolides, tetracyclines, lincomycin, chloramphenicol, fluoroquinolones [11,50,54], higher in MIC or resistance to relebactam [69] could raise MIC of cefiderocol b [41].
MexXY-OprMAminoglycosides, cefepime, fluoroquinolones, tetracyclines and macrolides [53,59,69].
MexCD-OprJFluoroquinolones, penems, and cefepime [59,61,62], carbanecillin, piperacillin, ceftolozane/tazobactam, and ceftazidime/avibactam c [63,64].
MexEF-OprNChloramphenicol, fluoroquinolones, trimethoprim, colistin, and imipenem d [65,66,67,68].
a MexAB-OprM exports all β-lactams, except imipenem. b The overexpression of MexAB-OprM alone cannot provide straightforward resistance to cefiderocol. c Resistance to carbanecillin, piperacillin, ceftolozane/tazobactam, and ceftazidime/avibactam occurs with a specific mutation for MexD. d Resistance to imipenem due to the contemporary downregulation of OprD.
Table 3. Phenotypic antibiogram of clinical strain P. aeruginosa, compatible with an overexpression of MexAB-OprM.
Table 3. Phenotypic antibiogram of clinical strain P. aeruginosa, compatible with an overexpression of MexAB-OprM.
P. aeruginosaBlood Culture
AntibioticMICSIR *
Aztreonam>16R
Amikacin≤8.0S
Tobramycin≤2S
Cefepime=8I
Ceftazidime=8I
Ceftazidime/Avibactam=4.0S
Ceftolozane/Tazobactam=1.0S
Ciprofloxacin=0.125I
Colistin=1.0S
Imipenem≤1I
Meropenem=4I
Piperacillin/Tazobactam=64R
MIC = minimum inhibitory concentration; SIR = Susceptible (S), Susceptible, Iincreased Eexposure (I), and Resistant (R).* Breakpoint sec. Clinical breakpoints (v 13.1) [44]. Comment: phenotype resistance to aztreonam, ticarcillin and piperacillin/tazobactam, susceptibility of aminoglycosides, increased MIC to cephalosporines of third and fourth generations and to meropenem. This phenotype is compatible withto an overexpression of MexAB-OprM.
Table 4. Phenotypic antibiogram of clinical strain P. aeruginosa, compatible with an overexpression of MexXY-OprM, probably associated with the overexpression of OprH.
Table 4. Phenotypic antibiogram of clinical strain P. aeruginosa, compatible with an overexpression of MexXY-OprM, probably associated with the overexpression of OprH.
P. aeruginosaBlood Culture
AntibioticMICSIR *
Aztreonam≤8S
Amikacin>16R
Tobramycin>2R
Cefepime16R
Ceftazidime≤2I
Ceftazidime/Avibactam≤2.0S
Ceftolozane/Tazobactam≤1.0S
Ciprofloxacin>0.5R
Levofloxacin>2R
Colistin>4R
Imipenem≤1I
Meropenem≤0.125S
Piperacillin/Tazobactam8I
MIC = minimum inhibitory concentration; SIR = Susceptible (S), Susceptible, Iincreased Eexposure (I), and Resistant (R).* Breakpoint sec. Clinical breakpoints (v 13.1) [44].Comment: phenotype resistance to aminoglycosides, cefepime, fluoroquinolones and colistin, susceptibility to other common β-lactams. This phenotype is compatible with an overexpression of MexXY-OprM associated with the overexpression of OprH, which is notable due to the resistance to colistin.

3.3. Penicillin-Binding Protein Mutations

Penicillin-binding proteins (PBPs) are a group of periplasmatic enzymes involved in the polymerization, cross-linking, and modification of bacterial peptidoglycan [70,71]. PBPs are classified by their molecular weight into High-Molecular-Mass (HMM) and Low-Molecular-Mass (LMM) [72,73]. The HMM PBPs are defined as “essential penicillin-binding proteins”, playing a crucial role in the lifecycle of the bacteria by acting in the final phase of the peptidoglycan synthesis. These included PBP1a/PBP1b, PBP2, and PBP3 [73,74]. They are further classified into Class A (e.g., PBP1) and Class B (e.g., PBP2 and PBP3) [72].
The LMM PBPS are PBP4, PBP5, and PBP7 [72,73], further divided into Class C PBPs [72]. Research focusing on the correlation between PBPs and antibiotic resistance, particularly in P. aeruginosa, has not fully elucidated the role of LMM PBPs in antibiotic activity. For instance, PBP5 has demonstrated direct β-lactamase activity in P. aeruginosa [75]. Mutations in the nonessential dacB gene, which encodes PBP4, are associated with AmpC-overexpression, leading to high-level β-lactams (BL) resistance [73,76], specifically reducing the susceptibility of piperacillin (PIP), cefotaxime (CTX), CAZ, FEP, and aztreonam (AZT) [76]. Moreover, not all mutations occurring in genes that encode PBP4 have the same impact on the overexpression of AmpC. In detail, the DacB-DacC-PbpG triple mutant has been linked to the highest basal and induced ampC expression levels, ultimately leading to more resistance to BL [77]. Mutations occurring in PBP3 result in resistance to CAZ, FEP, PIP-TZB, TOL-TZB, CAZ-AVI, and MEM [73].
Finally, LMM PBPs play a role in the intrinsic resistance to BL regardless of the relationship with AmpC overexpression [77].
Another important aspect is the ability of the various BL antibiotics to bind to the PBPs, both in number and tightness. The carbapenem IMP exhibits the most significant activity against P. aeruginosa due to the number and affinity of the PBPs it binds to. In contrast, TOL shows a marked binding affinity to PBP3 [73]. Furthermore, a correlation has been observed between the relative binding affinity of specific PBPs for a particular antipseudomonal agent. This correlation is influenced by the relative abundance of each PBP, depending on the expression and the absence of others [74]. For instance, the absence of PBP1a leads to a higher affinity of CAZ, TOL, and IMP to PBP1b. Conversely, some strains of Pan-BL-resistant P. aeruginosa exhibit a 50% increase in inhibitory concentrations (IC50s) when compared to susceptible strains for IMP-binding PBP2 and CAZ-, TOL-, and IMP-binding PBP3 [74]. Despite ongoing research, a clear correlation between certain PBP modifications (such as PBP5 or PBP7) and the emergence of a frank BL resistance has not been established. This suggests that PBPs are part of a more complex system influencing antibiotic resistance [74,78].

3.4. Antibiotic Inactivating Enzymes

3.4.1. β-Lactamases

β-lactamases are enzymes that inactivate BL antibiotics by cleaving the amide bond of the BL ring. They are categorized into four classes according to Ambler’s classification, based on their amino-acid sequence similarity [79]. Classes A, C, and D utilize serine for substrate hydrolysis, while class B enzyme hydrolysis BL involves a metal ion, most commonly a zinc ion [80,81]. Classes of β-lactamases are summarized in Table 5. β-Lactamases are encoded by either chromosomal genes or transferable genes located on plasmids and transposons. Moreover, β-lactamase genes (bla) frequently reside on integrons, which often carry multiple resistance determinants. When mobilized by transposable elements, integrons can facilitate the further dissemination of MDR among different bacterial species [82].
β-lactam inhibitors (BLI) diminish the effectiveness of β-lactamases. This class includes clavulanic acid (CLA), sulbactam (SUL), TZB, AVI, Vaborbactam (VAB), and Relebactam (REL) [83,84]. AVI is active against classes A, C, and some enzymes of class D β-lactamases; VAB can inhibit class A β-lactamases and REL for Class A and Class C enzymes [84].
Only one BL has a high stability against hydrolysis by most beta-lactamases, including classes A, B, C, and D. Therefore, FDC represents a valid option against the P. aeruginosa XDR stain [85].

3.4.2. Class A β-Lactamases

P. aeruginosa can acquire additional β-lactamase through horizontal gene transfer, particularly class A enzymes such as sulfhydryl variable (SHV), Temoniera (TEM), cefotaxime-M (CTX-M), Belgium extended β-lactamase (BEL), Pseudomonas extended resistant (PER), Vietnam extended-spectrum β -lactamase (VEB), Klebsiella pneumoniae carbapenemase (KPC), and Guiana extended-spectrum β-lactamases (GES) families [86,87,88,89,90,91]. A novel class A carbapenemase, German Pseudomonas carbapenemase (GPC-1), was recently discovered in P. aeruginosa [92].
The most important Extended-Spectrum β-Lactamases (ESBLs) in P. aeruginosa include TEM, SHV, CTX-M, BEL, PER, and VEB (Table 6) [93]. ESBLs can hydrolyze extended-spectrum cephalosporins and AZT, but they do not degrade second-generation cephalosporins (for example, cefoxitin). CLA, SUL, TZB, AVI, VAB, and REL can inhibit these enzymes [90]. Among the PER family, PER-1 and PER-2 are the most common and are less inhibited by CLA, TZB, and AVI compared to other class A β-lactamases [94]. ESBL-producing strains typically conserve sensitivity to IMP, carboxypenicillins plus BLI, and ureidopenicillin plus BLI.
The identification of ESBL can be conducted with phenotypic screening tests using the Kirby–Bauer method with cephalosporin (for example, with CAZ) and monobactam discs [93,95]. Confirmation tests rely on the synergy between cephalosporins and CLA. One of the methods used is the combined disc method, which compares the diameters of the inhibition areas of a cephalosporin disc and a cephalosporin plus CLA disc. If the stain produces ESBL, the inhibition area of the disc containing CLA is at least 5 mm larger than the inhibition area of the disc without [93]. The synergy test can also be performed with an E-test (having CAZ/CTX on one half and CAZ/CTX plus CLA on the other half) or with ESBL-AGAR medium.
Among the GES enzymes, only variants with alterations at amino acid 170, changing glycine to asparagine or serine with a polar uncharged side chain, can degrade cephalosporins like CAZ, FEP, AZT, carbapenems [96], and TOL-TZB [97].
Isolates of P. aeruginosa strains with different ESBL expressions are summarized in Table 6. The antibiogram compatible with GES expression is reported in Table 7.
KPC is a potent serine carbapenemase encoded by the blaKPC gene. In 2007, an isolate of P. aeruginosa exhibiting high resistance to carbapenems and harboring blaKPC was reported in Medellin, Colombia [98]. Since then, additional reports of such isolates have been reported, mainly in the Americas and Asian countries [99]. KPC confers a broad antibiotic resistance spectrum, having the capability to hydrolyze broad-spectrum penicillins, oxymino-cephalosporins, cephamycins, and carbapenems [97]. New BLI, such as AVI, REL, and VAB, can inhibit KPC [100] enzymes.
The global distribution of KPC is illustrated in Figure 1.
Phenotypic detection could be aided by screening tests that evaluate the growth of P. aeruginosa in the presence of MEM or IMP. Confirmation phenotypical tests use MEM discs and MEM plus boronic acid discs. A 5 mm or larger diameter between the MEM disc and the MEM plus boronic acid disc proves that the strain produces a class A carbapenemase [84,101]. Genotypic approaches with polymerase chain reaction (PCR) can facilitate direct carbapenemase-type detection with low costs and resource utilization [102,103].
Another class A β-lactamase is PIB-1, encoded in the core genome, and it can degrade IMP [104].
Antibiotics 12 01621 g001
Figure 1. Worldwide distribution of the P. aeruginosa blaKPC isolates [105,106].
Figure 1. Worldwide distribution of the P. aeruginosa blaKPC isolates [105,106].
Antibiotics 12 01621 g001

3.4.3. Class B β-Lactamases

Metallo- β-lactamases (MBL) are subclassified into B1, B2, and B3, based on functional and structural factors [107,108]. The dominant subclass in P. aeruginosa is B1, which contains the most significant number of relevant acquired MBL enzymes. Class B β-lactamases utilize Zn2+ atoms for hydrolysis [108,109]. MBL activity is reduced in the presence of divalent ion chelators, such as ethylenediaminetetraacetic acid (EDTA) and dipicolinic acid [93,107]. The MBL detection is based on a 5 mm or larger difference between the MEM disc and the MEM plus EDTA disc [110]. Disc tests and the E-test® have been used for several decades, but have poor specificity and no robust data supporting their routine clinical use. Colorimetric tests probably offer the best-proven specificity at the moment. Still, no test appears sufficiently specific for routine use in clinical practice. Therefore, PCR should be preferred to detect carbapenemases (Table 8) [102,103].
MBLs hydrolyzed a broad spectrum of BL, such as penicillins, cephalosporins, and carbapenems, but do not affect monobactams. Additionally, BLIs do inhibit this class of enzymes [111]. FDC could be a valid option in MBL-producing P. aeruginosa strains [112,113]
Class B enzymes are the most prevalent carbapenemases produced by P. aeruginosa. Verona Integron-encoded MBL (VIM) and Imipenemases (IMP) are, respectively, the first and the second most common MBLs found in clinical isolates. New Delhi MBL (NDM) has also been identified in various P. aeruginosa isolates. Numerous other enzymes such as Australian imipenemase (AIM), Central Alberta M.B.L. (CAM), Dutch imipenemase (DIM), Florence imipenemase (FIM), German imipenemase (GIM), Hamburg M.B.L. (HMB), São Paulo M.B.L. (SPM), and Seoul imipenemase (SIM) have been reported [107].

3.4.4. Class C β-Lactamases

P. aeruginosa possesses a chromosomally encoded class C β-lactamase known as AmpC [114]. These enzymes are resistant to penicillins (PIP) and cephalosporins (CAZ, cefoxitin). They are not susceptible to BLI, such as CLA [115]. AmpC has a limited hydrolysis activity against FEP and is inhibited by cloxacillin and oxacillin [116]. AmpC does not affect carbapenems [117]. The cefoxitin sensitivity reduction represents the phenotypic non-standard screening method. Other phenotypic methods for identifying AmpC involve the use of cloxacillin and boronic acid [93]. Table 9 shows a possible antibiogram with AmpC expression.
AmpC enzymes’ regulation is mediated by the transcriptional regulator AmpR. During peptidoglycan synthesis, the uridine diphosphate–N-Acetylmuramic acid (UDP-NAM) pentapeptide binds to AmpR, resulting in a complex AmpR-AmpC that inhibits the transcription of AmpC. Peptidoglycan fragments are processed for recycling by NagZ, AmpD, and other enzymes.
The inhibition of PBPs increases the intracellular concentrations of the N-Acetylglucosamine (NAG)-NAM pentapeptide, NAM pentapeptide, and NAM tripeptide that saturate AmpD, raising the intracellular concentration of the AmpR-activating compounds causing the expression of AmpC. PBPs, particularly the PBP4 protein, can influence the cytoplasmic concentration of NAG-NAM. The depression of PBP4 levels is a significant inducer of AmpC expression [77]. Mutations in dacB, encoding PBP4, are common in BL-resistant isolates and can contribute to AmpC overexpression [74]. PBP4 inhibition also activates the CreBC signaling, a global regulator of bacterial fitness, biofilm development, and AmpC expression [118]. AmpR mutants contribute to BL resistance, inhibiting the UDP-NAM from binding to AmpR, leading to the constitutive expression of AmpC at high levels [119]. The P. aeruginosa strain with increasing BL resistance was also found in AmpD mutations [80].
AmpC variants can be hundreds, with unusual substrate specificities. They are considered the leading cause of resistance of clinical strains of P. aeruginosa to antipseudomonal penicillins and cephalosporins. These mutants are known as extended-spectrum AmpC (ESAC) or Pseudomonas-derived cephalosporinase (PDC). Additionally, AmpC mutations can reduce the affinity of inhibitors such as AVI, TZB, and REL for AmpC [80,120,121]. Some AmpC mutants in Enterobacterales can also increase in FDC MICs by >32-fold, and this variant may contribute in part to the FDC-resistant P. aeruginosa phenotypes. The presence of some PDC with substitutions in the region of the AmpC omega loop contributes to reducing the activity of TOL-TZB, CAZ-AVI, and FDC. However, these strains potentially increase susceptibility to IMI-REL [122,123].
Transferable Class C enzymes, originating from chromosomal enzymes transferred to mobile elements, are relatively rare, but some have emerged through horizontal gene transfer, including FOX-4 and CMY-2 [80].
An example of an antibiogram with AmpC mutants is reported in Table 10.

3.4.5. Class D β-Lactamases

Class D β-lactamases encompass the OXA family, so named due to their high activity against oxacillin [124]. This superfamily of serine β-lactamases can degrade all BL [125]. OXA-10-like was the first enzyme of this class discovered in P. aeruginosa. It presented the ability to confer resistance to CAZ [126]. In a recent study, OXA-like enzymes showed higher prevalence, with 15.4% of P. aeruginosa isolates harboring OXA β-lactamases [127]. In P. aeruginosa, isolates have also been detected of OXA-9, which have the uncommon property of being inhibited by CLA and cloxacillin [128], OXA-13, OXA-17, OXA-18, OXA-20 [129], and OXA-31, which possesses the ability to hydrolyze FEP and cefpirome slightly [130].
Carbapenem-hydrolyzing Class D (CHDL) enzymes have relatively low activity against carbapenems and are not effectively inhibited by EDTA or CLA. In P. aeruginosa, the principal CHDL identified belonged to groups such as OXA-40-like, OXA-48-like, OXA-50-like, and OXA-198-like [107,131]. Less common CHDLs, such as OXA-23-like, have been associated with MDR phenotypes.
Certain enzymes can impact the susceptibility of newer anti-MDR cephalosporins. Enzymes such as OXA-2, OXA-46 and four variants of the OXA-10 subgroup can cause an 8-fold to 32-fold increase in FDC MICs. In P. aeruginosa encoding OXA-19 (derived from the OXA-10 subgroup), there is a significant reduction in the activity of CAZ, CAZ-AVI, TOL-TZB, and FDC. New CHLDs, such as OXA-539, can determine resistance to third–fourth generation cephalosporins, CAZ-AVI and TOL-TZB [132]

3.5. Interference with Antibacterial Agents

Modifying the antibiotic target is one of the most common strategies bacteria employ to evade the effects of antimicrobials. FQ inhibits bacterial DNA replication by targeting DNA gyrase and topoisomerase IV. Mutations in gyrA, gyrB (for DNA gyrase), parC, and par E (for topoisomerase IV) cause a reduced affinity for FQ to these two proteins [11].
Resistance to FQ can also be plasmid-mediated (PMQR). Three PMQR-mediated mechanisms were recognized, including qnr genes, the acetyltransferase aac(6′)-Ib-cr, and active efflux pumps such as QepA and OqxAB10,11 [133]. The qnr genes interfere with the binding of FQ to their protein targets [134].
Ribosomal mutations contribute significantly to resistance against aminoglycosides and polymyxins. Polymyxin resistance in P. aeruginosa was associated with the modification of the polymyxin-binding partner LPS by the addition of 4-amino-L-arabinose (L-Ara4N) to the phosphate groups within the lipid A moiety of LPS. Moreover, mutations in PhoPQ and PmrAB regulatory systems promoted the modification of aminoarabinose addition to lipid A, leading to enhanced Polymyxin resistance [11].

3.6. Fosfomycin Resistance Mechanisms

Fosfomycin (FOS) is an old antibiotic with activity against both Gram-positive and Gram-negative bacteria, including P. aeruginosa [135]. FOS is transported into the bacterial cells via GlpT and UhpT, glycerol-3-phosphate and glucose-6-phosphate symporters, respectively. Once inside the cell, FOS inhibits MurA activity, a crucial enzyme involved in transferring phosphoenolpyruvate (PEP) to the 30-hydroxyl group of UDP-N-acetylglucosamine, an initial step for bacterial cell wall biosynthesis [136,137,138]. A peculiarity of this drug is its enhanced efficacy under anaerobic conditions, unlike many antibiotics, whose activity diminishes in such environments [139,140,141,142].
P. aeruginosa harbors the gen fosA in the chromosome, encoding an enzyme that inactivates FOS [143,144]. Notably, P. aeruginosa lacks the genes encoding for the UhpT transporter, making FOS uptake solely dependent on the GlpT transporter [145,146]. However, P. aeruginosa infections often occur in oxygen-reduced environments, primarily when biofilm production occurs [147,148]. In these conditions, FOS is more active against P. aeruginosa [142]. In treating P. aeruginosa infections, FOS can be used in combination therapy due to its synergistic activity with lots of antipseudomonal antibiotics [149,150,151]. Furthermore, it is an essential drug against MDR P. aeruginosa due to its unique structure, which is dissimilar to other antipseudomonal agents, allowing it to retain its activity [152].

4. New Treatment Options

Managing P. aeruginosa infections has always been a clinical challenge due to its intrinsic and acquired resistance mechanisms. Traditionally, the primary treatment approach was monotherapy with antipseudomonal agents such as FQ, PIP-TZB, or carbapenems [153,154,155]. However, the emergence of MDR strains has prompted a shift towards combination therapy [156]. Due to their synergistic effects, common combinations include β-lactam agents with aminoglycosides or FQ [157]. Another reason for using combination therapy is to counter the bacteria’s ability to form biofilms, which are inherently resistant to many antibiotics. It is also crucial to consider the phenomenon of inducible resistance, where the bacteria can upregulate specific resistance genes in response to certain antibiotics [158]. This review will further discuss the different types of resistance mechanisms.
The rise of MDR strains has necessitated the development of new antibiotics. Notable additions to the therapeutic arsenal include TOL-TZB, CAZ-AVI, IMI-REL, and FDC.
TOL-TZB (Zerbaxa®) is a novel antibiotic combination with a next-generation cephalosporin and TZB, a suicidal BLI [159]. This combination has an enhanced affinity for PBPs and potent activity against P. aeruginosa, including ESBL and AmpC-producing strains [160]. Clinical studies have emphasized its efficacy against Pseudomonas infections, especially in complicated urinary tract (cUTI) and intra-abdominal infections (cIAI) [161]. Caston et al. treated 20 infections caused by P. aeruginosa MDR with TOL-TZB, which included 12 cases of septic shock, 6 cases of pneumonia, 1 case of otomastoiditis, and 1 Central Line-associate Bloodstream Infection (CLABSI), reporting a clinical success rate of 75% [162]. Gallagher et al. treated 205 infections caused by P. aeruginosa MDR, primarily pneumonia (59%), and reported a clinical success rate of 74%. Interestingly, they highlighted the importance of the prompt administration of TOL-TZB (within four days), identifying it as a predictor of clinical success [163]. This observation aligns with previous studies that associated a delay in initiating effective antibacterial therapy with increased mortality in serious bacterial infections, including HAP [164,165].
An observational study involving 200 patients compared the outcomes of a TOL-TZB-based regimen versus polymyxin or aminoglycoside-based therapy [166]. In this study, a favorable clinical outcome was observed in 81% of patients in the TOL-TZB arm versus 61% of patients in the polymyxin- or aminoglycoside-based regimen arm. This difference was statistically significant.
Recently, an ASPECT-NP study involving patients with nosocomial pneumonia caused by Gram-negative pathogens was published. Pneumonia is the most frequent healthcare-associated infection acquired in the Intensive Care Unit (ICU), with high mortality rates [167,168,169]. Hospital-acquired pneumonia (HAP) can be distinguished as ventilator-associated pneumonia (VAP) or hospital-acquired ventilator-requiring pneumonia (vHAP) [170]. Within HAP, vHAP has the highest mortality [167,171].
The ASPECT-NP trial demonstrated the noninferiority of TOL-TZB to MEM for treating vHAP and VAP in both the primary endpoint of 28-day all-cause mortality and the secondary endpoint of clinical cure at the test-of-cure visit, respectively [172]. In the subgroup of vHAP, the ASPECT-NP trial also demonstrated lower mortality in the arm of patients treated with TOL-TZB compared with the arm of patients treated with MEM [172]. This result was further evaluated with multivariable analysis by Kollef et al., confirming the protective effect of TOL-TZB in this special subgroup population [173], although additional studies are needed for confirmation of these findings.
The distinct pharmacological profile of TOL-TZB, marked by enhanced activity against P. aeruginosa, makes it a valuable option where resistant Pseudomonas strains are prevalent or suspected [174,175].
CAZ-AVI (Zavicefta®) combines CAZ, a third-generation cephalosporin with potent antipseudomonal activity, and AVI, a non-BL/BLI [176]. AVI effectively neutralizes a broad spectrum of β-lactamases, including carbapenemases like KPC, OXA-48 [177], and GES [170]. Horcajada et al. reported in vitro susceptibility to CAZ-AVI ranging from 66% to 86% for MDR P. aeruginosa strains collected from all over the world [178].
In the literature, some studies have highlighted the efficacy of CAZ-AVI in treating various infections due to MDR P. aeruginosa, from cUTIs to HAP [179,180,181]. However, clinical trials involving CAZ-AVI treatments are scarce. Stone et al. reported pooled data from five Randomized Controlled Trials (RCTs), showing a favorable clinical outcome in patients treated with CAZ-AVI versus patients treated with more traditional treatment, albeit within the limitations of the study [182].
Nevertheless, the literature concerning the real-world use of CAZ-AVI is spreading. Several studies have been published, underlying positive outcomes in favor of CAZ-AVI in treating MDR P. aeruginosa infections [183].
The Infectious Diseases Society of America (IDSA) indicates CAZ-AVI as one of the drugs of choice in the treatment of MDR and difficult-to-treat (DTR)-P. aeruginosa strains, both in urinary tract infections and outside urinary tract infections, when tested susceptible [184].
FDC (Fetcroja®) is a siderophore cephalosporin with a unique penetration mechanism. It utilizes the iron-transport mechanism to penetrate bacterial cells, making it active against a broad spectrum of Gram-negative microorganisms, including CRP [185,186]. It is also effective against MBL. Hacket et al. demonstrated in vitro its activity against most MDR P. aeruginosa (99.2%), including those resistant to CAZ-AVI and TOL-TZB [187]. Lasarte-Monterrubio et al. evaluated the in vitro activity of FDC (and other novel antibiotic combinations) against strains of P. aeruginosa specifically resistant to CAZ-AVI and TOL-TZB [188], showing that FDC was the most active agent.
The SIDERO surveillance program, conducted between 2014 and 2019, showed a susceptibility rate to FDC of CRP strains of 99.8%, according to CLSI breakpoints [189].
The randomized APESK-cUTI demonstrated the non-inferiority of FDC versus IMP-REL in the treatment of complicated urinary tract infections in hospitalized patients for the primary endpoint of composite microbiological eradication and clinical cure at the test-of-cure visit [190].
In the APESK-NP study evaluating the efficacy and safety of FDC for the treatment of nosocomial Gram-negative pneumonia, FDC demonstrated non-inferiority to the MEM treatment. Of all the cases, P. aeruginosa represented the second most common pathogen in the FDC arm. Clinical success was achieved in 67% of pneumonia cases caused by P. aeruginosa, without statistical difference from the pneumonia cases caused by P. aeruginosa in the MEM arm [191].
However, further studies on its efficacy in real life are needed to better assess its effectiveness.
IMP-REL (Recarbrio®) combines IMP, a carbapenem approved in 1985, and REL, a BLI that enhances IMP’s activity by protecting it from enzymatic degradation. This combination is active against class A and class C β-lactamases. On the other hand, it is ineffective against OXA-48 and MBLs [192].
The SMART study, a surveillance study conducted in several countries across the world, assessed the susceptibility of IMP-REL [193]. Furthermore, Lob et al. showed that the addition of REL restored the activity of IMP against P. aeruginosa strains resistant to IMP alone.
Mushtaq et al. collected P. aeruginosa clinical strains producing ESBL and Carbapenemases, showing an 80.5% susceptibility for IMP-REL [194]. In this study, the main mechanism of resistance was the production of beta-lactamases not susceptible to inhibition by REL, such as MBLs, OXAs, and GES.
In the RESTORE-IMI clinical trial, IMP-REL demonstrated greater efficacy than COL/MEM against P. aeruginosa infection (81% vs. 63%). However, this difference was not statistically significant due to the small sample size [195].
The RESTORE-IMI 2 clinical trial, a randomized, double-blind controlled trial, was conducted to assess the efficacy of IMP-REL in adult patients with HAP/VAP [196]. IMP-REL was non-inferior to the comparator (PIP-TZB) for both endpoints (day 28 all-cause mortality and favorable clinical response at early follow-up). In this study, P. aeruginosa was the second most abundant pathogen isolated.
IDSA guidelines recommend IMP-REL as one of the drugs of choice in the treatment of cUTIs and infections outside the urinary tract due to DTR P. aeruginosa strains when tested as susceptible [184].
In addition, promising antibiotics are coming into the pipeline, such as cefepime/enmetazobactam, cefepime/zidebactam, cefepime/taniborbactam, and plazomicine.
These FEP-based antibiotics had broad-spectrum activity against Gram-positive and Gram-negative bacteria. The distinguishing factor is the specific BLI paired with FEP to shield it from enzymatic degradation. While all four inhibitors fall under the category of next-generation BLI, Enmetazobactam is classified as a penicillanic acid sulfone, Taniborbactam as a boronic acid derivative, and Zidebactam as a diazabicyclooctane [197]. Their effectiveness is still being evaluated, but the clinical trials have yielded promising results [198,199,200]. However, no real-life studies compare these three molecules [201]. J Vázquez-Ucha et al. assessed the in vitro efficacy of these molecules, finding that cefepime/zidebactam was the most potent combination against carbapenemase-producing Enterobacterales, followed by cefepime/taniborbactam and cefepime/enmetazobactam. Furthermore, Moya et al. highlighted that zidebactam alone has significant activity against P. aeruginosa. This effect is due to the inhibition of PBP2, leading to the creation of spheroplasts, the disruption of the outer membrane, and, as a result, protection against common membrane-bound resistance mechanisms exhibited by P. aeruginosa [197].
Plazomicin is a next-generation aminoglycoside antibiotic synthetically derived from sisomicin [202]. It works by inhibiting bacterial protein synthesis, leading to dose-dependent bactericidal activity. One of its significant advantages is its activity against bacterial strains harboring clinically relevant AMEs [203]. However, it is worth noting that plazomicin is not active against bacterial isolates expressing ribosomal methyltransferases, which can lead to aminoglycoside resistance [203]. Focusing on P. aeruginosa, plazomicin has shown promising data [204]. The antibiotic demonstrates synergistic activity when combined with other agents like FEP, Doripenem, IMP, or PIP/TZB [205].

5. Conclusions

Managing P. aeruginosa infections remains a formidable challenge in the clinical setting, primarily due to the bacterium’s intrinsic and acquired resistance mechanisms. While traditional monotherapies have served as the cornerstone of treatment, the rise of multidrug-resistant strains has necessitated a shift towards combination therapies and the development of new antibiotics. The judicious use of antibiotics, guided by accurate antibiograms, is paramount. Understanding the myriad of resistance mechanisms employed by P. aeruginosa is essential for the effective treatment of patients. The correct interpretation of antibiograms allows for the selection of the most suitable antibiotic therapy, enhancing patient outcomes and minimizing the risk of treatment failure. Conversely, misinterpretation can lead to inappropriate antibiotic use, inadvertently promoting the selection of resistant strains and exacerbating the global issue of antibiotic resistance. Such mistakes jeopardize individual patient outcomes and have broader implications for public health. As the battle against P. aeruginosa continues, this review aims to equip readers with the knowledge to interpret antibiograms accurately, fostering better clinical decision-making. Further studies are essential to elucidate the efficacy of new antibiotics against P. aeruginosa, enabling a deeper understanding of how to strategically deploy these drugs against this resilient bacterium. Such knowledge is pivotal to prevent the emergence of new resistance mechanisms, ensuring the sustained effectiveness of our therapeutic arsenal.

Author Contributions

Conceptualization F.G. and N.G.; methodology, N.G., A.D.V., and N.G.; validation F.G., A.D.V., G.M., S.G.P., and N.G.; investigation, N.G.; writing—review and editing, F.G., A.D.V., and N.G.; supervision, G.M., S.G.P., and N.G.; writing—original draft preparation, F.G., A.D.V., and N.G.; writing—review and editing, F.G., A.D.V., and N.G. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

References

  1. Moradali, M.F.; Ghods, S.; Rehm, B.H.A. Pseudomonas aeruginosa Lifestyle: A Paradigm for Adaptation, Survival, and Persistence. Front. Cell. Infect. Microbiol. 2017, 7, 39. [Google Scholar] [CrossRef]
  2. Lewenza, S.; Abboud, J.; Poon, K.; Kobryn, M.; Humplik, I.; Bell, J.R.; Mardan, L.; Reckseidler-Zenteno, S. Pseudomonas aeruginosa Displays a Dormancy Phenotype during Long-Term Survival in Water. PLoS ONE 2018, 13, e0198384. [Google Scholar] [CrossRef] [PubMed]
  3. Hutchins, C.F.; Moore, G.; Thompson, K.A.; Webb, J.; Walker, J.T. Contamination of Hospital Tap Water: The Survival and Persistence of Pseudomonas aeruginosa on Conventional and “antimicrobial” Outlet Fittings. J. Hosp. Infect. 2017, 97, 156–161. [Google Scholar] [CrossRef] [PubMed]
  4. Lanini, S.; D’Arezzo, S.; Puro, V.; Martini, L.; Imperi, F.; Piselli, P.; Montanaro, M.; Paoletti, S.; Visca, P.; Ippolito, G. Molecular Epidemiology of a Pseudomonas aeruginosa Hospital Outbreak Driven by a Contaminated Disinfectant-Soap Dispenser. PLoS ONE 2011, 6, e17064. [Google Scholar] [CrossRef]
  5. Kelsey, M. Pseudomonas in Augmented Care: Should We Worry? J. Antimicrob. Chemother. 2013, 68, 2697–2700. [Google Scholar] [CrossRef] [PubMed]
  6. Lieberman, D.; Lieberman, D. Pseudomonal Infections in Patients with COPD: Epidemiology and Management. Am. J. Respir. Med. 2003, 2, 459–468. [Google Scholar] [CrossRef]
  7. Davies, J.C. Pseudomonas aeruginosa in Cystic Fibrosis: Pathogenesis and Persistence. Paediatr. Respir. Rev. 2002, 3, 128–134. [Google Scholar] [CrossRef] [PubMed]
  8. Holder, I.A.P. aeruginosa Burn Infections: Pathogenesis and Treatment. In Pseudomonas aeruginosa as an Opportunistic Pathogen; Springer: Berlin/Heidelberg, Germany, 1993; pp. 275–295. [Google Scholar] [CrossRef]
  9. Ramírez-Estrada, S.; Borgatta, B.; Rello, J. Pseudomonas aeruginosa Ventilator-Associated Pneumonia Management. Infect. Drug Resist. 2016, 9, 7. [Google Scholar] [CrossRef] [PubMed]
  10. Yang, Y.W.; Jiang, Y.Z.; Hsu, C.M.; Chen, L.W. Pseudomonas aeruginosa Ventilator-Associated Pneumonia Induces Lung Injury through TNF-α/c-Jun NH2-Terminal Kinase Pathways. PLoS ONE 2017, 12, e0169267. [Google Scholar] [CrossRef]
  11. Pang, Z.; Raudonis, R.; Glick, B.R.; Lin, T.J.; Cheng, Z. Antibiotic Resistance in Pseudomonas aeruginosa: Mechanisms and Alternative Therapeutic Strategies. Biotechnol. Adv. 2019, 37, 177–192. [Google Scholar] [CrossRef] [PubMed]
  12. Okamoto, K.; Gotoh, N.; Nishino, T. Pseudomonas aeruginosa Reveals High Intrinsic Resistance to Penem Antibiotics: Penem Resistance Mechanisms and Their Interplay. Antimicrob. Agents Chemother. 2001, 45, 1964. [Google Scholar] [CrossRef]
  13. Poole, K. Pseudomonas aeruginosa: Resistance to the Max. Front. Microbiol. 2011, 2, 65. [Google Scholar] [CrossRef] [PubMed]
  14. Thi, M.T.T.; Wibowo, D.; Rehm, B.H.A. Pseudomonas aeruginosa Biofilms. Int. J. Mol. Sci. 2020, 21, 8671. [Google Scholar] [CrossRef] [PubMed]
  15. Langendonk, R.F.; Neill, D.R.; Fothergill, J.L. The Building Blocks of Antimicrobial Resistance in Pseudomonas Aeruginosa: Implications for Current Resistance-Breaking Therapies. Front. Cell Infect. Microbiol. 2021, 11. [Google Scholar] [CrossRef] [PubMed]
  16. Angus, B.L.; Carey, A.M.; Caron, D.A.; Kropinski, A.M.; Hancock, R.E. Outer Membrane Permeability in Pseudomonas aeruginosa: Comparison of a Wild-Type with an Antibiotic-Supersusceptible Mutant. Antimicrob. Agents Chemother. 1982, 21, 299–309. [Google Scholar] [CrossRef] [PubMed]
  17. Janda, J.M.; Bottone, E.J. Pseudomonas aeruginosa Enzyme Profiling: Predictor of Potential Invasiveness and Use as an Epidemiological Tool. J. Clin. Microbiol. 1981, 14, 55. [Google Scholar] [CrossRef] [PubMed]
  18. Michaelis, C.; Grohmann, E. Horizontal Gene Transfer of Antibiotic Resistance Genes in Biofilms. Antibiotics 2023, 12, 328. [Google Scholar] [CrossRef]
  19. Peng, Y.; Shi, J.; Bu, T.; Li, Y.; Ye, X.; Chen, X.; Yao, Z. Alarming and Increasing Prevalence of Multidrug-Resistant Pseudomonas aeruginosa among Healthcare-Associated Infections in China: A Meta-Analysis of Cross-Sectional Studies. J. Glob. Antimicrob. Resist. 2015, 3, 155–160. [Google Scholar] [CrossRef]
  20. Yang, A.F.; Huang, V.; Samaroo-Campbell, J.; Augenbraun, M. Multi-Drug Resistant Pseudomonas Aeruginosa: A 2019–2020 Single Center Retrospective Case Control Study. Infect. Prev. Pract. 2023, 5, 100296. [Google Scholar] [CrossRef] [PubMed]
  21. ECDC. Antimicrobial Resistance Surveillance in Europe; ECDC: Solna, Sweden, 2022.
  22. Reyes, J.; Komarow, L.; Chen, L.; Ge, L.; Hanson, B.M.; Cober, E.; Herc, E.; Alenazi, T.; Kaye, K.S.; Garcia-Diaz, J.; et al. Global Epidemiology and Clinical Outcomes of Carbapenem-Resistant Pseudomonas aeruginosa and Associated Carbapenemases (POP): A Prospective Cohort Study. Lancet Microbe 2023, 4, e159–e170. [Google Scholar] [CrossRef] [PubMed]
  23. Tacconelli, E.; Carrara, E.; Savoldi, A.; Harbarth, S.; Mendelson, M.; Monnet, D.L.; Pulcini, C.; Kahlmeter, G.; Kluytmans, J.; Carmeli, Y.; et al. Discovery, Research, and Development of New Antibiotics: The WHO Priority List of Antibiotic-Resistant Bacteria and Tuberculosis. Lancet Infect. Dis. 2018, 18, 318–327. [Google Scholar] [CrossRef]
  24. Sathe, N.; Beech, P.; Croft, L.; Suphioglu, C.; Kapat, A.; Athan, E. Pseudomonas aeruginosa: Infections and Novel Approaches to Treatment “Knowing the Enemy” the Threat of Pseudomonas aeruginosa and Exploring Novel Approaches to Treatment. Infect. Med. 2023, 2, 178–194. [Google Scholar] [CrossRef]
  25. Duplantier, M.; Lohou, E.; Sonnet, P. Quorum Sensing Inhibitors to Quench P. aeruginosa Pathogenicity. Pharmaceuticals 2021, 14, 1262. [Google Scholar] [CrossRef] [PubMed]
  26. Salomoni, R.; Léo, P.; Montemor, A.F.; Rinaldi, B.G.; Rodrigues, M.F.A. Antibacterial Effect of Silver Nanoparticles in Pseudomonas aeruginosa. Nanotechnol. Sci. Appl. 2017, 10, 115–121. [Google Scholar] [CrossRef] [PubMed]
  27. Köhler, T.; Luscher, A.; Falconnet, L.; Resch, G.; McBride, R.; Mai, Q.A.; Simonin, J.L.; Chanson, M.; Maco, B.; Galiotto, R.; et al. Personalized Aerosolised Bacteriophage Treatment of a Chronic Lung Infection Due to Multidrug-Resistant Pseudomonas aeruginosa. Nat. Commun. 2023, 14, 3629. [Google Scholar] [CrossRef]
  28. Vaitekenas, A.; Tai, A.S.; Ramsay, J.P.; Stick, S.M.; Kicic, A. Pseudomonas aeruginosa Resistance to Bacteriophages and Its Prevention by Strategic Therapeutic Cocktail Formulation. Antibiotics 2021, 10, 145. [Google Scholar] [CrossRef] [PubMed]
  29. Losito, A.R.; Raffaelli, F.; Del Giacomo, P.; Tumbarello, M. New Drugs for the Treatment of Pseudomonas aeruginosa Infections with Limited Treatment Options: A Narrative Review. Antibiotics 2022, 11, 579. [Google Scholar] [CrossRef] [PubMed]
  30. Kunz Coyne, A.J.; El Ghali, A.; Holger, D.; Rebold, N.; Rybak, M.J. Therapeutic Strategies for Emerging Multidrug-Resistant Pseudomonas aeruginosa. Infect. Dis. Ther. 2022, 11, 661. [Google Scholar] [CrossRef]
  31. Marino, A.; Stracquadanio, S.; Campanella, E.; Munafò, A.; Gussio, M.; Ceccarelli, M.; Bernardini, R.; Nunnari, G.; Cacopardo, B. Intravenous Fosfomycin: A Potential Good Partner for Cefiderocol. Clinical Experience and Considerations. Antibiotics 2022, 12, 49. [Google Scholar] [CrossRef] [PubMed]
  32. Ayoub Moubareck, C.; Hammoudi Halat, D.; Akkawi, C.; Nabi, A.; AlSharhan, M.A.; AlDeesi, Z.O.; Peters, C.C.; Celiloglu, H.; Karam Sarkis, D. Role of Outer Membrane Permeability, Efflux Mechanism, and Carbapenemases in Carbapenem-Nonsusceptible Pseudomonas aeruginosa from Dubai Hospitals: Results of the First Cross-Sectional Survey. Int. J. Infect. Dis. 2019, 84, 143–150. [Google Scholar] [CrossRef]
  33. Bellido, F.; Martin, N.L.; Siehnel, R.J.; Hancock, R.E. Reevaluation, Using Intact Cells, of the Exclusion Limit and Role of Porin OprF in Pseudomonas aeruginosa Outer Membrane Permeability. J. Bacteriol. 1992, 174, 5196–5203. [Google Scholar] [CrossRef] [PubMed]
  34. Hancock, R.E.W.; Brinkman, F.S.L. Function of Pseudomonas Porins in Uptake and Efflux. Annu. Rev. Microbiol. 2002, 56, 17–38. [Google Scholar] [CrossRef] [PubMed]
  35. Sugawara, E.; Nestorovich, E.M.; Bezrukov, S.M.; Nikaido, H. Pseudomonas aeruginosa Porin OprF Exists in Two Different Conformations. J. Biol. Chem. 2006, 281, 16220–16229. [Google Scholar] [CrossRef] [PubMed]
  36. Bouffartigues, E.; Moscoso, J.A.; Duchesne, R.; Rosay, T.; Fito-Boncompte, L.; Gicquel, G.; Maillot, O.; Bénard, M.; Bazire, A.; Brenner-Weiss, G.; et al. The Absence of the Pseudomonas aeruginosa OprF Protein Leads to Increased Biofilm Formation through Variation in C-Di-GMP Level. Front. Microbiol. 2015, 6, 630. [Google Scholar] [CrossRef]
  37. Stewart, P.S.; William Costerton, J. Antibiotic Resistance of Bacteria in Biofilms. Lancet 2001, 358, 135–138. [Google Scholar] [CrossRef] [PubMed]
  38. Li, H.; Luo, Y.-F.; Williams, B.J.; Blackwell, T.S.; Xie, C.-M. Structure and Function of OprD Protein in Pseudomonas aeruginosa: From Antibiotic Resistance to Novel Therapies. Int. J. Med. Microbiol. 2012, 302, 63–68. [Google Scholar] [CrossRef] [PubMed]
  39. Fang, Z.; Zhang, L.; Huang, Y.; Qing, Y.; Cao, K.; Tian, G.; Huang, X. OprD Mutations and Inactivation in Imipenem-Resistant Pseudomonas aeruginosa Isolates from China. Infect. Genet. Evol. 2014, 21, 124–128. [Google Scholar] [CrossRef]
  40. Biggel, M.; Johler, S.; Roloff, T.; Tschudin-Sutter, S.; Bassetti, S.; Siegemund, M.; Egli, A.; Stephan, R.; Seth-Smith, H.M.B. PorinPredict: In Silico Identification of OprD Loss from WGS Data for Improved Genotype-Phenotype Predictions of P. aeruginosa Carbapenem Resistance. Microbiol. Spectr. 2023, 11, e03588-22. [Google Scholar] [CrossRef]
  41. Ito, A.; Sato, T.; Ota, M.; Takemura, M.; Nishikawa, T.; Toba, S.; Kohira, N.; Miyagawa, S.; Ishibashi, N.; Matsumoto, S.; et al. In Vitro Antibacterial Properties of Cefiderocol, a Novel Siderophore Cephalosporin, against Gram-Negative Bacteria. Antimicrob. Agents Chemother. 2018, 62, 01454-17. [Google Scholar] [CrossRef]
  42. Bell, A.; Bains, M.; Hancock, R.E. Pseudomonas aeruginosa Outer Membrane Protein OprH: Expression from the Cloned Gene and Function in EDTA and Gentamicin Resistance. J. Bacteriol. 1991, 173, 6657–6664. [Google Scholar] [CrossRef] [PubMed]
  43. Macfarlane, E.L.A.; Kwasnicka, A.; Ochs, M.M.; Hancock, R.E.W. PhoP-PhoQ Homologues in Pseudomonas aeruginosa Regulate Expression of the Outer-Membrane Protein OprH and Polymyxin B Resistance. Mol. Microbiol. 1999, 34, 305–316. [Google Scholar] [CrossRef]
  44. European Committee. European Committee on Antimicrobial Susceptibility Testing Breakpoint Tables for Interpretation of MICs and Zone Diameters Version 13.0; EUCAST: Copenhagen, Denmark, 2022.
  45. Piddock, L.J.V. Multidrug-Resistance Efflux Pumps? Not Just for Resistance. Nat. Rev. Microbiol. 2006, 4, 629–636. [Google Scholar] [CrossRef] [PubMed]
  46. Sun, J.; Deng, Z.; Yan, A. Bacterial Multidrug Efflux Pumps: Mechanisms, Physiology and Pharmacological Exploitations. Biochem. Biophys. Res. Commun. 2014, 453, 254–267. [Google Scholar] [CrossRef]
  47. Hassan, K.A.; Liu, Q.; Elbourne, L.D.H.; Ahmad, I.; Sharples, D.; Naidu, V.; Chan, C.L.; Li, L.; Harborne, S.P.D.; Pokhrel, A.; et al. Pacing across the Membrane: The Novel PACE Family of Efflux Pumps Is Widespread in Gram-Negative Pathogens. Res. Microbiol. 2018, 169, 450–454. [Google Scholar] [CrossRef] [PubMed]
  48. Li, X.-Z.; Nikaido, H. Efflux-Mediated Drug Resistance in Bacteria. Drugs 2009, 69, 1555–1623. [Google Scholar] [CrossRef]
  49. Valot, B.; Guyeux, C.; Rolland, J.Y.; Mazouzi, K.; Bertrand, X.; Hocquet, D. What It Takes to Be a Pseudomonas aeruginosa? The Core Genome of the Opportunistic Pathogen Updated. PLoS ONE 2015, 10, e0126468. [Google Scholar] [CrossRef] [PubMed]
  50. Daury, L.; Orange, F.; Taveau, J.-C.; Verchère, A.; Monlezun, L.; Gounou, C.; Marreddy, R.K.R.; Picard, M.; Broutin, I.; Pos, K.M.; et al. Tripartite Assembly of RND Multidrug Efflux Pumps. Nat. Commun. 2016, 7, 10731. [Google Scholar] [CrossRef] [PubMed]
  51. Lorusso, A.B.; Carrara, J.A.; Barroso, C.D.N.; Tuon, F.F.; Faoro, H. Role of Efflux Pumps on Antimicrobial Resistance in Pseudomonas aeruginosa. Int. J. Mol. Sci. 2022, 23, 15779. [Google Scholar] [CrossRef]
  52. Choudhury, D.; Das Talukdar, A.; Choudhury, M.D.; Maurya, A.P.; Paul, D.; Chanda, D.D.; Chakravorty, A.; Bhattacharjee, A. Transcriptional Analysis of MexAB-OprM Efflux Pumps System of Pseudomonas aeruginosa and Its Role in Carbapenem Resistance in a Tertiary Referral Hospital in India. PLoS One 2015, 10, e0133842. [Google Scholar] [CrossRef] [PubMed]
  53. Zahedi bialvaei, A.; Rahbar, M.; Hamidi-Farahani, R.; Asgari, A.; Esmailkhani, A.; Mardani dashti, Y.; Soleiman-Meigooni, S. Expression of RND Efflux Pumps Mediated Antibiotic Resistance in Pseudomonas aeruginosa Clinical Strains. Microb. Pathog. 2021, 153, 104789. [Google Scholar] [CrossRef] [PubMed]
  54. Oliver, A.; Mulet, X.; López-Causapé, C.; Juan, C. The Increasing Threat of Pseudomonas aeruginosa High-Risk Clones. Drug Resist. Updates 2015, 21–22, 41–59. [Google Scholar] [CrossRef] [PubMed]
  55. Grosjean, M.; Tazrout, S.; Bour, M.; Triponey, P.; Muller, C.; Jeannot, K.; Plésiat, P. Reassessment of the Cooperativity between Efflux System MexAB-OprM and Cephalosporinase AmpC in the Resistance of Pseudomonas aeruginosa to β-Lactams. J. Antimicrob. Chemother. 2021, 76, 536–539. [Google Scholar] [CrossRef]
  56. Mine, T.; Morita, Y.; Kataoka, A.; Mizushima, T.; Tsuchiya, T. Expression in Escherichia coli of a New Multidrug Efflux Pump, MexXY, from Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 1999, 43, 415–417. [Google Scholar] [CrossRef] [PubMed]
  57. Westbrock-Wadman, S.; Sherman, D.R.; Hickey, M.J.; Coulter, S.N.; Zhu, Y.Q.; Warrener, P.; Nguyen, L.Y.; Shawar, R.M.; Folger, K.R.; Stover, C.K. Characterization of a Pseudomonas aeruginosa Efflux Pump Contributing to Aminoglycoside Impermeability. Antimicrob. Agents Chemother. 1999, 43, 2975–2983. [Google Scholar] [CrossRef]
  58. Seupt, A.; Schniederjans, M.; Tomasch, J.; Häussler, S. Expression of the MexXY Aminoglycoside Efflux Pump and Presence of an Aminoglycoside-Modifying Enzyme in Clinical Pseudomonas aeruginosa Isolates Are Highly Correlated. Antimicrob. Agents Chemother. 2020, 65, 01166-20. [Google Scholar] [CrossRef]
  59. Vettoretti, L.; Plésiat, P.; Muller, C.; El Garch, F.; Phan, G.; Attrée, I.; Ducruix, A.; Llanes, C. Efflux Unbalance in Pseudomonas aeruginosa Isolates from Cystic Fibrosis Patients. Antimicrob. Agents Chemother. 2009, 53, 1987–1997. [Google Scholar] [CrossRef] [PubMed]
  60. Shigemura, K.; Osawa, K.; Kato, A.; Tokimatsu, I.; Arakawa, S.; Shirakawa, T.; Fujisawa, M. Association of Overexpression of Efflux Pump Genes with Antibiotic Resistance in Pseudomonas aeruginosa Strains Clinically Isolated from Urinary Tract Infection Patients. J. Antibiot. 2015, 68, 568–572. [Google Scholar] [CrossRef]
  61. Poole, K.; Gotoh, N.; Tsujimoto, H.; Zhao, Q.; Wada, A.; Yamasaki, T.; Neshat, S.; Yamagishi, J.; Li, X.-Z.; Nishino, T. Overexpression of the MexC-MexD-OprJ Efflux Operon in NfxB-Type Multidrug-Resistant Strains of Pseudomonas aeruginosa. Mol. Microbiol. 1996, 21, 713–725. [Google Scholar] [CrossRef]
  62. Masuda, N.; Gotoh, N.; Ohya, S.; Nishino, T. Quantitative Correlation between Susceptibility and OprJ Production in NfxB Mutants of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 1996, 40, 909–913. [Google Scholar] [CrossRef]
  63. Mao, W.; Warren, M.S.; Black, D.S.; Satou, T.; Murata, T.; Nishino, T.; Gotoh, N.; Lomovskaya, O. On the Mechanism of Substrate Specificity by Resistance Nodulation Division (RND)-Type Multidrug Resistance Pumps: The Large Periplasmic Loops of MexD from Pseudomonas aeruginosa Are Involved in Substrate Recognition. Mol. Microbiol. 2002, 46, 889–901. [Google Scholar] [CrossRef]
  64. Gomis-Font, M.A.; Pitart, C.; del Barrio-Tofiño, E.; Zboromyrska, Y.; Cortes-Lara, S.; Mulet, X.; Marco, F.; Vila, J.; López-Causapé, C.; Oliver, A. Emergence of Resistance to Novel Cephalosporin–β-Lactamase Inhibitor Combinations through the Modification of the Pseudomonas aeruginosa MexCD-OprJ Efflux Pump. Antimicrob. Agents Chemother. 2021, 65, 00089-21. [Google Scholar] [CrossRef]
  65. Ko¨hler, T.; Michéa-Hamzehpour, M.; Henze, U.; Gotoh, N.; Kocjancic Curty, L.; Pechère, J. Characterization of MexE–MexF–OprN, a Positively Regulated Multidrug Efflux System of Pseudomonas aeruginosa. Mol. Microbiol. 1997, 23, 345–354. [Google Scholar] [CrossRef]
  66. Horna, G.; López, M.; Guerra, H.; Saénz, Y.; Ruiz, J. Interplay between MexAB-OprM and MexEF-OprN in Clinical Isolates of Pseudomonas aeruginosa. Sci. Rep. 2018, 8, 16463. [Google Scholar] [CrossRef]
  67. Sherrard, L.J.; Wee, B.A.; Duplancic, C.; Ramsay, K.A.; Dave, K.A.; Ballard, E.; Wainwright, C.E.; Grimwood, K.; Sidjabat, H.E.; Whiley, D.M.; et al. Emergence and Impact of OprD Mutations in Pseudomonas aeruginosa Strains in Cystic Fibrosis. J. Cyst. Fibros. 2022, 21, e35–e43. [Google Scholar] [CrossRef]
  68. Mlynarcik, P.; Kolar, M. Molecular Mechanisms of Polymyxin Resistance and Detection of Mcr Genes. Biomed. Pap. 2019, 163, 28–38. [Google Scholar] [CrossRef] [PubMed]
  69. Oliver, A.; Monogue, M. SIDP Breakpoints Podcast Episode #59 Resistance in Pseudomonas aeruginosa. In Proceedings of the SIDP Pseudomonas aeruginosa Resistance to Beta-Lactams; Oliver, A., Monogue, M., Eds.; Audacy: Philadelphia, CA, USA, 2022. [Google Scholar]
  70. Typas, A.; Banzhaf, M.; Gross, C.A.; Vollmer, W. From the Regulation of Peptidoglycan Synthesis to Bacterial Growth and Morphology. Nat. Rev. Microbiol. 2012, 10, 123–136. [Google Scholar] [CrossRef] [PubMed]
  71. Sauvage, E.; Kerff, F.; Terrak, M.; Ayala, J.A.; Charlier, P. The Penicillin-Binding Proteins: Structure and Role in Peptidoglycan Biosynthesis. FEMS Microbiol. Rev. 2008, 32, 234–258. [Google Scholar] [CrossRef]
  72. Lister, P.D.; Wolter, D.J.; Hanson, N.D. Antibacterial-Resistant Pseudomonas aeruginosa: Clinical Impact and Complex Regulation of Chromosomally Encoded Resistance Mechanisms. Clin. Microbiol. Rev. 2009, 22, 582–610. [Google Scholar] [CrossRef] [PubMed]
  73. Rossolini, G.M.; Tascini, C.; Viaggi, B. La Diagnostica Molecolare Sindromica e Convenzionale Come Strumento Clinico per La Scelta Della Terapia Antibiotica Nelle Infezioni Da Gram-Negativi MDR; BioMérieux: Marcy-l’Étoile, France, 2022. [Google Scholar]
  74. Moyá, B.; Beceiro, A.; Cabot, G.; Juan, C.; Zamorano, L.; Alberti, S.; Oliver, A. Pan-β-Lactam Resistance Development in Pseudomonas aeruginosa Clinical Strains: Molecular Mechanisms, Penicillin-Binding Protein Profiles, and Binding Affinities. Antimicrob. Agents Chemother. 2012, 56, 4771–4778. [Google Scholar] [CrossRef]
  75. Smith, J.D.; Kumarasiri, M.; Zhang, W.; Hesek, D.; Lee, M.; Toth, M.; Vakulenko, S.; Fisher, J.F.; Mobashery, S.; Chen, Y. Structural Analysis of the Role of Pseudomonas aeruginosa Penicillin-Binding Protein 5 in β-Lactam Resistance. Antimicrob. Agents Chemother. 2013, 57, 3137–3146. [Google Scholar] [CrossRef]
  76. Moya, B.; Dötsch, A.; Juan, C.; Blázquez, J.; Zamorano, L.; Haussler, S.; Oliver, A. β-Lactam Resistance Response Triggered by Inactivation of a Nonessential Penicillin-Binding Protein. PLoS Pathog. 2009, 5, e1000353. [Google Scholar] [CrossRef] [PubMed]
  77. Ropy, A.; Cabot, G.; Sánchez-Diener, I.; Aguilera, C.; Moya, B.; Ayala, J.A.; Oliver, A. Role of Pseudomonas aeruginosa Low-Molecular-Mass Penicillin-Binding Proteins in AmpC Expression, β-Lactam Resistance, and Peptidoglycan Structure. Antimicrob. Agents Chemother. 2015, 59, 3925–3934. [Google Scholar] [CrossRef] [PubMed]
  78. Ealand, C.S.; Machowski, E.E.; Kana, B.D. Β-lactam Resistance: The Role of Low Molecular Weight Penicillin Binding Proteins, Β-lactamases and LD-transpeptidases in Bacteria Associated with Respiratory Tract Infections. IUBMB Life 2018, 70, 855–868. [Google Scholar] [CrossRef] [PubMed]
  79. Tooke, C.L.; Hinchliffe, P.; Bragginton, E.C.; Colenso, C.K.; Hirvonen, V.H.A.; Takebayashi, Y.; Spencer, J. β-Lactamases and β-Lactamase Inhibitors in the 21st Century. J. Mol. Biol. 2019, 431, 3472–3500. [Google Scholar] [CrossRef] [PubMed]
  80. Glen, K.A.; Lamont, I.L. β-Lactam Resistance in Pseudomonas aeruginosa: Current Status, Future Prospects. Pathogens 2021, 10, 1638. [Google Scholar] [CrossRef]
  81. Colombo, F.; Waheed, A.; Panese, S.; Scarparo, C.; Solinas, M.; Parisi, S.G.; Geremia, N. Treatment with Cefiderocol in K. Pneumoniae KPC Nosocomial External Ventricular Drainage Meningitis: A Brief Report. Infez. Med. 2022, 30, 454. [Google Scholar] [CrossRef]
  82. Weldhagen, G.F. Integrons and β-Lactamases—A Novel Perspective on Resistance. Int. J. Antimicrob. Agents 2004, 23, 556–562. [Google Scholar] [CrossRef]
  83. Bush, K.; Bradford, P.A. β-Lactams and β-Lactamase Inhibitors: An Overview. Cold Spring Harb. Perspect. Med. 2016, 6, a025247. [Google Scholar] [CrossRef]
  84. Yahav, D.; Giske, C.G.; Grāmatniece, A.; Abodakpi, H.; Tam, V.H.; Leibovici, L. New β-Lactam–β-Lactamase Inhibitor Combinations. Clin. Microbiol. Rev. 2020, 34, 00115-20. [Google Scholar] [CrossRef]
  85. Soriano, A.; Mensa, J. Mechanism of Action of Cefiderocol. Rev. Española Quimioter. 2022, 35, 16–19. [Google Scholar] [CrossRef]
  86. Dehbashi, S.; Tahmasebi, H.; Alikhani, M.Y.; Keramat, F.; Arabestani, M.R. Distribution of Class B and Class A β-Lactamases in Clinical Strains of Pseudomonas aeruginosa: Comparison of Phenotypic Methods and High-Resolution Melting Analysis (HRMA) Assay. Infect. Drug Resist. 2020, 13, 2037–2052. [Google Scholar] [CrossRef] [PubMed]
  87. Danel, F.; Hall, L.M.C.; Gur, D.; Akalin, H.E.; Livermore, D.M. Transferable Production of PER-1 β-Lactamase in Pseudomonas aeruginosa. J. Antimicrob. Chemother. 1995, 35, 281–294. [Google Scholar] [CrossRef] [PubMed]
  88. Polotto, M.; Casella, T.; de Lucca Oliveira, M.G.; Rúbio, F.G.; Nogueira, M.L.; de Almeida, M.T.; Nogueira, M.C. Detection of P. aeruginosa Harboring Bla CTX-M-2, Bla GES-1 and Bla GES-5, Bla IMP-1 and Bla SPM-1causing Infections in Brazilian Tertiary-Care Hospital. BMC Infect. Dis. 2012, 12, 176. [Google Scholar] [CrossRef] [PubMed]
  89. Qing, Y.; Cao, K.-Y.; Fang, Z.-L.; Huang, Y.-M.; Zhang, X.-F.; Tian, G.-B.; Huang, X. Outbreak of PER-1 and Diversity of β-Lactamases among Ceftazidime-Resistant Pseudomonas aeruginosa Clinical Isolates. J. Med. Microbiol. 2014, 63, 386–392. [Google Scholar] [CrossRef]
  90. Haghighi, S.; Reza Goli, H. High Prevalence of BlaVEB, BlaGES and BlaPER Genes in Beta-Lactam Resistant Clinical Isolates of Pseudomonas aeruginosa. AIMS Microbiol. 2022, 8, 153–166. [Google Scholar] [CrossRef]
  91. Poirel, L.; Brinas, L.; Verlinde, A.; Ide, L.; Nordmann, P. BEL-1, a Novel Clavulanic Acid-Inhibited Extended-Spectrum β-Lactamase, and the Class 1 Integron In120 in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2005, 49, 3743–3748. [Google Scholar] [CrossRef]
  92. Schauer, J.; Gatermann, S.G.; Hoffmann, D.; Hupfeld, L.; Pfennigwerth, N. GPC-1, a Novel Class A Carbapenemase Detected in a Clinical Pseudomonas aeruginosa Isolate. J. Antimicrob. Chemother. 2020, 75, 911–916. [Google Scholar] [CrossRef] [PubMed]
  93. Bălăşoiu, M.; Bălăşoiu, A.T.; Mănescu, R.; Avramescu, C.; Ionete, O. Pseudomonas aeruginosa Resistance Phenotypes and Phenotypic Highlighting Methods. Curr. Health Sci. J. 2014, 40, 85. [Google Scholar] [PubMed]
  94. Ortiz de la Rosa, J.-M.; Nordmann, P.; Poirel, L. ESBLs and Resistance to Ceftazidime/Avibactam and Ceftolozane/Tazobactam Combinations in Escherichia coli and Pseudomonas aeruginosa. J. Antimicrob. Chemother. 2019, 74, 1934–1939. [Google Scholar] [CrossRef]
  95. Sahni, R.; Mathai, D.; Sudarsanam, T.; Balaji, V.; Brahamadathan, K.; Jesudasan, M.; Lalitha, M. Extended-Spectrum Beta-Lactamase Producers: Detection for the Diagnostic Laboratory. J. Glob. Infect. Dis. 2018, 10, 140. [Google Scholar] [CrossRef]
  96. Frase, H.; Shi, Q.; Testero, S.A.; Mobashery, S.; Vakulenko, S.B. Mechanistic Basis for the Emergence of Catalytic Competence against Carbapenem Antibiotics by the GES Family of β-Lactamases. J. Biol. Chem. 2009, 284, 29509–29513. [Google Scholar] [CrossRef] [PubMed]
  97. Gill, C.M.; Nicolau, D.P.; Aktas, E.; Alfouzan, W.; Bourassa, L.; Brink, A.; Burnham, C.-A.D.; Canton, R.; Carmeli, Y.; Falcone, M.; et al. Phenotypic and Genotypic Profile of Ceftolozane/Tazobactam-Non-Susceptible, Carbapenem-Resistant Pseudomonas aeruginosa. J. Antimicrob. Chemother. 2023, 78, 252–256. [Google Scholar] [CrossRef] [PubMed]
  98. Villegas, M.V.; Lolans, K.; Correa, A.; Kattan, J.N.; Lopez, J.A.; Quinn, J.P. First Identification of Pseudomonas aeruginosa Isolates Producing a KPC-Type Carbapenem-Hydrolyzing β-Lactamase. Antimicrob. Agents Chemother. 2007, 51, 1553–1555. [Google Scholar] [CrossRef] [PubMed]
  99. Hagemann, J.B.; Pfennigwerth, N.; Gatermann, S.G.; von Baum, H.; Essig, A. KPC-2 Carbapenemase-Producing Pseudomonas aeruginosa Reaching Germany. J. Antimicrob. Chemother. 2018, 73, 1812–1814. [Google Scholar] [CrossRef]
  100. Pasteran, F.; Mendez, T.; Guerriero, L.; Rapoport, M.; Corso, A. Sensitive Screening Tests for Suspected Class A Carbapenemase Production in Species of Enterobacteriaceae. J. Clin. Microbiol. 2009, 47, 1631–1639. [Google Scholar] [CrossRef] [PubMed]
  101. Zhanel, G.G.; Golden, A.R.; Zelenitsky, S.; Wiebe, K.; Lawrence, C.K.; Adam, H.J.; Idowu, T.; Domalaon, R.; Schweizer, F.; Zhanel, M.A.; et al. Cefiderocol: A Siderophore Cephalosporin with Activity Against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli. Drugs 2019, 79, 271–289. [Google Scholar] [CrossRef]
  102. Gill, C.M.; Asempa, T.E.; Tickler, I.A.; dela Cruz, C.; Tenover, F.C.; Nicolau, D.P. Evaluation of the Xpert Carba-R NxG Assay for Detection of Carbapenemase Genes in a Global Challenge Set of Pseudomonas aeruginosa Isolates. J. Clin. Microbiol. 2020, 58, 01098-20. [Google Scholar] [CrossRef]
  103. Kabir, M.H.; Meunier, D.; Hopkins, K.L.; Giske, C.G.; Woodford, N. A Two-Centre Evaluation of RAPIDEC ® CARBA NP for Carbapenemase Detection in Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp. J. Antimicrob. Chemother. 2016, 71, 1213–1216. [Google Scholar] [CrossRef]
  104. Fajardo, A.; Hernando-Amado, S.; Oliver, A.; Ball, G.; Filloux, A.; Martinez, J.L. Characterization of a Novel Zn2+-Dependent Intrinsic Imipenemase from Pseudomonas aeruginosa. J. Antimicrob. Chemother. 2014, 69, 2972–2978. [Google Scholar] [CrossRef]
  105. del Barrio-Tofiño, E.; López-Causapé, C.; Oliver, A. Pseudomonas aeruginosa Epidemic High-Risk Clones and Their Association with Horizontally-Acquired β-Lactamases: 2020 Update. Int. J. Antimicrob. Agents 2020, 56, 106196. [Google Scholar] [CrossRef]
  106. Forero-Hurtado, D.; Corredor-Rozo, Z.L.; Ruiz-Castellanos, J.S.; Márquez-Ortiz, R.A.; Abril, D.; Vanegas, N.; Lafaurie, G.I.; Chambrone, L.; Escobar-Pérez, J. Worldwide Dissemination of BlaKPC Gene by Novel Mobilization Platforms in Pseudomonas aeruginosa: A Systematic Review. Antibiotics 2023, 12, 658. [Google Scholar] [CrossRef]
  107. Yoon, E.-J.; Jeong, S.H. Mobile Carbapenemase Genes in Pseudomonas aeruginosa. Front. Microbiol. 2021, 12, 614058. [Google Scholar] [CrossRef]
  108. Frère, J.-M.; Galleni, M.; Bush, K.; Dideberg, O. Is It Necessary to Change the Classification of β-Lactamases? J. Antimicrob. Chemother. 2005, 55, 1051–1053. [Google Scholar] [CrossRef]
  109. Palzkill, T. Metallo-β-lactamase Structure and Function. Ann. N. Y. Acad. Sci. 2013, 1277, 91–104. [Google Scholar] [CrossRef]
  110. Miriagou, V.; Cornaglia, G.; Edelstein, M.; Galani, I.; Giske, C.G.; Gniadkowski, M.; Malamou-Lada, E.; Martinez-Martinez, L.; Navarro, F.; Nordmann, P.; et al. Acquired Carbapenemases in Gram-Negative Bacterial Pathogens: Detection and Surveillance Issues. Clin. Microbiol. Infect. 2010, 16, 112–122. [Google Scholar] [CrossRef]
  111. Walsh, T.R.; Toleman, M.A.; Poirel, L.; Nordmann, P. Metallo-β-Lactamases: The Quiet before the Storm? Clin. Microbiol. Rev. 2005, 18, 306–325. [Google Scholar] [CrossRef] [PubMed]
  112. Takemura, M.; Wise, M.G.; Hackel, M.A.; Sahm, D.F.; Yamano, Y. In Vitro Activity of Cefiderocol against MBL-Producing Gram-Negative Bacteria Collected in North America and Europe in Five Consecutive Annual Multinational SIDERO-WT Surveillance Studies (2014–2019). J. Antimicrob. Chemother. 2023, 78, 2019–2027. [Google Scholar] [CrossRef] [PubMed]
  113. Timsit, J.F.; Paul, M.; Shields, R.K.; Echols, R.; Baba, T.; Yamano, Y.; Portsmouth, S. Cefiderocol for the Treatment of Infections Due to Metallo-B-Lactamase–Producing Pathogens in the CREDIBLE-CR and APEKS-NP Phase 3 Randomized Studies. Clin. Infect. Dis. 2022, 75, 1081–1084. [Google Scholar] [CrossRef] [PubMed]
  114. Zhu, B.; Zhang, P.; Huang, Z.; Yan, H.; Wu, A.H.; Zhang, G.; Mao, Q. Study on drug resistance of Pseudomonas aeruginosa plasmid-mediated AmpC β-lactamase. Mol. Med. Rep. 2013, 7, 664–668. [Google Scholar] [CrossRef]
  115. Livermore, D.M. Clinical Significance of Beta-Lactamase Induction and Stable Derepression in Gram-Negative Rods. Eur. J. Clin. Microbiol. 1987, 6, 439–445. [Google Scholar] [CrossRef] [PubMed]
  116. Drawz, S.M.; Bonomo, R.A. Three Decades of β-Lactamase Inhibitors. Clin. Microbiol. Rev. 2010, 23, 160–201. [Google Scholar] [CrossRef]
  117. Rafiee, R.; Eftekhar, F.; Tabatabaei, S.A.; Minaee Tehrani, D. Prevalence of Extended-Spectrum and Metallo β-Lactamase Production in AmpC β-Lactamase Producing Pseudomonas aeruginosa Isolates from Burns. Jundishapur J. Microbiol. 2014, 7, e16436. [Google Scholar] [CrossRef]
  118. Zamorano, L.; Moyà, B.; Juan, C.; Mulet, X.; Blázquez, J.; Oliver, A. The Pseudomonas aeruginosa CreBC Two-Component System Plays a Major Role in the Response to β-Lactams, Fitness, Biofilm Growth, and Global Regulation. Antimicrob. Agents Chemother. 2014, 58, 5084–5095. [Google Scholar] [CrossRef]
  119. Bagge, N.; Ciofu, O.; Hentzer, M.; Campbell, J.I.A.; Givskov, M.; Høiby, N. Constitutive High Expression of Chromosomal β-Lactamase in Pseudomonas aeruginosa Caused by a New Insertion Sequence (IS 1669) Located in AmpD. Antimicrob. Agents Chemother. 2002, 46, 3406–3411. [Google Scholar] [CrossRef]
  120. Berrazeg, M.; Jeannot, K.; Ntsogo Enguéné, V.Y.; Broutin, I.; Loeffert, S.; Fournier, D.; Plésiat, P. Mutations in β-Lactamase AmpC Increase Resistance of Pseudomonas aeruginosa Isolates to Antipseudomonal Cephalosporins. Antimicrob. Agents Chemother. 2015, 59, 6248–6255. [Google Scholar] [CrossRef] [PubMed]
  121. Fraile-Ribot, P.A.; Zamorano, L.; Orellana, R.; del Barrio-Tofiño, E.; Sánchez-Diener, I.; Cortes-Lara, S.; López-Causapé, C.; Cabot, G.; Bou, G.; Martínez-Martínez, L.; et al. Activity of Imipenem-Relebactam against a Large Collection of Pseudomonas aeruginosa Clinical Isolates and Isogenic β-Lactam-Resistant Mutants. Antimicrob. Agents Chemother. 2020, 64, 02165-19. [Google Scholar] [CrossRef] [PubMed]
  122. Simner, P.J.; Beisken, S.; Bergman, Y.; Posch, A.E.; Cosgrove, S.E.; Tamma, P.D. Cefiderocol Activity Against Clinical Pseudomonas aeruginosa Isolates Exhibiting Ceftolozane-Tazobactam Resistance. Open Forum. Infect. Dis. 2021, 8, ofab311. [Google Scholar] [CrossRef] [PubMed]
  123. Rodríguez-Martínez, J.-M.; Poirel, L.; Nordmann, P. Extended-Spectrum Cephalosporinases in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2009, 53, 1766–1771. [Google Scholar] [CrossRef] [PubMed]
  124. Queenan, A.M.; Bush, K. Carbapenemases: The Versatile β-Lactamases. Clin. Microbiol. Rev. 2007, 20, 440–458. [Google Scholar] [CrossRef] [PubMed]
  125. Golemi, D.; Maveyraud, L.; Vakulenko, S.; Samama, J.-P.; Mobashery, S. Critical Involvement of a Carbamylated Lysine in Catalytic Function of Class D β-Lactamases. Proc. Natl. Acad. Sci. USA 2001, 98, 14280–14285. [Google Scholar] [CrossRef]
  126. Evans, B.A.; Amyes, S.G.B. OXA β-Lactamases. Clin. Microbiol. Rev. 2014, 27, 241–263. [Google Scholar] [CrossRef]
  127. Antunes, N.; Fisher, J. Acquired Class D β-Lactamases. Antibiotics 2014, 3, 398–434. [Google Scholar] [CrossRef]
  128. Poirel, L.; Cabanne, L.; Collet, L.; Nordmann, P. Class II Transposon-Borne Structure Harboring Metallo-β-Lactamase Gene Bla VIM-2 in Pseudomonas Putida. Antimicrob. Agents Chemother. 2006, 50, 2889–2891. [Google Scholar] [CrossRef] [PubMed]
  129. Poirel, L.; Naas, T.; Nordmann, P. Diversity, Epidemiology, and Genetics of Class D β-Lactamases. Antimicrob. Agents Chemother. 2010, 54, 24–38. [Google Scholar] [CrossRef]
  130. Aubert, D.; Poirel, L.; Chevalier, J.; Leotard, S.; Pages, J.-M.; Nordmann, P. Oxacillinase-Mediated Resistance to Cefepime and Susceptibility to Ceftazidime in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2001, 45, 1615–1620. [Google Scholar] [CrossRef]
  131. Girlich, D.; Naas, T.; Nordmann, P. Biochemical Characterization of the Naturally Occurring Oxacillinase OXA-50 of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2004, 48, 2043–2048. [Google Scholar] [CrossRef]
  132. Fraile-Ribot, P.A.; Mulet, X.; Cabot, G.; del Barrio-Tofiño, E.; Juan, C.; Pérez, J.L.; Oliver, A. In Vivo Emergence of Resistance to Novel Cephalosporin–β-Lactamase Inhibitor Combinations through the Duplication of Amino Acid D149 from OXA-2 β-Lactamase (OXA-539) in Sequence Type 235 Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2017, 61, 01117-17. [Google Scholar] [CrossRef] [PubMed]
  133. Saki, M.; Farajzadeh Sheikh, A.; Seyed-Mohammadi, S.; Asareh Zadegan Dezfuli, A.; Shahin, M.; Tabasi, M.; Veisi, H.; Keshavarzi, R.; Khani, P. Occurrence of Plasmid-Mediated Quinolone Resistance Genes in Pseudomonas aeruginosa Strains Isolated from Clinical Specimens in Southwest Iran: A Multicentral Study. Sci. Rep. 2022, 12, 2296. [Google Scholar] [CrossRef] [PubMed]
  134. Cayci, Y.T.; Coban, A.; Gunaydin, M. Investigation of Plasmid-Mediated Quinolone Resistance in Pseudomonas aeruginosa Clinical Isolates. Indian J. Med. Microbiol. 2014, 32, 285–289. [Google Scholar] [CrossRef]
  135. Díez-Aguilar, M.; Cantón, R. New Microbiological Aspects of Fosfomycin. Rev. Española Quimioter. 2019, 32, 8. [Google Scholar]
  136. Kadner, R.J.; Winkler, H.H. Isolation and Characterization of Mutations Affecting the Transport of Hexose Phosphates in Escherichia coli. J. Bacteriol. 1973, 113, 895–900. [Google Scholar] [CrossRef] [PubMed]
  137. Argast, M.; Ludtke, D.; Silhavy, T.J.; Boos, W. A Second Transport System for Sn-Glycerol-3-Phosphate in Escherichia coli. J. Bacteriol. 1978, 136, 1070–1083. [Google Scholar] [CrossRef] [PubMed]
  138. Bush, K. Antimicrobial Agents Targeting Bacterial Cell Walls and Cell Membranes. Rev. Sci. Et. Tech. L’oie 2012, 31, 43–56. [Google Scholar] [CrossRef] [PubMed]
  139. Bryant, R.E.; Fox, K.; Oh, G.; Morthland, V.H. β-Lactam Enhancement of Aminoglycoside Activity under Conditions of Reduced PH and Oxygen Tension That May Exist in Infected Tissues. J. Infect. Dis. 1992, 165, 676–682. [Google Scholar] [CrossRef]
  140. Morrissey, I.; Smith, J.T. The Importance of Oxygen in the Killing of Bacteria by Ofloxacin and Ciprofloxacin. Microbios 1994, 79, 43–53. [Google Scholar]
  141. Kohanski, M.A.; Dwyer, D.J.; Collins, J.J. How Antibiotics Kill Bacteria: From Targets to Networks. Nat. Rev. Microbiol. 2010, 8, 423–435. [Google Scholar] [CrossRef] [PubMed]
  142. Inouye, S.; Watanabe, T.; Tsuruoka, T.; Kitasato, I. An Increase in the Antimicrobial Activity In Vitro of Fosfomycin under Anaerobic Conditions. J. Antimicrob. Chemother. 1989, 24, 657–666. [Google Scholar] [CrossRef] [PubMed]
  143. Rigsby, R.E.; Rife, C.L.; Fillgrove, K.L.; Newcomer, M.E.; Armstrong, R.N. Phosphonoformate: A Minimal Transition State Analogue Inhibitor of the Fosfomycin Resistance Protein, FosA. Biochemistry 2004, 43, 13666–13673. [Google Scholar] [CrossRef]
  144. Rigsby, R.E.; Fillgrove, K.L.; Beihoffer, L.A.; Armstrong, R.N. Fosfomycin Resistance Proteins: A Nexus of Glutathione Transferases and Epoxide Hydrolases in a Metalloenzyme Superfamily. Methods Enzymol. 2005, 401, 367–379. [Google Scholar]
  145. Stover, C.K.; Pham, X.Q.; Erwin, A.L.; Mizoguchi, S.D.; Warrener, P.; Hickey, M.J.; Brinkman, F.S.L.; Hufnagle, W.O.; Kowalik, D.J.; Lagrou, M.; et al. Complete Genome Sequence of Pseudomonas aeruginosa PAO1, an Opportunistic Pathogen. Nature 2000, 406, 959–964. [Google Scholar] [CrossRef]
  146. Castaneda-García, A.; Rodríguez-Rojas, A.; Guelfo, J.R.; Blázquez, J. The Glycerol-3-Phosphate Permease GlpT Is the Only Fosfomycin Transporter in Pseudomonas aeruginosa. J. Bacteriol. 2009, 191, 6968–6974. [Google Scholar] [CrossRef]
  147. Worlitzsch, D.; Tarran, R.; Ulrich, M.; Schwab, U.; Cekici, A.; Meyer, K.C.; Birrer, P.; Bellon, G.; Berger, J.; Weiss, T.; et al. Effects of Reduced Mucus Oxygen Concentration in Airway Pseudomonas Infections of Cystic Fibrosis Patients. J. Clin. Investig. 2002, 109, 317–325. [Google Scholar] [CrossRef] [PubMed]
  148. Yoon, S.S.; Hennigan, R.F.; Hilliard, G.M.; Ochsner, U.A.; Parvatiyar, K.; Kamani, M.C.; Allen, H.L.; DeKievit, T.R.; Gardner, P.R.; Schwab, U.; et al. Pseudomonas aeruginosa Anaerobic Respiration in Biofilms. Dev. Cell 2002, 3, 593–603. [Google Scholar] [CrossRef] [PubMed]
  149. Hirakawa, H.; Kurabayashi, K.; Tanimoto, K.; Tomita, H. Oxygen Limitation Enhances the Antimicrobial Activity of Fosfomycin in Pseudomonas aeruginosa Following Overexpression of GlpT Which Encodes Glycerol-3-Phosphate/Fosfomycin Symporter. Front. Microbiol. 2018, 9, 1950. [Google Scholar] [CrossRef] [PubMed]
  150. Grabein, B.; Graninger, W.; Rodríguez Baño, J.; Dinh, A.; Liesenfeld, D.B. Intravenous Fosfomycin—Back to the Future. Systematic Review and Meta-Analysis of the Clinical Literature. Clin. Microbiol. Infect. 2017, 23, 363–372. [Google Scholar] [CrossRef]
  151. Mikhail, S.; Singh, N.B.; Kebriaei, R.; Rice, S.A.; Stamper, K.C.; Castanheira, M.; Rybak, M.J. Evaluation of the Synergy of Ceftazidime-Avibactam in Combination with Meropenem, Amikacin, Aztreonam, Colistin, or Fosfomycin against Well-Characterized Multidrug-Resistant Klebsiella Pneumoniae and Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2019, 63, 00779-19. [Google Scholar] [CrossRef]
  152. Cassir, N.; Rolain, J.-M.; Brouqui, P. A New Strategy to Fight Antimicrobial Resistance: The Revival of Old Antibiotics. Front. Microbiol. 2014, 5, 551. [Google Scholar] [CrossRef]
  153. Gribble, M.J.; Chow, A.W.; Naiman, S.C.; Smith, J.A.; Bowie, W.R.; Sacks, S.L.; Grossman, L.; Buskard, N.; Growe, G.H.; Plenderleith, L.H. Prospective Randomized Trial of Piperacillin Monotherapy versus Carboxypenicillin-Aminoglycoside Combination Regimens in the Empirical Treatment of Serious Bacterial Infections. Antimicrob. Agents Chemother. 1983, 24, 388. [Google Scholar] [CrossRef]
  154. Landman, D.; Bratu, S.; Kochar, S.; Panwar, M.; Trehan, M.; Doymaz, M.; Quale, J. Evolution of Antimicrobial Resistance among Pseudomonas aeruginosa, Acinetobacter Baumannii and Klebsiella Pneumoniae in Brooklyn, NY. J. Antimicrob. Chemother. 2007, 60, 78–82. [Google Scholar] [CrossRef]
  155. Burgess, D.S.; Nathisuwan, S. Cefepime, Piperacillin/Tazobactam, Gentamicin, Ciprofloxacin, and Levofloxacin Alone and in Combination against Pseudomonas aeruginosa. Diagn. Microbiol. Infect. Dis. 2002, 44, 35–41. [Google Scholar] [CrossRef]
  156. Paul, M.; Leibovici, L.; Maki, D.G.; Safdar, N. Combination Antibiotic Therapy for Pseudomonas aeruginosa Bacteraemia. Lancet Infect. Dis. 2005, 5, 192–193. [Google Scholar] [CrossRef] [PubMed]
  157. Davis, B.D. Bactericidal Synergism between Beta-Lactams and Aminoglycosides: Mechanism and Possible Therapeutic Implications. Rev. Infect. Dis. 1982, 4, 237–245. [Google Scholar] [CrossRef] [PubMed]
  158. Breidenstein, E.B.M.; de la Fuente-Núñez, C.; Hancock, R.E.W. Pseudomonas aeruginosa: All Roads Lead to Resistance. Trends Microbiol. 2011, 19, 419–426. [Google Scholar] [CrossRef]
  159. Cluck, D.; Lewis, P.; Stayer, B.; Spivey, J.; Moorman, J. Ceftolozane-Tazobactam: A New-Generation Cephalosporin. Am. J. Health Syst. Pharm. 2015, 72, 2135–2146. [Google Scholar] [CrossRef]
  160. Bassetti, M.; Vena, A.; Giacobbe, D.R.; Falcone, M.; Tiseo, G.; Giannella, M.; Pascale, R.; Meschiari, M.; Digaetano, M.; Oliva, A.; et al. Ceftolozane/Tazobactam for Treatment of Severe ESBL-Producing Enterobacterales Infections: A Multicenter Nationwide Clinical Experience (CEFTABUSE II Study). Open Forum. Infect. Dis. 2020, 7, ofaa139. [Google Scholar] [CrossRef] [PubMed]
  161. Zhanel, G.G.; Chung, P.; Adam, H.; Zelenitsky, S.; Denisuik, A.; Schweizer, F.; Lagacé-Wiens, P.R.S.; Rubinstein, E.; Gin, A.S.; Walkty, A.; et al. Ceftolozane/Tazobactam: A Novel Cephalosporin/β-Lactamase Inhibitor Combination with Activity against Multidrug-Resistant Gram-Negative Bacilli. Drugs 2014, 74, 31–51. [Google Scholar] [CrossRef]
  162. Castón, J.J.; De la Torre, Á.; Ruiz-Camps, I.; Sorlí, M.L.; Torres, V.; Torre-Cisneros, J. Salvage Therapy with Ceftolozane-Tazobactam for Multidrug-Resistant Pseudomonas aeruginosa Infections. Antimicrob. Agents Chemother. 2017, 61, 02136-16. [Google Scholar] [CrossRef]
  163. Gallagher, J.C.; Satlin, M.J.; Elabor, A.; Saraiya, N.; McCreary, E.K.; Molnar, E.; El-Beyrouty, C.; Jones, B.M.; Dixit, D.; Heil, E.L.; et al. Ceftolozane-Tazobactam for the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Infections: A Multicenter Study. Open Forum. Infect. Dis. 2018, 5, ofy280. [Google Scholar] [CrossRef]
  164. Albin, O.R.; Henig, O.; Patel, T.S.; Valley, T.S.; Pogue, J.M.; Petty, L.A.; Mills, J.P.; Brancaccio, A.; Martin, E.T.; Kaye, K.S. Clinical Implications of Microbiologic Treatment Failure in the Setting of Clinical Cure of Bacterial Pneumonia. Clin. Infect. Dis. 2020, 71, 3033–3041. [Google Scholar] [CrossRef] [PubMed]
  165. Bonine, N.G.; Berger, A.; Altincatal, A.; Wang, R.; Bhagnani, T.; Gillard, P.; Lodise, T. Impact of Delayed Appropriate Antibiotic Therapy on Patient Outcomes by Antibiotic Resistance Status from Serious Gram-Negative Bacterial Infections. Am. J. Med. Sci. 2019, 357, 103–110. [Google Scholar] [CrossRef]
  166. Pogue, J.M.; Kaye, K.S.; Veve, M.P.; Patel, T.S.; Gerlach, A.T.; Davis, S.L.; Puzniak, L.A.; File, T.M.; Olson, S.; Dhar, S.; et al. Ceftolozane/Tazobactam vs Polymyxin or Aminoglycoside-Based Regimens for the Treatment of Drug-Resistant Pseudomonas aeruginosa. Clin. Infect. Dis. 2020, 71, 304–310. [Google Scholar] [CrossRef]
  167. Talbot, G.H.; Das, A.; Cush, S.; Dane, A.; Wible, M.; Echols, R.; Torres, A.; Cammarata, S.; Rex, J.H.; Powers, J.H.; et al. Evidence-Based Study Design for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia. J. Infect. Dis. 2019, 219, 1536–1544. [Google Scholar] [CrossRef] [PubMed]
  168. Torres, A.; Niederman, M.S.; Chastre, J.; Ewig, S.; Fernandez-Vandellos, P.; Hanberger, H.; Kollef, M.; Li Bassi, G.; Luna, C.M.; Martin-Loeches, I.; et al. International ERS/ESICM/ESCMID/ALAT Guidelines for the Management of Hospital-Acquired Pneumonia and Ventilator-Associated Pneumonia. Eur. Respir. J. 2017, 50, 1700582. [Google Scholar] [CrossRef] [PubMed]
  169. Kalil, A.C.; Metersky, M.L.; Klompas, M.; Muscedere, J.; Sweeney, D.A.; Palmer, L.B.; Napolitano, L.M.; O’Grady, N.P.; Bartlett, J.G.; Carratalà, J.; et al. Management of Adults with Hospital-Acquired and Ventilator-Associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin. Infect. Dis. 2016, 63, e61–e111. [Google Scholar] [CrossRef]
  170. Cantón, R.; Jehl, F.; Rossolini, G.M.; Soriano, A.; Tascini, C.; Viaggi, B. Mdr Infections in Critically Ill Patients. From the Microlab Bench to the Patient’s Bedside; EDIMES: Pavia, Italy, 2022. [Google Scholar]
  171. Esperatti, M.; Ferrer, M.; Theessen, A.; Liapikou, A.; Valencia, M.; Saucedo, L.M.; Zavala, E.; Welte, T.; Torres, A. Nosocomial Pneumonia in the Intensive Care Unit Acquired by Mechanically Ventilated versus Nonventilated Patients. Am. J. Respir. Crit. Care Med. 2010, 182, 1533–1539. [Google Scholar] [CrossRef]
  172. Kollef, M.H.; Nováček, M.; Kivistik, Ü.; Réa-Neto, Á.; Shime, N.; Martin-Loeches, I.; Timsit, J.-F.; Wunderink, R.G.; Bruno, C.J.; Huntington, J.A.; et al. Ceftolozane-Tazobactam versus Meropenem for Treatment of Nosocomial Pneumonia (ASPECT-NP): A Randomised, Controlled, Double-Blind, Phase 3, Non-Inferiority Trial. Lancet Infect. Dis. 2019, 19, 1299–1311. [Google Scholar] [CrossRef]
  173. Kollef, M.H.; Timsit, J.-F.; Martin-Loeches, I.; Wunderink, R.G.; Huntington, J.A.; Jensen, E.H.; Yu, B.; Bruno, C.J. Outcomes in Participants with Failure of Initial Antibacterial Therapy for Hospital-Acquired/Ventilator-Associated Bacterial Pneumonia Prior to Enrollment in the Randomized, Controlled Phase 3 ASPECT-NP Trial of Ceftolozane/Tazobactam versus Meropenem. Crit. Care 2022, 26, 373. [Google Scholar] [CrossRef] [PubMed]
  174. Bergas, A.; Albasanz-Puig, A.; Fernández-Cruz, A.; Machado, M.; Novo, A.; van Duin, D.; Garcia-Vidal, C.; Hakki, M.; Ruiz-Camps, I.; del Pozo, J.L.; et al. Real-Life Use of Ceftolozane/Tazobactam for the Treatment of Bloodstream Infection Due to Pseudomonas aeruginosa in Neutropenic Hematologic Patients: A Matched Control Study (ZENITH Study). Microbiol. Spectr. 2022, 10, e02292-21. [Google Scholar] [CrossRef] [PubMed]
  175. Montesinos, I.L.; Luisa Sorlí, M.M.; Horcajada, J.P. Ceftolozane-Tazobactam: When, How and Why Using It? Rev. Esp. Quim. 2021, 34 (Suppl. 1), 35–37. [Google Scholar] [CrossRef]
  176. Zhong, H.; Zhao, X.Y.; Zhang, Z.L.; Gu, Z.C.; Zhang, C.; Gao, Y.; Cui, M. Evaluation of the Efficacy and Safety of Ceftazidime/Avibactam in the Treatment of Gram-Negative Bacterial Infections: A Systematic Review and Meta-Analysis. Int. J. Antimicrob. Agents 2018, 52, 443–450. [Google Scholar] [CrossRef]
  177. Fröhlich, C.; Sørum, V.; Thomassen, A.M.; Johnsen, P.J.; Leiros, H.-K.S.; Samuelsen, Ø. OXA-48-Mediated Ceftazidime-Avibactam Resistance Is Associated with Evolutionary Trade-Offs. mSphere 2019, 4, e00024-19. [Google Scholar] [CrossRef]
  178. Horcajada, J.P.; Montero, M.; Oliver, A.; Sorlí, L.; Luque, S.; Gómez-Zorrilla, S.; Benito, N.; Grau, S. Epidemiology and Treatment of Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa Infections. Clin. Microbiol. Rev. 2019, 32, 00031-19. [Google Scholar] [CrossRef]
  179. Carmeli, Y.; Armstrong, J.; Laud, P.J.; Newell, P.; Stone, G.; Wardman, A.; Gasink, L.B. Ceftazidime-Avibactam or Best Available Therapy in Patients with Ceftazidime-Resistant Enterobacteriaceae and Pseudomonas aeruginosa Complicated Urinary Tract Infections or Complicated Intra-Abdominal Infections (REPRISE): A Randomised, Pathogen-Directed, Phase 3 Study. Lancet Infect. Dis. 2016, 16, 661–673. [Google Scholar] [CrossRef] [PubMed]
  180. Mazuski, J.E.; Wagenlehner, F.; Torres, A.; Carmeli, Y.; Chow, J.W.; Wajsbrot, D.; Stone, G.G.; Irani, P.; Bharucha, D.; Cheng, K.; et al. Clinical and Microbiological Outcomes of Ceftazidime-Avibactam Treatment in Adults with Gram-Negative Bacteremia: A Subset Analysis from the Phase 3 Clinical Trial Program. Infect. Dis. Ther. 2021, 10, 2399. [Google Scholar] [CrossRef] [PubMed]
  181. Marino, A.; Campanella, E.; Stracquadanio, S.; Calvo, M.; Migliorisi, G.; Nicolosi, A.; Cosentino, F.; Marletta, S.; Spampinato, S.; Prestifilippo, P.; et al. Ceftazidime/Avibactam and Meropenem/Vaborbactam for the Management of Enterobacterales Infections: A Narrative Review, Clinical Considerations, and Expert Opinion. Antibiotics 2023, 12, 1521. [Google Scholar] [CrossRef]
  182. Stone, G.G.; Newell, P.; Gasink, L.B.; Broadhurst, H.; Wardman, A.; Yates, K.; Chen, Z.; Song, J.; Chow, J.W. Clinical Activity of Ceftazidime/Avibactam against MDR Enterobacteriaceae and Pseudomonas aeruginosa: Pooled Data from the Ceftazidime/Avibactam Phase III Clinical Trial Programme. J. Antimicrob. Chemother. 2018, 73, 2519–2523. [Google Scholar] [CrossRef] [PubMed]
  183. Daikos, G.L.; da Cunha, C.A.; Rossolini, G.M.; Stone, G.G.; Baillon-Plot, N.; Tawadrous, M.; Irani, P. Review of Ceftazidime-Avibactam for the Treatment of Infections Caused by Pseudomonas aeruginosa. Antibiotics 2021, 10, 1126. [Google Scholar] [CrossRef]
  184. Tamma, P.D.; Aitken, S.L.; Bonomo, R.A.; Mathers, A.J.; van Duin, D.; Clancy, C.J. Infectious Diseases Society of America 2022 Guidance on the Treatment of Extended-Spectrum β-Lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa). Clin. Infect. Dis. 2022, 75, 187–212. [Google Scholar] [CrossRef] [PubMed]
  185. Wu, J.Y.; Srinivas, P.; Pogue, J.M. Cefiderocol: A Novel Agent for the Management of Multidrug-Resistant Gram-Negative Organisms. Infect. Dis. Ther. 2020, 9, 17. [Google Scholar] [CrossRef]
  186. Ybanez Garcia, L.; Manzano Lorenzo, R.; Martinez Segasti, F.; Martinez Sesmero, J.M. Real-Life Experience with Cefiderocol for the Treatment of Difficult-to-Treat Gram-Negative Infections. Infect. Dis. Trop. Med. 2023, 9, e1157. [Google Scholar]
  187. Hackel, M.A.; Tsuji, M.; Yamano, Y.; Echols, R.; Karlowsky, J.A.; Sahm, D.F. In Vitro Activity of the Siderophore Cephalosporin, Cefiderocol, against Carbapenem-Nonsusceptible and Multidrug-Resistant Isolates of Gram-Negative Bacilli Collected Worldwide in 2014 to 2016. Antimicrob. Agents Chemother. 2018, 62, 01968-17. [Google Scholar] [CrossRef]
  188. Lasarte-Monterrubio, C.; Fraile-Ribot, P.A.; Vázquez-Ucha, J.C.; Cabot, G.; Guijarro-Sánchez, P.; Alonso-García, I.; Rumbo-Feal, S.; Galán-Sánchez, F.; Beceiro, A.; Arca-Suárez, J.; et al. Activity of Cefiderocol, Imipenem/Relebactam, Cefepime/Taniborbactam and Cefepime/Zidebactam against Ceftolozane/Tazobactam- and Ceftazidime/Avibactam-Resistant Pseudomonas aeruginosa. J. Antimicrob. Chemother. 2022, 77, 2809–2815. [Google Scholar] [CrossRef] [PubMed]
  189. Karlowsky, J.A.; Hackel, M.A.; Takemura, M.; Yamano, Y.; Echols, R.; Sahm, D.F. In Vitro Susceptibility of Gram-Negative Pathogens to Cefiderocol in Five Consecutive Annual Multinational SIDERO-WT Surveillance Studies, 2014 to 2019. Antimicrob. Agents Chemother. 2022, 66, e01990-21. [Google Scholar] [CrossRef]
  190. Portsmouth, S.; van Veenhuyzen, D.; Echols, R.; Machida, M.; Ferreira, J.C.A.; Ariyasu, M.; Tenke, P.; Nagata, T. Den Cefiderocol versus Imipenem-Cilastatin for the Treatment of Complicated Urinary Tract Infections Caused by Gram-Negative Uropathogens: A Phase 2, Randomised, Double-Blind, Non-Inferiority Trial. Lancet Infect. Dis. 2018, 18, 1319–1328. [Google Scholar] [CrossRef] [PubMed]
  191. Wunderink, R.G.; Matsunaga, Y.; Ariyasu, M.; Clevenbergh, P.; Echols, R.; Kaye, K.S.; Kollef, M.; Menon, A.; Pogue, J.M.; Shorr, A.F.; et al. Cefiderocol versus High-Dose, Extended-Infusion Meropenem for the Treatment of Gram-Negative Nosocomial Pneumonia (APEKS-NP): A Randomised, Double-Blind, Phase 3, Non-Inferiority Trial. Lancet Infect. Dis. 2021, 21, 213–225. [Google Scholar] [CrossRef] [PubMed]
  192. Reig, S.; Le Gouellec, A.; Bleves, S. What Is New in the Anti–Pseudomonas aeruginosa Clinical Development Pipeline Since the 2017 WHO Alert? Front. Cell. Infect. Microbiol. 2022, 12, 862. [Google Scholar] [CrossRef]
  193. Lob, S.H.; Hackel, M.A.; Kazmierczak, K.M.; Young, K.; Motyl, M.R.; Karlowsky, J.A.; Sahm, D.F. In Vitro Activity of Imipenem-Relebactam against Gram-Negative ESKAPE Pathogens Isolated by Clinical Laboratories in the United States in 2015 (Results from the SMART Global Surveillance Program). Antimicrob. Agents Chemother. 2017, 61, 02209-16. [Google Scholar] [CrossRef]
  194. Mushtaq, S.; Meunier, D.; Vickers, A.; Woodford, N.; Livermore, D.M. Activity of Imipenem/Relebactam against Pseudomonas aeruginosa Producing ESBLs and Carbapenemases. J. Antimicrob. Chemother. 2021, 76, 434–442. [Google Scholar] [CrossRef]
  195. Motsch, J.; De Oliveira, C.U.M.; Stus, V.; Kö Ksal, I.; Lyulko, O.; Boucher, H.W.; Kaye, K.S.; File, T.M.; Brown, M.L.; Khan, I.; et al. RESTORE-IMI 1: A Multicenter, Randomized, Double-Blind Trial Comparing Efficacy and Safety of Imipenem/Relebactam vs Colistin Plus Imipenem in Patients with Imipenem-Nonsusceptible Bacterial Infections. Clin. Infect. Dis. 2020, 70, 1799–1808. [Google Scholar] [CrossRef]
  196. Titov, I.; Wunderink, R.G.; Roquilly, A.; Rodríguez Gonzalez, D.; David-Wang, A.; Boucher, H.W.; Kaye, K.S.; Losada, M.C.; Du, J.; Tipping, R.; et al. A Randomized, Double-Blind, Multicenter Trial Comparing Efficacy and Safety of Imipenem/Cilastatin/Relebactam Versus Piperacillin/Tazobactam in Adults wth Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia (RESTORE-IMI 2 Study). Clin. Infect. Dis. 2021, 73, e4539–e4548. [Google Scholar] [CrossRef]
  197. Isler, B.; Harris, P.; Stewart, A.G.; Paterson, D.L. An Update on Cefepime and Its Future Role in Combination with Novel β-Lactamase Inhibitors for MDR Enterobacterales and Pseudomonas aeruginosa. J. Antimicrob. Chemother. 2021, 76, 550–560. [Google Scholar] [CrossRef]
  198. ClinicalTrials.gov Safety and Efficacy Study of Cefepime-AAI101 in the Treatment of Complicated Urinary Tract Infections. Available online: https://clinicaltrials.gov/study/NCT03687255?intr=cefepime%2Fenmetazobactam&rank=4#publications (accessed on 11 October 2023).
  199. ClinicalTrials.gov Safety and Efficacy Study of Cefepime/VNRX-5133 in Patients with Complicated Urinary Tract Infections. Available online: https://clinicaltrials.gov/study/NCT03840148?intr=cefepime-taniborbactam&rank=2#publications (accessed on 11 October 2023).
  200. ClinicalTrials.gov Study of Cefepime-Zidebactam (FEP-ZID) in Complicated Urinary Tract Infection (CUTI) or Acute Pyelonephritis (AP). Available online: https://clinicaltrials.gov/study/NCT04979806 (accessed on 11 October 2023).
  201. Vázquez-Ucha, J.C.; Lasarte-Monterrubio, C.; Guijarro-Sánchez, P.; Oviaño, M.; Álvarez-Fraga, L.; Alonso-García, I.; Arca-Suárez, J.; Bou, G.; Beceiro, A. Assessment of Activity and Resistance Mechanisms to Cefepime in Combination with the Novel β-Lactamase Inhibitors Zidebactam, Taniborbactam, and Enmetazobactam against a Multicenter Collection of Carbapenemase-Producing Enterobacterales. Antimicrob. Agents Chemother. 2022, 66, e01676-21. [Google Scholar] [CrossRef] [PubMed]
  202. Eljaaly, K.; Alharbi, A.; Alshehri, S.; Ortwine, J.K.; Pogue, J.M. Plazomicin: A Novel Aminoglycoside for the Treatment of Resistant Gram-Negative Bacterial Infections. Drugs 2019, 79, 243–269. [Google Scholar] [CrossRef] [PubMed]
  203. Golkar, T.; Bassenden, A.V.; Maiti, K.; Arya, D.P.; Schmeing, T.M.; Berghuis, A.M. Structural Basis for Plazomicin Antibiotic Action and Resistance. Commun. Biol. 2021, 4, 729. [Google Scholar] [CrossRef] [PubMed]
  204. Wagenlehner, F.M.E.; Cloutier, D.J.; Komirenko, A.S.; Cebrik, D.S.; Krause, K.M.; Keepers, T.R.; Connolly, L.E.; Miller, L.G.; Friedland, I.; Dwyer, J.P. Once-Daily Plazomicin for Complicated Urinary Tract Infections. J. Urol. 2019, 202, 641–642. [Google Scholar] [CrossRef] [PubMed]
  205. Thwaites, M.; Hall, D.; Stoneburner, A.; Shinabarger, D.; Serio, A.W.; Krause, K.M.; Marra, A.; Pillar, C. Activity of Plazomicin in Combination with Other Antibiotics against Multidrug-Resistant Enterobacteriaceae. Diagn. Microbiol. Infect. Dis. 2018, 92, 338–345. [Google Scholar] [CrossRef]
Table 5. Enzyme types and their activity against antibiotics.
Table 5. Enzyme types and their activity against antibiotics.
ClassActive SiteEnzyme Type Substrates
ASerinePenicillinases:
Broad-spectrumBenzylpenicillin, aminopenicillins, carboxypenicillins, ureidopenicillins,
narrow-spectrum Cephalosporins
Extended-spectrum
(β-lactamase)		Substrates of broad-spectrum plus
oxymino-β-lactams (cefotaxime,
ceftazidime, ceftriaxone) and
aztreonam
CarbapenemasesSubstrates of extended-spectrum plus
cephamycins and carbapenems
BZn2+CarbapenemasesSubstrates of extended-spectrum plus
cephamycins and carbapenems
CSerineCephalosporinasesSubstrates of extended-spectrum plus
cephamycins
DSerineOxacillinases:
Broad-spectrumAminopenicillins, ureidopenicillin,
cloxacillin, methicillin, oxacillin, and
some narrow-spectrum cephalosporins
Extended-spectrum
(β-lactamase)		Substrates of broad-spectrum plus
oxymino-β-lactams and monobactams
CarbapenemasesSubstrates of extended-spectrum plus
cephamycins and carbapenems
Table 6. ESBL variants in P. aeruginosa and their MICs against principal antibiotics.
Table 6. ESBL variants in P. aeruginosa and their MICs against principal antibiotics.
StrainESBLMIC (mg/L)
IMPMEMCAZCAZ-AVI aCAZ-AVI bCAZ-AVI cTOL-TZB dTOL-TZB eTOL-TZB fPIP-TZB
R1189GES-1121622232321616
R184GES-21632644221684128
R186GES-532128641688888128
R3451GES-616643222232323264
R1188CTX-M183284441132
R1192PER-10.51>5126416165121286464
R1185BEL-1123242288864
R1187BEL-20.52128842323232128
R1205VEB-181625684464323232
R1217TEM-410.582110.50.50.54
R136SHV-2a1232442442256
IPM, imipenem; MEM, meropenem; CAZ, ceftazidime; CAZ-AVI, ceftazidime/avibactam; TOL-TZB, ceftolozane/tazobactam; PIP-TZP, piperacillin/tazobactam.a Avibactam at 4 mg/L, b Avibactam at 8 mg/L, c Avibactam at 16 mg/L.d Tazobactam at 4 mg/L, e Tazobactam at 8 mg/L, f Tazobactam at 16 mg/L.
Table 7. Phenotypic antibiogram of clinical strain P. aeruginosa compatible with a GES enzyme expression.
Table 7. Phenotypic antibiogram of clinical strain P. aeruginosa compatible with a GES enzyme expression.
P. aeruginosaRectal Swab
AntibioticMICSIR *
Amikacin≤4.0S
Cefepime>16.0R
Ceftazidime>64.0R
Ceftazidime/Avibactam=8.0S
Ceftolozane/Tazobactam=64.0R
Ciprofloxacin=0.5I
Colistin=1.0S
Meropenem=16.0R
Piperacillin/Tazobactam>128.0R
MIC = minimum inhibitory concentration; SIR = Susceptible (S), Susceptible, Iincreased Eexposure (I), and Resistant (R).* Breakpoint sec. Clinical breakpoints (v 13.1) [44].Comment: pPhenotype resistant to cefepime, ceftazidime, piperacillin/tazobactam, meropenem and ceftolozane/tazobactam. The phenotype could be compatible with a GES enzyme expression.
Table 8. The use of genetic technique sequencing plus the phenotypic antibiogram. The GeneXpert® via PCR method detected VIM. The phenotypic antibiogram correlates with the MBL detected.
Table 8. The use of genetic technique sequencing plus the phenotypic antibiogram. The GeneXpert® via PCR method detected VIM. The phenotypic antibiogram correlates with the MBL detected.
P. aeruginosaBlood Culture
GeneXprt®
KPCNot detected
VIMDetected
IMPNot detected
NDMNot detected
OXA-48Not detected
AntibioticMICSIR *
Amikacin=16.0S
Cefepime>16.0R
Ceftazidime>64.0R
Ceftazidime/Avibactam>64.0R
Ceftolozane/Tazobactam>64.0R
Ciprofloxacin>1.0R
Colistin=1.0S
Meropenem>64.0R
Piperacillin/Tazobactam>128.0R
Cefiderocol≤2.0S
MIC = minimum inhibitory concentration; SIR = Susceptible (S), Susceptible, Iincreased Eexposure (I), and Resistant (R). * Breakpoint sec. Clinical breakpoints (v 13.1) [44]. Comment: tThe antibiogram shows a resistance profile to all BL and new BL/BLI. Cefiderocol is susceptible. PCR detected VIM. This phenotype is compatible with the VIM MBL P. aeruginosa strain.
Table 9. Phenotypic antibiogram of clinical strain P. aeruginosa compatible with the production of AmpC enzyme.
Table 9. Phenotypic antibiogram of clinical strain P. aeruginosa compatible with the production of AmpC enzyme.
P. aeruginosaEcoculture
AntibioticMICSIR *
Amikacin=8.0S
Cefepime=4.0I
Ceftazidime=16.0R
Ceftazidime/Avibactam=2.0S
Ceftolozane/Tazobactam=1.0S
Ciprofloxacin=0.125I
Colistin=1.0S
Meropenem=0.25S
Piperacillin/Tazobactam=32.0R
MIC = minimum inhibitory concentration; SIR = Susceptible (S), Susceptible, Iincreased Eexposure (I), and Resistant (R).* Breakpoint sec. Clinical breakpoints (v 13.1) [44].Comment: tThe antibiogram shows a resistance profile to ceftazidime and piperacillin/tazobactam. Instead, cCefepime is still intermediate. Meropenem and new BL/BLIs are susceptible. This phenotype is compatible with the AmpC P. aeruginosa strain.
Table 10. Phenotypic antibiogram of clinical strain P. aeruginosa shows mutated AmpC enzyme production.
Table 10. Phenotypic antibiogram of clinical strain P. aeruginosa shows mutated AmpC enzyme production.
P. aeruginosaBronchoalveolar Lavage
AntibioticMICSIR *
Amikacin≤4.0S
Cefepime=8.0I
Ceftazidime=64.0R
Ceftazidime/Avibactam=64.0R
Ceftolozane/Tazobactam=64.0R
Ciprofloxacin=0.5I
Colistin≤0.5S
Meropenem=8.0I
Piperacillin/Tazobactam=16.0R
MIC = minimum inhibitory concentration; SIR = Susceptible (S), Susceptible, Iincreased Eexposure (I), and Resistant (R). * Breakpoint sec. Clinical breakpoints (v 13.1) [44]. Comment: pPhenotype resistant to ceftazidime, piperacillin/tazobactam, and new BL/BLIs. Increasing MIC of cefepime and meropenem. The phenotype could be compatible with an AmpC mutation in P. aeruginosa strain.
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Giovagnorio, F.; De Vito, A.; Madeddu, G.; Parisi, S.G.; Geremia, N. Resistance in Pseudomonas aeruginosa: A Narrative Review of Antibiogram Interpretation and Emerging Treatments. Antibiotics 2023, 12, 1621. https://doi.org/10.3390/antibiotics12111621

AMA Style

Giovagnorio F, De Vito A, Madeddu G, Parisi SG, Geremia N. Resistance in Pseudomonas aeruginosa: A Narrative Review of Antibiogram Interpretation and Emerging Treatments. Antibiotics. 2023; 12(11):1621. https://doi.org/10.3390/antibiotics12111621

Chicago/Turabian Style

Giovagnorio, Federico, Andrea De Vito, Giordano Madeddu, Saverio Giuseppe Parisi, and Nicholas Geremia. 2023. "Resistance in Pseudomonas aeruginosa: A Narrative Review of Antibiogram Interpretation and Emerging Treatments" Antibiotics 12, no. 11: 1621. https://doi.org/10.3390/antibiotics12111621

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