Next Article in Journal
Early Years of Carbapenem-Resistant Enterobacterales Epidemic in Abu Dhabi
Next Article in Special Issue
Population Pharmacokinetics of Orally Administered Clindamycin to Treat Prosthetic Joint Infections: A Prospective Study
Previous Article in Journal
Antimicrobial Resistance Policy Protagonists and Processes—A Qualitative Study of Policy Advocacy and Implementation
Previous Article in Special Issue
Antimicrobial Stewardship: Leveraging the “Butterfly Effect” of Hand Hygiene
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Antimicrobial Treatment of Pseudomonas aeruginosa Severe Sepsis

Division of Infectious Diseases, American University of Beirut Medical Center, P.O. Box 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon
Department of Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Department of Internal Medicine, Cleveland Clinic Fairview Hospital, Cleveland, OH 44111, USA
Division of Infectious Diseases, Department of Medicine, College of Medicine, Mayo Clinic, Rochester, MN 55902, USA
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Antibiotics 2022, 11(10), 1432;
Submission received: 29 September 2022 / Revised: 12 October 2022 / Accepted: 13 October 2022 / Published: 18 October 2022


Pseudomonas aeruginosa is a pathogen often encountered in a healthcare setting. It has consistently ranked among the most frequent pathogens seen in nosocomial infections, particularly bloodstream and respiratory tract infections. Aside from having intrinsic resistance to many antibiotics, it rapidly acquires resistance to novel agents. Given the high mortality of pseudomonal infections generally, and pseudomonal sepsis particularly, and with the rise of resistant strains, treatment can be very challenging for the clinician. In this paper, we will review the latest evidence for the optimal treatment of P. aeruginosa sepsis caused by susceptible as well as multidrug-resistant strains including the difficult to treat pathogens. We will also discuss the mode of drug infusion, indications for combination therapy, along with the proper dosing and duration of treatment for various conditions with a brief discussion of the use of non-antimicrobial agents.

1. Introduction

Pseudomonas aeruginosa is the third most common cause of Gram-negative bloodstream infections (BSI) with a mortality rate of up to 30% at 30 days, which surpasses that of Staphylococcus aureus and other Gram-negative bacteria causing BSI [1,2,3,4,5]. In neutropenic cancer patients, pseudomonal sepsis is the leading cause of death [6,7]. Furthermore, P. aeruginosa is classified as a “critical” pathogen by the World Health Organization (WHO), a “serious threat” by the Center for Disease Control and Prevention (CDC) and was included as one of the “ESKAPE” pathogens causing nosocomial infections worldwide [8]. Aside from its intrinsic resistance to many antimicrobials, acquired resistance makes treatment even more challenging. As resistant strains become more predominant, the risk of inappropriate empiric treatment increases, which results in higher risk of mortality [9,10].
P. aeruginosa sepsis is most often encountered in the setting of nosocomial infections in neutropenic patients, critically ill patients, or patients with burn injuries, cystic fibrosis, catheter-associated urinary tract infections (UTIs), surgical site infections, or intra-abdominal infections [11,12]. P. aeruginosa is a rare cause of community acquired sepsis except in immunocompromised patients, or patients with structural lung disease [13,14,15]. Given the severity of pseudomonal sepsis and increased antimicrobial resistance (AMR), initial management is often suboptimal. In fact, multidrug resistant P. aeruginosa (MDR-PA) has been reported as an independent risk factor for mortality in patients with hospital-acquired pneumonia [16]. Moreover, delayed proper therapy for pseudomonas pneumonia has been shown to significantly increase mortality when compared to appropriate therapy [17]. Therefore, it is essential to identify patients at risk for P. aeruginosa generally and MDR-PA particularly, to guide empiric therapy. Patients with invasive devices (indwelling catheters), intensive care unit (ICU) admission, bedridden status, diabetes mellitus, tracheostomy, recent history of treatment with broad-spectrum antimicrobials, history of carbapenem-resistant P. aeruginosa (CRPA) infection, burn wounds, pressure ulcers, neutropenia or other immunocompromising conditions should be considered at high risk for MDR-PA sepsis [18,19,20,21]. Moreover, some sites of infection are more likely to result in sepsis than others. For instance, P. aeruginosa pneumonia has been associated with the highest risk of sepsis, severe disease course, and mortality [5].
Although some dermatologic findings such as ecthyma gangrenosum, diffuse maculopapular lesions, tender vesicles or pustules in clusters, and areas of cellulitis that may progress to necrosis may be suggestive of pseudomonal sepsis, it is clinically indiscernible from sepsis due to other pathogens [22]. In addition, fever, tachycardia, tachypnea, and hypotension are unspecific signs that accompany most other Gram-negative sepsis syndromes. Hence, in the presence of risk factors for P. aeruginosa infection, antipseudomonal empirical antibiotic therapy (EAT) should be quickly initiated to reduce the risk for inadequate initial therapy, a well-established risk factor for increased 30-day mortality [23,24,25,26]. Prompt bacterial identification and susceptibility testing are essential to guide definitive antibiotic therapy. Conventional techniques that rely on bacterial culture often take several days to be reported and increase the risk of inadequate EAT. Novel techniques like whole genome sequencing (WGS), whole metagenomic sequencing (WMS) and matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) can reduce time to microbial identification and susceptibility testing from days to hours and even minutes. However, high cost, necessity for a database, lack of standardization, and inability to determine the minimum inhibitory concentration (MIC) are limiting the wider use of those techniques [27].
In this article, we will be discussing the latest evidence regarding the management of P. aeruginosa sepsis including the selection of antimicrobials for empiric and targeted therapy, as well as key factors such as dosing, duration of treatment, data on combination therapy, and alternative therapies.

2. Empirical Antimicrobial Therapy

EAT in sepsis should consider the patient’s allergies, comorbidities, the primary site of infection, prior antibiotic exposure, as well as local susceptibility patterns [20]. AMR should be highly suspected if there is recent admission to a hospital unit where prevalence of MDR-PA is greater than 20% or if the patient has received antipseudomonal beta-lactam antimicrobials within the past three months [28]. Although some studies reported trends towards decreased resistance of P. aeruginosa [29], low and middle income countries (LMICs) still suffer from a high burden of AMR [30]. The CDC reports that 32,600 cases of MDR-PA infections occurred in patients hospitalized in the United States in 2017, resulting in 2700 deaths [31]. For P. aeruginosa, MDR is defined as resistance to at least one agent in three or more antibiotic classes, extensive drug resistance (XDR) is defined as resistance to at least one agent in all but two or fewer antibiotic classes, and pan-drug resistance (PDR) is non-susceptibility to all agents [32]. Most recently, it was suggested to label MDR-PA as difficult to treat (DTR) when it is resistant to piperacillin-tazobactam, ceftazidime, cefepime, aztreonam, meropenem, imipenem-cilastatin, ciprofloxacin and levofloxacin [33,34].
Combination therapy in P. aeruginosa is often used to decrease the risk of inadequate EAT by combining drugs with multiple mechanisms of action. In a recently published multicenter retrospective study including 1017 neutropenic patients with P. aeruginosa bacteremic pneumonia, inappropriate EAT was given to 23% of patients and was associated with infection with MDR-PA. Additionally, inappropriate EAT was associated with increased 30-day mortality while appropriate EAT was independently associated with improved survival [10]. No consensus has been reached regarding the use of empirical combination versus monotherapy in P. aeruginosa sepsis, mainly due to the lack of robust prospective studies to provide strong levels of evidence [35]. In fact, a prospective study found no differences in outcomes between patients who received empirical combination antibiotics when compared to monotherapy [36]. A meta-analysis that included 1721 patients showed no difference in mortality among patients with pseudomonal infections who were treated empirically with beta-lactam monotherapy or combination therapy with the addition of an aminoglycoside (AG) or a fluoroquinolone (FQ) [37]. Furthermore, a Cochrane review that included 69 randomized controlled trials (RCTs) with a total of 7863 patients comparing beta lactam monotherapy and combination with an AG in the management of sepsis showed no difference in mortality in the P. aeruginosa subgroup analysis and significantly increased nephrotoxicity with combination therapy [38]. Moreover, a post hoc analysis of 593 patients with P. aeruginosa bacteremia showed no benefit of empiric combination therapy [39] and another meta-analysis of 4980 patients showed no difference in mortality, microbiological, or clinical cure when using empirical combination vs. monotherapy for patients with P. aeruginosa BSI or pneumonia [40]. On the other hand, a retrospective cohort study by Micek et al. including 305 patients with P. aeruginosa BSI showed that using combination therapy while awaiting for identification and susceptibility testing decreased the risk of inadequate EAT from 79.4% to 65.5% (p-value = 0.011). Additionally, mortality was significantly higher in patients who received inappropriate EAT (30.7% versus 17.8%, p-value = 0.018). In that study, inappropriate EAT, respiratory failure and septic shock were found to be independent risk factors for in-hospital mortality [41]. A recent meta-analysis of four studies that evaluated all-cause mortality (total of 148 patients), showed a significant decrease in mortality with combination therapy for severe infections caused by P. aeruginosa (OR 0.31, 95% CI 0.1–0.97, p-value = 0.045) [42].
Given the rise of AMR and the risk of inadequate EAT, combination empiric therapy should be highly considered in cases of severe sepsis [43]. The Surviving Sepsis campaign recommends combination empirical therapy during acute illness [44]. Two different mechanisms of action are preferred, typically a backbone beta-lactam (conventional or novel depending on risk of AMR) combined with an AG or a FQ [18,28]. Although one study suggested better outcomes when FQ was used instead of AG as a second agent [45], the choice of agent should be guided by local susceptibility patterns [28]. A retrospective cross-sectional analysis of blood and respiratory P. aeruginosa isolates from patients admitted to the ICU found that the combination with the highest susceptibility was piperacillin-tazobactam combined with an AG, while the combination with the lowest susceptibility was a carbapenem combined with a FQ [46]. Additionally, isolates were found to have less resistance to combinations with AG than those with FQ. A pharmacokinetic/pharmacodynamic (PK/PD) prospective randomized controlled trial suggested that a higher dose of amikacin (25 mg/kg) for patients with severe sepsis and at risk for P. aeruginosa infection was more likely to achieve an MIC that is closest to the EUCAST susceptibility breakpoint than standard dosing (15 mg/kg) [47]. Above all, the choice of empiric antimicrobial regimen should consider the potential for co-resistance to multiple first-line agents. For instance, a multinational microbiological study including 1783 isolates of MDR-PA from patients with P. aeruginosa BSI reported that co-resistance to many first-line antipseudomonal agents was very common, especially between piperacillin-tazobactam, meropenem and ceftazidime. Among antimicrobials that were included in the study, only Ceftolozane-tazobactam (C/T), a novel beta-lactam-beta-lactamase inhibitor combination, achieved significant additional activity against strains that exhibited resistance to one of the first-line agents [48]. Those findings suggest that C/T may be considered for empirical therapy if local rates of PA resistance to first-line agents is high. If combination empiric therapy is used, we highly recommend prompt de-escalation once there is clinical improvement and susceptibility results are available (Scheme 1). Additionally, although 40% of P. aeruginosa BSIs will have an unidentifiable origin, we recommend prompt source control when possible to improve patient outcomes [4,7].

3. Targeted Therapy for P. aeruginosa Sepsis

3.1. P. aeruginosa Sensitive to First Line Antipseudomonal Agents

P. aeruginosa is intrinsically resistant to several antibiotics due to the low permeability of its outer membrane, expression of various efflux pumps, and the production of antibiotic-inactivating enzymes such as inducible cephalosporinases. First-line beta-lactam agents for P. aeruginosa coverage include beta-lactam/beta-lactamase-inhibitor combinations (BL/BLI) (piperacillin-tazobactam and ticarcillin-clavulanate) and cephalosporins with antipseudomonal activity (ceftazidime, cefepime, and cefoperazone). Cefepime is the most commonly used beta-lactam antibiotic for P. aeruginosa [49]. Fluoroquinolones (ciprofloxacin and levofloxacin) remain currently the only oral treatment options for quinolone-sensitive P. aeruginosa. However, ciprofloxacin is superior to levofloxacin given the higher risk of emergence of quinolone-resistant P. aeruginosa with the use of levofloxacin [50]. Additionally, older FQ are less effective in acidic environments like UTIs [51]. Newer FQ such as finafloxacin and delafloxacin offer more activity in acidic environments but are yet to be widely available [52].
Second line agents for P. aeruginosa sepsis are carbapenems, including meropenem, imipenem, and doripenem. Meropenem is often preferred over imipenem given the latter’s higher propensity to induce resistance during treatment [53]. Doripenem was shown to be more active in vitro against P. aeruginosa compared to meropenem and imipenem but this has not been proven in clinical studies [54,55]. Nonetheless, cephalosporins should be favored over carbapenems when applicable due to more potent activity and narrower spectrum [56] as well as less propensity to select for future resistance [57].
Other agents include the monobactam class (aztreonam) which can be used as an alternative for patients with penicillin allergy. Gentamicin, tobramycin, and amikacin are all AG that can be active against P. aeruginosa but are not indicated as monotherapy except for UTIs, as they are associated with higher mortality rates [58]. In the case of severe sepsis, the pathophysiological shifts may lead to an increased volume of distribution and augmented renal clearance and may lead to suboptimal AG concentrations and potentially poorer outcomes [59]. For optimal coverage, we prefer tobramycin or amikacin over gentamicin [60]. Otherwise, plazomicin, a newer AG, was shown to be less effective and is currently only indicated in the treatment of UTIs [61].
Emergence of resistance during the course of treatment is a serious concern. Such is the case of a cohort of 271 patients with various P. aeruginosa infections receiving antipseudomonal antimicrobial therapy, where emergent resistance was reported in up to 10% of cases [57]. Additionally, standard susceptibility testing may not be as accurate in identifying resistance when hospitalization duration increases. This is likely due to development of resistance or acquisition of drug-resistant hospital-acquired strains, especially with prolonged stay in the ICU. Studies have indicated that initial antibiograms become unreliable as a predictor of susceptibility of P. aeruginosa after 1–2 weeks of hospitalization, particularly in the ICU, with a significant increase in MIC for multiple anti-pseudomonal agents [62,63]. Among conventional treatment agents, imipenem was the most likely to cause resistance emergence and ceftazidime was the least likely [57].

3.2. P. aeruginosa Resistant to First Line Therapy

P. aeruginosa can develop resistance through multiple mechanisms including selection of chromosomal mutations or horizontal acquisition of broad-spectrum resistance genes. Many resistance mechanisms are involved and include beta-lactamase production, AG-modifying enzymes, efflux pumps, porin loss, and various target site modifications [56]. Treatment options for CRPA is challenging given the variety of resistance mechanisms like the production of carbapenemases of different classes, outer membrane protein modification (OprD) or efflux pumps (MexAB, MexXY) (Table 1). Novel anti-pseudomonal drugs have been developed in response to this challenge to address the increase in resistance, which has been reported in up to 54% of nosocomial P. aeruginosa infections [64,65,66]. These include novel BL-BLI like C/T, ceftazidime/avibactam (CAZ/AVI), and imipenem-cilastatin/relebactam (IMI/REL) or novel cephalosporins like cefiderocol [20].
C/T has potent intrinsic anti-pseudomonal activity owing to its greater affinity to all essential penicillin-binding proteins (PBP) including PBP1b, PBP1c, and PBP3. Based on RCTs, the US Food and Drug association (FDA) and the European Medicines Agency (EMA) have approved the use of C/T in complicated intra-abdominal infections (IAIs), UTIs, and hospital-acquired pneumonia including ventilator-associated pneumonia (VAP) [72]. Subset analysis in the clinical trials showed that patients with P. aeruginosa had a favorable outcome compared to carbapenems in the HAP trial [73], carbapenems combined with metronidazole in the complicated IAI trial [74], and levofloxacin in the complicated UTIs trial [75]. CAZ/AVI is a novel BL/BLI combination approved by the FDA and the EMA for treatment of complicated UTIs, IAIs and infections with Gram negative resistant pathogens [76,77]. C/T and CAZ/AVI have been considered key therapeutic agents against resistant P. aeruginosa strains. However, since the commercialization of these agents, there has been emergence of resistance of P. aeruginosa following therapy, particularly with highly cephalosporin-resistant conferring mutations [78]. Data for treatment associated resistance in novel agents is still inconclusive, but it appears that the highest risk is with C/T and CAZ/AVI with common cross resistance to both agents [79,80]. Currently, real-world data is scarce and does not show superiority of an agent compared to another and therefore the choice of antimicrobial therapy should be based on the susceptibility profile which can vary according to the local epidemiology with regional variability [81]. Since the introduction of C/T, case reports and case series of MDR P. aeruginosa infections treated with C/T have demonstrated the clinical efficacy of this formulation, including its use to treat infections in critically ill patients, and those with cystic fibrosis [82,83]. The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recent guidelines for the treatment of infections caused by MDR Gram-negative bacilli suggest treatment with C/T as the single first choice for severe pseudomonal infections like severe sepsis [35]. As for the Infectious Diseases Society of America (IDSA), their guidelines recommend treatment with either C/T, CAZ/AVI, or imipenem/relebactam for infections with DTR P. aeruginosa outside the urinary tract [33]. In fact, although experience with CAZ/AVI in the management of P. aeruginosa infections is more limited, adding avibactam to ceftazidime has shown success in lowering MICs of many XDR P. aeruginosa isolates [84]. When considering XDR P. aeruginosa, an important concept is that although C/T is more likely to be active than CAZ/AVI, there are some C/T-resistant strains that can be susceptible to CAZ/AVI [85]. Therefore, in vitro susceptibilities to both agents should be obtained whenever possible.
Cefiderocol is a novel siderophore cephalosporin that can overcome efflux pumps. The IDSA recommends this agent as an alternative therapy when other novel BL/BLI agents are unavailable or if there is resistance or intolerance. A recent RCT compared the outcomes of patients with infections due to carbapenem-resistant bacteria treated with cefiderocol or best available therapy (BAT) [86]. Although the mortality rate was higher in the cefiderocol arm, the number of patients with P. aeruginosa infection was small, and increased mortality was only observed in patients with a mono- or polymicrobial infection including Acinetobacter baumannii. Furthermore, the results suggest that cefiderocol performed as well as BAT, but was not associated with significantly decreased mortality or reduced adverse events like what was reported from studies on newer BL/BLIs [87,88]. A recently published study of P. aeruginosa isolates resistant to C/T and CAZ/AVI concluded that cefiderocol was the most active agent against these isolates, with only one resistant clinical isolate (R504C substitution in PBP3) [78]. Imipenem-cilastatin/relebactam was also active against all isolates except two that carried the VIM-20 carbapenemase. In the same study, newer combinations such as cefepime/zidebactam and cefepime/taniborbactam displayed activity against most of the isolates, but resistance was observed in some strains with PBP3 amino acid substitutions and those that overexpressed mexAB-oprM or mexXY efflux pumps.
Evidence for the combination IMI/REL is derived from the RESTORE-IMI 1, a randomized controlled phase 3 trial, comparing IMI/REL to a combination of colistin and imipenem for patients with Gram-negative infections of which 77% were due to P. aeruginosa. There was a trend of lower mortality in the arm that was treated with the novel agent compared to combination therapy, but a significantly lower rate of adverse effects and nephrotoxicity [87]. In the subgroup analysis, patients with pneumonia as well as those with renal insufficiency had a higher mortality perhaps owing to lower concentration achieved with the given doses (86). As for meropenem/vaborbactam, it is not recommended given that the addition of vaborbactam was not found to restore susceptibility to meropenem-resistant strains [33].
Despite great outcomes associated with novel agents, these therapies remain inactive against most metallo-beta-lactamase-(MBL)-producing P. aeruginosa strains. The monobactam aztreonam is unique by demonstrating stability to hydrolysis by MBLs and may maintain activity against MBL-producing P. aeruginosa [89]. Many strains of MBL-producing P. aeruginosa will also contain mechanisms of resistance against aztreonam, such as increased expression of pseudomonas derived cephalosporinases (PDCs). Nevertheless, aztreonam is an attractive option in combination with CAZ/AVI for the treatment of infections caused by MBL-producing P. aeruginosa [90]. Cefiderocol has also shown activity against all carbapenemase classes including MBL but more clinical evidence is needed [91].
As for polymyxins (polymyxin B and colistin), the IDSA’s latest guidelines for the treatment of DTR P. aeruginosa recommends against their use when novel options with less nephrotoxicity are available [33]. However, given the increase in resistance rates and scarcity of novel antibiotics in LMICs, colistin has been increasingly used. Studies have shown that colistin can be used as salvage therapy when options are limited [92], and that it can be associated with a lower expected incidence of nephrotoxicity than previously expected. However, renal function should be closely monitored during therapy with appropriate dose adjustments.
Fosfomycin is an interesting choice for DTR P. aeruginosa given that it retains activity against some XDR and PDR strains which may be useful especially in critically ill patients with severe sepsis [93]. A case series including 48 critically ill patients, of whom 17 had infection with MDR-PA and 10 with severe sepsis, evaluated the efficacy of intravenous fosfomycin mainly in combination with colistin. Patients who received fosfomycin were found to have an all-cause 28-day mortality of 37.5%. Additionally, adverse events were minor and included nausea and reversible hypokalemia while resistance emergence to fosfomycin was found in only 3 patients [94]. Another retrospective study comparing outcomes between patients with CRPA pneumonia receiving a combination of doripenem and colistin or doripenem and fosfomycin found similar outcomes between both groups; however, results should be cautiously interpreted given the small size of the study’s population (49 patients) [94]. It should be noted that intravenous fosfomycin should not be given as monotherapy except in cases of uncomplicated UTI; otherwise, it should be given in combination with other agents for bacteremia, nosocomial pneumonia and complicated skin and soft tissue infection to avoid emergence of resistance [43].
While definitive combination therapy may exert a synergistic effect and possibly reduce the emergence of resistance, it can also result in increased side effects and unnecessary costs [56]. We have previously discussed the lack of rigorous evidence regarding the efficacy and safety of empirical combination therapy. Similarly, the evidence concerning the efficacy and safety of definitive combination antimicrobial therapy is still inconclusive and guidelines are yet to make a specific recommendation regarding combination therapy once susceptibility results are available. A retrospective study of 187 patients with P. aeruginosa BSI found that there was significant decrease in mortality in patients treated with definitive combination therapy compared to monotherapy by multivariate analysis (HR 0.30, 95% CI 0.13–0.71, p = 0.006) [1]. On the other hand, many studies have found no differences in outcomes between patients who received definitive combination vs. monotherapy [36]. For example, a retrospective study including 183 patients with P. aeruginosa VAP found similar outcomes with combination vs. monotherapy [95]. Furthermore, a meta-analysis found no difference in mortality between combination and monotherapy for patients with P. aeruginosa infections [37]. Hence, a single agent (preferably a beta-lactam based on susceptibility profile) should be used for definitive antimicrobial therapy since continuing combination therapy is unlikely to have any added value once susceptibilities are available [18].

4. Key Factors Related to Therapy

4.1. Antimicrobial Dosing

Due to the high level of intrinsic and acquired resistance among pseudomonal isolates, higher doses or extended infusions (EI) of beta-lactams may be necessary to ensure early attainment of target concentrations and maximize the duration of drug concentration required to exceed the MIC of the organism in severe infections [96]. The recommended doses for resistant and severe infections in the IDSA and ESCMID’s guidelines are higher than those used for other susceptible and mild infections [33,35]. In fact, in patients with severe sepsis or septic shock, the PK of most antibiotics are altered in the setting of an increased volume of distribution due to fluid administration and increased vascular permeability, altered renal clearance, and serum protein levels [97,98,99]. Hence, patients may require higher doses of antimicrobials to achieve efficient microbial killing [100]. For instance, a study using Monte Carlo simulation suggested that severe infections due to P. aeruginosa should preferably be treated with 2 g prolonged infusion of meropenem every 8 h rather than standard dosing (1 g every 8 h) [101]. Similarly, a PK/PD study reported that standard meropenem dosing may not be adequate for patients with non-susceptible organisms given that standard dosing did not achieve serum concentration over 2-times the MIC for over 40% of treatment duration in more than one-third of the patients. Instead, their PK modeling suggests that a higher dosage consisting of 500 mg bolus followed by 1500 mg extended infusion over 3 h every 8 h would achieve more adequate serum concentrations [102].
Another study aiming to optimize C/T dosing for the treatment of CRPA found that only the combination of C/T with amikacin as a loading dose of 20–25 mg/kg followed by 10–15 mg/kg/day achieved a cumulative fraction of response of >90% [103]. It should also be noted that critically ill patients who need renal replacement therapy may require higher dosing regimens to maintain effective serum concentrations [104]. In fact, although standard dosing of C/T of 1 g every 8 h achieves a serum concentration above the MIC for more than 40% of the treatment duration, a high dose of 2 g every 8 h might be needed to maintain a serum concentration above the MIC during the whole treatment duration [105]. In addition, the recommended dose of C/T for treatment of pneumonia is 3 g every 8 h based on the PK/PD modeling and according to which the ASPECT-NP trial dosing was based [73,106].

4.2. Infusion Rate

As previously discussed, the mainstay of treatment for P. aeruginosa sepsis are beta-lactams. However, beta-lactams exhibit a time-dependent effect on bacterial eradication and only achieve favorable microbiological and clinical outcomes when serum levels are maintained above the MIC during most of the duration of therapy. Prolonged infusion, whether given as extended infusion (EI) over multiple hours or as continuous infusions throughout the day, may help achieve a more sustainable serum concentration superior to the causative organism’s MIC. Despite all the challenges of EI, such as lack of intravenous access, tubing residuals, Y-site incompatibilities, and necessity for trained professionals, clinicians should opt for EI whenever possible to harvest its benefits. On many occasions, studies have shown that prolonged infusion may help improve patient outcomes. For instance, a retrospective cohort study including 194 patients with P. aeruginosa infections reported a 19.4% decrease in the 14-day mortality rate when comparing EI over four hours to standard intermittent infusion (p-value = 0.04). EI also shortened the duration of hospital stay by 17 days (p-value = 0.02) [107]. Another retrospective study including 87 patients with P. aeruginosa pneumonia and/or bacteremia who were treated with cefepime found that the overall mortality, length of stay in the ICU, and the need for ventilation were significantly lower in the EI group compared with the intermittent-infusion group [108]. According to a meta-analysis comparing EI to intermittent bolus (IB) (infusion over 0.5–1 h) in critically ill patients with severe P. aeruginosa, EI increases the probability of attaining serum concentrations superior to the causative organism’s susceptibility breakpoint, which is especially important for critically ill patients. In fact, using cefepime and piperacillin/tazobactam as EI consistently achieved concentrations above the breakpoints of susceptible agents only, but not concentrations above the breakpoints of resistant organisms. On the other hand, using EI for meropenem or doripenem achieved concentrations above the breakpoints for both susceptible and resistant organisms [109]. The accumulating evidence in favor of EI has lead both the IDSA and ESCMID to recommend its use for the treatment of non-susceptible strains [33].
On the other hand, the evidence regarding continuous infusion is still inconclusive. For example, a multicenter randomized controlled trial, the BLING II study, which included a total of 432 critically ill patients, showed no significant difference between intermittent and continuous infusion in ICU-free days, 90-day survival, duration of bacteremia, organ failure free days and clinical cure [110]. Additionally, 3 other meta-analyses have failed to show superiority of continuous infusion compared to IB [111,112,113]. Contrarily, the beta-lactam infusion in severe sepsis (BLISS) trial, which included a smaller population of 140 patients, found a higher clinical cure and fewer days on mechanical ventilation with continuous infusion [114] along with other clinical trials [115,116]. Thus, more randomized controlled trials are needed to draw definitive conclusions on the efficacy of continuous infusion of antimicrobial treatment for resistant P. aeruginosa sepsis.

4.3. Duration of Therapy

While many studies have supported the use of shorter antimicrobial courses to decrease AMR, cost, and adverse effects [117], the evidence on shortening the duration of treatment for a pseudomonal infection remains inconclusive. The duration of treatment for P. aeruginosa severe sepsis should be individualized according to the primary site of infection, the patient’s risk factors and underlying comorbidities, source control, susceptibility testing, trends of inflammatory biomarkers, and clinical improvement [118]. A recently published retrospective study comparing a short (6–10 days) course of antibiotics to a longer (11–15 days) course for P. aeruginosa bacteremia found no difference in mortality or bacteremia recurrence but found a significantly reduced hospitalization duration with shorter duration of treatment [119]. Moreover, a randomized controlled trial of 249 patients with P. aeruginosa BSI found no difference in mortality or recurrence when a course of 7 days was used compared to a course of 14 days and also reported shorter duration of hospitalization [120]. Hence, a shorter duration of treatment may be considered in immunocompetent patients who are showing clinical improvement and with a susceptible P. aeruginosa. However, a shorter duration may not be an option in immunocompromised patients like hematopoietic stem cell transplant (HSCT) patients who have a higher risk of recurrence if treated for less than 14 days [121]. For patients with sepsis secondary to pneumonia, we do not recommend a shortened treatment course of less than 14 days due to the high rate of recurrence in studies that compared short to long treatment durations [122,123].

5. Alternative Therapies

5.1. Phage Therapy

Phage therapy is a promising alternative therapies for patients who did not respond to conventional antibiotics [124]. Phages are viruses that can infect bacteria and are usually found in any natural environment where bacteria are present [125]. In clinical settings, phages can be used to target specific bacteria by migrating towards the site of infection, adhering to the cell surface of the targeted bacteria, and injecting their DNA into it. Phage therapy has the ability to significantly decrease bacterial loads, especially in P. aeruginosa biofilms, which is where antibiotics usually fail [126,127,128]. To date, there are over 700 phages infecting P. aeruginosa isolated and sequenced [129]. Several studies using phages against P. aeruginosa showed significant decrease in bacterial loads in vitro and ex vivo and improved survival rates in animals [126,130,131]. Three phages produced in Georgia are currently commercialized for use in P. aeruginosa sepsis. One clinical trial (NCT04636554) on personalized phage therapy in patients with COVID-19 and bacterial co-infection (including P. aeruginosa bacteremia/sepsis) is currently ongoing [132]. There are various case reports in humans showing clearance of P. aeruginosa using single or cocktail phage therapy in numerous infections, namely pressure ulcers with bacteremia [133], chronic wounds [134], chronic otitis [135], venous leg ulcers [136], and vascular graft infection [137]. Phage therapy was also combined with antibiotics (phage-antibiotic synergy) to increase bacterial killing of MDR P. aeruginosa in vitro [138,139]. There are several case reports of a combination of antibiotics with phage therapy to treat resistant P. aeruginosa infections, particularly in cases of chronic infections: antibiotics in various reports consisted of ceftazidime in endovascular infection with bacteremia [140]; meropenem, tobramycin, and polymyxin B in endovascular infection with bacteremia [141]; cefiderocol in cranial osteomyelitis [142], meropenem and colistin in UTI [143], CAZ/AVI in femur osteomyelitis [144], piperacillin/tazobactam, tobramycin, and colistin in lung transplant recipients [145], and other conventional antibiotics for empyema [146]. However, to date there is no data on the efficacy of phage therapy in sepsis.

5.2. Antibodies/Vaccines

Several vaccines targeting major components of P. aeruginosa have been developed to date, especially in patients with cystic fibrosis. These include vaccines against lipopolysaccharides, flagella, pili, type 3 secretion system, outer membrane proteins, and outer membrane vesicles as well as inactivated whole-cell [147]. The overwhelming majority of these vaccines have been focusing on eradicating or preventing lung infections, with few studies on P. aeruginosa bacteremia or sepsis [148]. Although vaccines have promising clinical applications, none have been marketed yet. A randomized clinical trial assessing the efficacy, safety, and immunogenicity of IC43 recombinant P. aeruginosa vaccine for mechanically ventilated ICU patients found that the vaccine achieved adequate immunogenicity but with no clinical benefits compared to placebo [149]. On the other hand, the PcrV protein, a part of the type three secretion system which allows the secretion of 4 exotoxins: U, S, T, and Y [150], has been associated with poorer clinical outcomes which has led to the development of monoclonal antibodies (mAb) against PcrV [151]. An anti-PcrV PE Gylated monoclonal antibody was assessed in a randomized double-blind controlled clinical trial and showed a favorable tolerance profile and a decreased P. aeruginosa pneumonia incidence in patients mechanically ventilated and colonized with P. aeruginosa [152]. This monoclonal antibody was also associated with improved survival when used in combination with antibiotics in mice [153]. Bispecific antibodies with a mAb targeting P. aeruginosa cross-linked with a mAb targeting the complement were tested in primates and showed a degree of protection against the bacterium [154]. Nevertheless, there are no clinical trials investigating the role of antibodies in the setting of P. aeruginosa sepsis and data might be extrapolated from studies on different sites of infection.

5.3. Quorum Sensing

P. aeruginosa uses quorum sensing, which is a signaling system implicating the exchange of chemical signals (or auto-inducers) within bacterial populations to regulate its phenotype and density. The concentration of these chemical signals can alter the gene expression of these bacteria by switching gene transcription on and off [155]. P. aeruginosa depends mainly on three interconnected quorum sensing systems (las, rhli, and the Pseudomonas quinolone signal (PQS)) which may be clinically relevant [156]. Several compounds have been shown to inhibit quorum sensing in P. aeruginosa including furanones, azithromycin, plant extracts, and garlic, in patients with cystic fibrosis who are chronically infected with P. aeruginosa [157,158,159,160].

5.4. Bacteriocins

Bacteriocins are peptides produced by bacteria that have a wide range of antimicrobial activity [161]. They are still in the early phase of assessment as potential alternatives to usual antimicrobial drugs, especially in catheter-associated UTI caused by P. aeruginosa [162,163].

6. Conclusions

The burden and mortality of P. aeruginosa severe sepsis is further exacerbated by the increased prevalence of resistant strains. Clinicians should have a high index of suspicion for pseudomonal sepsis in immunocompromised patients, those critically ill and patients with comorbidities and multiple hospitalizations. Treatment options for MDR and DTR strains are limited. Given the high mortality of severe sepsis due to P. aeruginosa, combination empirical treatment with two different mechanisms of action should be initiated without delay while waiting for the susceptibility results. However, de-escalation to monotherapy with an antimicrobial with the narrowest spectrum is highly advised once susceptibility is known. The introduction of the novel beta lactams has been a welcomed addition to the treatment armamentarium with good clinical efficacy and safety profile. The polymyxins are not recommended because of their significant nephrotoxicity and should only be used when no other options are available. Proper management leads to significant improvement in patient outcomes. Key factors including source control, EI, dosing adjustment, and appropriate treatment duration should be considered in the management of P. aeruginosa sepsis. With the advent of novel agents, emergence of resistance has been reported and the need for alternative therapies might be warranted. Several alternative treatments show early promising results but need to be tested in more rigorous studies. Applying stewardship principles in the management of patients is essential to ensure good outcomes and prevent the emergence of future resistance.

Author Contributions

Conceptualization, S.S.K.; writing—original draft preparation, J.Z., S.L.S., J.-R.H. and S.F.H.; writing—review and editing, J.Z., S.L.S., J.-R.H. and S.F.H.; supervision, S.S.K. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Tschudin-Sutter, S.; Fosse, N.; Frei, R.; Widmer, A.F. Combination therapy for treatment of Pseudomonas aeruginosa bloodstream infections. PLoS ONE 2018, 13, e0203295. [Google Scholar] [CrossRef] [PubMed]
  2. Horino, T.; Chiba, A.; Kawano, S.; Kato, T.; Sato, F.; Maruyama, Y.; Nakazawa, Y.; Yoshikawa, K.; Yoshida, M.; Hori, S. Clinical characteristics and risk factors for mortality in patients with bacteremia caused by Pseudomonas aeruginosa. Intern. Med. Tokyo Jpn. 2012, 51, 59–64. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Kang, C.-I.; Kim, S.-H.; Kim, H.-B.; Park, S.-W.; Choe, Y.-J.; Oh, M.; Kim, E.-C.; Choe, K.-W. Pseudomonas aeruginosa Bacteremia: Risk Factors for Mortality and Influence of Delayed Receipt of Effective Antimicrobial Therapy on Clinical Outcome. Clin. Infect. Dis. 2003, 37, 745–751. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Magill, S.S.; Edwards, J.R.; Bamberg, W.; Beldavs, Z.G.; Dumyati, G.; Kainer, M.A.; Lynfield, R.; Maloney, M.; McAllister-Hollod, L.; Nadle, J.; et al. Multistate point-prevalence survey of health care-associated infections. N. Engl. J. Med. 2014, 370, 1198–1208. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Thaden, J.T.; Park, L.P.; Maskarinec, S.A.; Ruffin, F.; Fowler, V.G.; van Duin, D. Results from a 13-Year Prospective Cohort Study Show Increased Mortality Associated with Bloodstream Infections Caused by Pseudomonas aeruginosa Compared to Other Bacteria. Antimicrob. Agents Chemother. 2017, 61, e02671-16. [Google Scholar] [CrossRef] [Green Version]
  6. Cattaneo, C.; Antoniazzi, F.; Casari, S.; Ravizzola, G.; Gelmi, M.; Pagani, C.; D’Adda, M.; Morello, E.; Re, A.; Borlenghi, E.; et al. P. aeruginosa bloodstream infections among hematological patients: An old or new question? Ann. Hematol. 2012, 91, 1299–1304. [Google Scholar] [CrossRef]
  7. Tofas, P.; Samarkos, M.; Piperaki, E.-T.; Kosmidis, C.; Triantafyllopoulou, I.-D.; Kotsopoulou, M.; Pantazatou, A.; Perlorentzou, S.; Poulli, A.; Vagia, M.; et al. Pseudomonas aeruginosa bacteraemia in patients with hematologic malignancies: Risk factors, treatment and outcome. Diagn. Microbiol. Infect. Dis. 2017, 88, 335–341. [Google Scholar] [CrossRef]
  8. Botelho, J.; Grosso, F.; Peixe, L. Antibiotic resistance in Pseudomonas aeruginosa—Mechanisms, epidemiology and evolution. Drug Resist. Updates 2019, 44, 100640. [Google Scholar] [CrossRef]
  9. Babich, T.; Naucler, P.; Valik, J.K.; Giske, C.G.; Benito, N.; Cardona, R.; Rivera, A.; Pulcini, C.; Fattah, M.A.; Haquin, J.; et al. Risk factors for mortality among patients with Pseudomonas aeruginosa bacteraemia: A retrospective multicentre study. Int. J. Antimicrob. Agents 2020, 55, 105847. [Google Scholar] [CrossRef]
  10. Albasanz-Puig, A.; Durà-Miralles, X.; Laporte-Amargós, J.; Mussetti, A.; Ruiz-Camps, I.; Puerta-Alcalde, P.; Abdala, E.; Oltolini, C.; Akova, M.; Montejo, J.M.; et al. Effect of Combination Antibiotic Empirical Therapy on Mortality in Neutropenic Cancer Patients with Pseudomonas aeruginosa Pneumonia. Microorganisms 2022, 10, 733. [Google Scholar] [CrossRef]
  11. Nakamura, A.; Miyake, K.; Misawa, S.; Kuno, Y.; Horii, T.; Kondo, S.; Tabe, Y.; Ohsaka, A. Meropenem as predictive risk factor for isolation of multidrug-resistant Pseudomonas aeruginosa. J. Hosp. Infect. 2013, 83, 153–155. [Google Scholar] [CrossRef] [PubMed]
  12. Aloush, V.; Navon-Venezia, S.; Seigman-Igra, Y.; Cabili, S.; Carmeli, Y. Multidrug-resistant Pseudomonas aeruginosa: Risk factors and clinical impact. Antimicrob. Agents Chemother. 2006, 50, 43–48. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Mendelson, M.H.; Gurtman, A.; Szabo, S.; Neibart, E.; Meyers, B.R.; Policar, M.; Cheung, T.W.; Lillienfeld, D.; Hammer, G.; Reddy, S. Pseudomonas aeruginosa bacteremia in patients with AIDS. Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 1994, 18, 886–895. [Google Scholar] [CrossRef] [PubMed]
  14. Flores, G.; Stavola, J.J.; Noel, G.J. Bacteremia due to Pseudomonas aeruginosa in children with AIDS. Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 1993, 16, 706–708. [Google Scholar] [CrossRef]
  15. Zidaru, A.; Sofjan, A.K.; Devarajan, S.R.; Tam, V.H. Clinical outcomes of cystic fibrosis patients with Pseudomonas aeruginosa bloodstream infection. J. Glob. Antimicrob. Resist. 2022, 29, 551–552. [Google Scholar] [CrossRef]
  16. Micek, S.T.; Wunderink, R.G.; Kollef, M.H.; Chen, C.; Rello, J.; Chastre, J.; Antonelli, M.; Welte, T.; Clair, B.; Ostermann, H.; et al. An international multicenter retrospective study of Pseudomonas aeruginosa nosocomial pneumonia: Impact of multidrug resistance. Crit. Care Lond. Engl. 2015, 19, 219. [Google Scholar] [CrossRef] [Green Version]
  17. Tumbarello, M.; De Pascale, G.; Trecarichi, E.M.; Spanu, T.; Antonicelli, F.; Maviglia, R.; Pennisi, M.A.; Bello, G.; Antonelli, M. Clinical outcomes of Pseudomonas aeruginosa pneumonia in intensive care unit patients. Intensive Care Med. 2013, 39, 682–692. [Google Scholar] [CrossRef]
  18. Bassetti, M.; Vena, A.; Croxatto, A.; Righi, E.; Guery, B. How to manage Pseudomonas aeruginosa infections. Drugs Context 2018, 7, 212527. [Google Scholar] [CrossRef]
  19. Jabbour, J.-F.; Sharara, S.L.; Kanj, S.S. Treatment of multidrug-resistant Gram-negative skin and soft tissue infections. Curr. Opin. Infect. Dis. 2020, 33, 146–154. [Google Scholar] [CrossRef]
  20. Ibrahim, D.; Jabbour, J.-F.; Kanj, S.S. Current choices of antibiotic treatment for Pseudomonas aeruginosa infections. Curr. Opin. Infect. Dis. 2020, 33, 464–473. [Google Scholar] [CrossRef]
  21. Herrera, S.; Bodro, M.; Soriano, A. Predictors of multidrug resistant Pseudomonas aeruginosa involvement in bloodstream infections. Curr. Opin. Infect. Dis. 2021, 34, 686–692. [Google Scholar] [CrossRef] [PubMed]
  22. Forkner, C.E.; Frei, E.; Edgcomb, J.H.; Utz, J.P. Pseudomonas septicemia; observations on twenty-three cases. Am. J. Med. 1958, 25, 877–889. [Google Scholar] [CrossRef]
  23. Bassetti, M.; Righi, E.; Carnelutti, A. Bloodstream infections in the Intensive Care Unit. Virulence 2016, 7, 267–279. [Google Scholar] [CrossRef] [PubMed]
  24. Tansarli, G.S.; Andreatos, N.; Pliakos, E.E.; Mylonakis, E. A Systematic Review and Meta-analysis of Antibiotic Treatment Duration for Bacteremia Due to Enterobacteriaceae. Antimicrob. Agents Chemother. 2019, 63, e02495-18. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Van Duin, D.; Kaye, K.S.; Neuner, E.A.; Bonomo, R.A. Carbapenem-resistant Enterobacteriaceae: A review of treatment and outcomes. Diagn. Microbiol. Infect. Dis. 2013, 75, 115–120. [Google Scholar] [CrossRef] [Green Version]
  26. Falcone, M.; Bassetti, M.; Tiseo, G.; Giordano, C.; Nencini, E.; Russo, A.; Graziano, E.; Tagliaferri, E.; Leonildi, A.; Barnini, S.; et al. Time to appropriate antibiotic therapy is a predictor of outcome in patients with bloodstream infection caused by KPC-producing Klebsiella pneumoniae. Crit. Care Lond. Engl. 2020, 24, 29. [Google Scholar] [CrossRef] [Green Version]
  27. Kaprou, G.D.; Bergšpica, I.; Alexa, E.A.; Alvarez-Ordóñez, A.; Prieto, M. Rapid Methods for Antimicrobial Resistance Diagnostics. Antibiotics 2021, 10, 209. [Google Scholar] [CrossRef]
  28. Bassetti, M.; Vena, A.; Russo, A.; Croxatto, A.; Calandra, T.; Guery, B. Rational approach in the management of Pseudomonas aeruginosa infections. Curr. Opin. Infect. Dis. 2018, 31, 578–586. [Google Scholar] [CrossRef]
  29. Jernigan, J.A.; Hatfield, K.M.; Wolford, H.; Nelson, R.E.; Olubajo, B.; Reddy, S.C.; McCarthy, N.; Paul, P.; McDonald, L.C.; Kallen, A.; et al. Multidrug-Resistant Bacterial Infections in U.S. Hospitalized Patients, 2012–2017. N. Engl. J. Med. 2020, 382, 1309–1319. [Google Scholar] [CrossRef]
  30. Rosenthal, V.D.; Al-Abdely, H.M.; El-Kholy, A.A.; AlKhawaja, S.A.A.; Leblebicioglu, H.; Mehta, Y.; Rai, V.; Hung, N.V.; Kanj, S.S.; Salama, M.F.; et al. International Nosocomial Infection Control Consortium report, data summary of 50 countries for 2010-2015: Device-associated module. Am. J. Infect. Control 2016, 44, 1495–1504. [Google Scholar] [CrossRef]
  31. 2019 Antibiotic Resistance Threats Report. Available online: (accessed on 31 July 2022).
  32. Magiorakos, A.-P.; Srinivasan, A.; Carey, R.B.; Carmeli, Y.; Falagas, M.E.; Giske, C.G.; Harbarth, S.; Hindler, J.F.; Kahlmeter, G.; Olsson-Liljequist, B.; et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: An international expert proposal for interim standard definitions for acquired resistance. Clin. Microbiol. Infect. Off. Publ. Eur. Soc. Clin. Microbiol. Infect. Dis. 2012, 18, 268–281. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Tamma, P.D.; Aitken, S.L.; Bonomo, R.A.; Mathers, A.J.; van Duin, D.; Clancy, C.J. IDSA Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections: Version 1.0; IDSA: Arlington, VA, USA, 2022; Available online: (accessed on 31 July 2022).
  34. Kadri, S.S.; Adjemian, J.; Lai, Y.L.; Spaulding, A.B.; Ricotta, E.; Prevots, D.R.; Palmore, T.N.; Rhee, C.; Klompas, M.; Dekker, J.P.; et al. Difficult-To-Treat Resistance in Gram-Negative Bacteremia at 173 US Hospitals: Retrospective Cohort Analysis of Prevalence, Predictors, and Outcome of Resistance to All First-Line Agents. Clin. Infect. Dis. 2018, 67, 1803–1814. Available online: (accessed on 28 September 2022). [CrossRef] [PubMed] [Green Version]
  35. Paul, M.; Carrara, E.; Retamar, P.; Tängdén, T.; Bitterman, R.; Bonomo, R.A.; de Waele, J.; Daikos, G.L.; Akova, M.; Harbarth, S.; et al. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli (endorsed by European society of intensive care medicine). Clin. Microbiol. Infect. 2022, 28, 521–547. [Google Scholar] [CrossRef]
  36. Díaz-Cañestro, M.; Periañez, L.; Mulet, X.; Martin-Pena, M.L.; Fraile-Ribot, P.A.; Ayestarán, I.; Colomar, A.; Nuñez, B.; Maciá, M.; Novo, A.; et al. Ceftolozane/tazobactam for the treatment of multidrug resistant Pseudomonas aeruginosa: Experience from the Balearic Islands. Eur. J. Clin. Microbiol. Infect. Dis. 2018, 37, 2191–2200. [Google Scholar] [CrossRef]
  37. Vardakas, K.Z.; Tansarli, G.S.; Bliziotis, I.A.; Falagas, M.E. β-Lactam plus aminoglycoside or fluoroquinolone combination versus β-lactam monotherapy for Pseudomonas aeruginosa infections: A meta-analysis. Int. J. Antimicrob. Agents 2013, 41, 301–310. [Google Scholar] [CrossRef] [PubMed]
  38. Paul, M.; Lador, A.; Grozinsky-Glasberg, S.; Leibovici, L. Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst. Rev. 2014, 2014, CD003344. [Google Scholar] [CrossRef] [PubMed]
  39. Peña, C.; Suarez, C.; Ocampo-Sosa, A.; Murillas, J.; Almirante, B.; Pomar, V.; Aguilar, M.; Granados, A.; Calbo, E.; Rodríguez-Baño, J.; et al. Effect of Adequate Single-Drug vs Combination Antimicrobial Therapy on Mortality in Pseudomonas aeruginosa Bloodstream Infections: A Post Hoc Analysis of a Prospective Cohort. In Clinical Infectious Diseases; Oxford Academic: Oxford, UK, 2013; Available online: (accessed on 31 July 2022).
  40. Onorato, L.; Macera, M.; Calò, F.; Cirillo, P.; Di Caprio, G.; Coppola, N. Beta-lactam monotherapy or combination therapy for bloodstream infections or pneumonia due to Pseudomonas aeruginosa: A meta-analysis. Int. J. Antimicrob. Agents 2022, 59, 106512. [Google Scholar] [CrossRef]
  41. Micek, S.T.; Lloyd, A.E.; Ritchie, D.J.; Reichley, R.M.; Fraser, V.J.; Kollef, M.H. Pseudomonas aeruginosa bloodstream infection: Importance of appropriate initial antimicrobial treatment. Antimicrob. Agents Chemother. 2005, 49, 1306–1311. [Google Scholar] [CrossRef] [Green Version]
  42. Fiore, M.; Corrente, A.; Pace, M.C.; Alfieri, A.; Simeon, V.; Ippolito, M.; Giarratano, A.; Cortegiani, A. Ceftolozane-Tazobactam Combination Therapy Compared to Ceftolozane-Tazobactam Monotherapy for the Treatment of Severe Infections: A Systematic Review and Meta-Analysis; Antibiotics: Basel, Switzerland, 2021. Available online: (accessed on 31 July 2022).
  43. Al Salman, J.; Al Dabal, L.; Bassetti, M.; Alfouzan, W.A.; Al Maslamani, M.; Alraddadi, B.; Elhoufi, A.; Enani, M.; Khamis, F.A.; Mokkadas, E.; et al. Management of infections caused by WHO critical priority Gram-negative pathogens in Arab countries of the Middle East: A consensus paper. Int. J. Antimicrob. Agents 2020, 56, 106104. [Google Scholar] [CrossRef]
  44. Rhodes, A.; Evans, L.E.; Alhazzani, W.; Levy, M.M.; Antonelli, M.; Ferrer, R.; Kumar, A.; Sevransky, J.E.; Sprung, C.L.; Nunnally, M.E.; et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit. Care Med. 2017, 45, 486–552. [Google Scholar] [CrossRef]
  45. Paulsson, M.; Granrot, A.; Ahl, J.; Tham, J.; Resman, F.; Riesbeck, K.; Månsson, F. Antimicrobial combination treatment including ciprofloxacin decreased the mortality rate of Pseudomonas aeruginosa bacteraemia: A retrospective cohort study. Eur. J. Clin. Microbiol. Infect. Dis. 2017, 36, 1187–1196. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Puzniak, L.; DePestel, D.D.; Srinivasan, A.; Ye, G.; Murray, J.; Merchant, S.; DeRyke, C.A.; Gupta, V. A Combination Antibiogram Evaluation for Pseudomonas aeruginosa in Respiratory and Blood Sources from Intensive Care Unit (ICU) and Non-ICU Settings in U.S. Hospitals. Antimicrob. Agents Chemother. 2019, 63, e02564-18. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. De Winter, S.; Wauters, J.; Meersseman, W.; Verhaegen, J.; Van Wijngaerden, E.; Peetermans, W.; Annaert, P.; Verelst, S.; Spriet, I. Higher versus standard amikacin single dose in emergency department patients with severe sepsis and septic shock: A randomised controlled trial. Int. J. Antimicrob. Agents 2018, 51, 562–570. [Google Scholar] [CrossRef] [PubMed]
  48. Moise, P.A.; Gonzalez, M.; Alekseeva, I.; Lopez, D.; Akrich, B.; DeRyke, C.A.; Chen, W.-T.; Pavia, J.; Palermo, B.; Hackel, M.; et al. Collective assessment of antimicrobial susceptibility among the most common Gram-negative respiratory pathogens driving therapy in the ICU. JAC-Antimicrob. Resist. 2021, 3, dlaa129. [Google Scholar] [CrossRef]
  49. Britt, N.S.; Ritchie, D.J.; Kollef, M.H.; Burnham, C.A.; Durkin, M.J.; Hampton, N.B.; Micek, S.T. Importance of Site of Infection and Antibiotic Selection in the Treatment of Carbapenem-Resistant Pseudomonas aeruginosa Sepsis. Antimicrob. Agents Chemother. 2018, 62, e02400-17. [Google Scholar] [CrossRef] [Green Version]
  50. Kaye, K.S.; Kanafani, Z.A.; Dodds, A.E.; Engemann, J.J.; Weber, S.G.; Carmeli, Y. Differential Effects of Levofloxacin and Ciprofloxacin on the Risk for Isolation of Quinolone-Resistant Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2006, 50, 2192–2196. [Google Scholar] [CrossRef] [Green Version]
  51. McKeage, K. Finafloxacin: First global approval. Drugs 2015, 75, 687–693. [Google Scholar] [CrossRef]
  52. Kocsis, B.; Gulyás, D.; Szabó, D. Delafloxacin, Finafloxacin, and Zabofloxacin: Novel Fluoroquinolones in the Antibiotic Pipeline. Antibiotics 2021, 10, 1506. [Google Scholar] [CrossRef]
  53. Gimeno, C.; Cantón, R.; García, A.; Gobernado, M. Grupo Español de Estudio de Doripenem [Comparative activity of doripenem, meropenem, and imipenem in recent clinical isolates obtained during the COMPACT-Spain epidemiological surveillance study]. Rev. Espanola Quimioter. Publicacion Of. Soc. Espanola Quimioter. 2010, 23, 144–152. [Google Scholar]
  54. Pillar, C.M.; Torres, M.K.; Brown, N.P.; Shah, D.; Sahm, D.F. In vitro activity of doripenem, a carbapenem for the treatment of challenging infections caused by gram-negative bacteria, against recent clinical isolates from the United States. Antimicrob. Agents Chemother. 2008, 52, 4388–4399. [Google Scholar] [CrossRef] [Green Version]
  55. Korten, V.; Söyletir, G.; Yalçın, A.N.; Oğünç, D.; Dokuzoğuz, B.; Esener, H.; Ulusoy, S.; Tünger, A.; Aygen, B.; Sümerkan, B.; et al. Comparative evaluation of in vitro activities of carbapenems against gram-negative pathogens: Turkish data of COMPACT study. Mikrobiyol. Bul. 2011, 45, 197–209. [Google Scholar] [PubMed]
  56. Kanj, S.S.; Kanafani, Z.A. Current Concepts in Antimicrobial Therapy Against Resistant Gram-Negative Organisms: Extended-Spectrum β-Lactamase–Producing Enterobacteriaceae, Carbapenem-Resistant Enterobacteriaceae, and Multidrug-Resistant Pseudomonas aeruginosa. Mayo Clin. Proc. 2011, 86, 250–259. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Carmeli, Y.; Troillet, N.; Eliopoulos, G.M.; Samore, M.H. Emergence of antibiotic-resistant Pseudomonas aeruginosa: Comparison of risks associated with different antipseudomonal agents. Antimicrob. Agents Chemother. 1999, 43, 1379–1382. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Phe, K.; Bowers, D.R.; Babic, J.T.; Tam, V.H. Outcomes of empiric aminoglycoside monotherapy for Pseudomonas aeruginosa bacteremia. Diagn. Microbiol. Infect. Dis. 2019, 93, 346–348. [Google Scholar] [CrossRef] [PubMed]
  59. Varghese, J.M.; Roberts, J.A.; Lipman, J. Antimicrobial Pharmacokinetic and Pharmacodynamic Issues in the Critically Ill with Severe Sepsis and Septic Shock-Critical Care Clinics; Elsevier: Amsterdam, The Netherlands, 2011; Available online: (accessed on 16 September 2022).
  60. Kluge, R.M.; Standiford, H.C.; Tatem, B.; Young, V.M.; Greene, W.H.; Schimpff, S.C.; Calia, F.M.; Hornick, R.B. Comparative activity of tobramycin, amikacin, and gentamicin alone and with carbenicillin against Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 1974, 6, 442–446. [Google Scholar] [CrossRef] [Green Version]
  61. Zhanel, G.G.; Lawson, C.D.; Zelenitsky, S.; Findlay, B.; Schweizer, F.; Adam, H.; Walkty, A.; Rubinstein, E.; Gin, A.S.; Hoban, D.J.; et al. Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin. Expert Rev. Anti Infect. Ther. 2012, 10, 459–473. [Google Scholar] [CrossRef]
  62. Anderson, D.J.; Miller, B.; Marfatia, R.; Drew, R. Ability of an antibiogram to predict Pseudomonas aeruginosa susceptibility to targeted antimicrobials based on hospital day of isolation. Infect. Control Hosp. Epidemiol. 2012, 33, 589–593. [Google Scholar] [CrossRef] [Green Version]
  63. Riou, M.; Carbonnelle, S.; Avrain, L.; Mesaros, N.; Pirnay, J.-P.; Bilocq, F.; De Vos, D.; Simon, A.; Piérard, D.; Jacobs, F.; et al. In vivo development of antimicrobial resistance in Pseudomonas aeruginosa strains isolated from the lower respiratory tract of Intensive Care Unit patients with nosocomial pneumonia and receiving antipseudomonal therapy. Int. J. Antimicrob. Agents 2010, 36, 513–522. [Google Scholar] [CrossRef] [Green Version]
  64. De Matos, E.C.O.; De Matos, H.J.; da Conceição, M.L.; Rodrigues, Y.C.; Carneiro, I.C.D.R.S.; Lima, K.V.B. Clinical and microbiological features of infections caused by Pseudomonas aeruginosa in patients hospitalized in intensive care units. Rev. Soc. Bras. Med. Trop. 2016, 49, 305–311. [Google Scholar] [CrossRef]
  65. Peng, Y.; Bi, J.; Shi, J.; Li, Y.; Ye, X.; Chen, X.; Yao, Z. Multidrug-resistant Pseudomonas aeruginosa infections pose growing threat to health care–associated infection control in the hospitals of Southern China: A case-control surveillance study. Am. J. Infect. Control 2014, 42, 1308–1311. [Google Scholar] [CrossRef]
  66. Jeong, S.J.; Yoon, S.S.; Bae, I.K.; Jeong, S.H.; Kim, J.M.; Lee, K. Risk factors for mortality in patients with bloodstream infections caused by carbapenem-resistant Pseudomonas aeruginosa: Clinical impact of bacterial virulence and strains on outcome. Diagn. Microbiol. Infect. Dis. 2014, 80, 130–135. [Google Scholar] [CrossRef] [PubMed]
  67. Fetroja® (Cefiderocol). Antimicrobial Activity. Available online: (accessed on 22 September 2022).
  68. Torrens, G.; Cabot, G.; Ocampo-Sosa, A.A.; Conejo, M.C.; Zamorano, L.; Navarro, F.; Pascual, Á.; Martínez-Martínez, L.; Oliver, A. Activity of Ceftazidime-Avibactam against Clinical and Isogenic Laboratory Pseudomonas aeruginosa Isolates Expressing Combinations of Most Relevant β-Lactam Resistance Mechanisms. Antimicrob. Agents Chemother. 2016, 60, 6407–6410. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Iregui, A.; Khan, Z.; Landman, D.; Quale, J. Activity of Cefiderocol Against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii Endemic to Medical Centers in New York City. Microb. Drug Resist. 2020, 26, 722–726. [Google Scholar] [CrossRef] [Green Version]
  70. 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, e02165-19. [Google Scholar] [CrossRef] [PubMed]
  71. Doi, Y. Treatment Options for Carbapenem-resistant Gram-negative Bacterial Infections. In Clinical Infectious Diseases; Oxford Academic: Oxford, UK, 2019; Available online: (accessed on 22 September 2022).
  72. EMA. Zerbaxa. Available online: (accessed on 28 September 2022).
  73. 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]
  74. Solomkin, J.; Hershberger, E.; Miller, B.; Popejoy, M.; Friedland, I.; Steenbergen, J.; Yoon, M.; Collins, S.; Yuan, G.; Barie, P.S.; et al. Ceftolozane/Tazobactam Plus Metronidazole for Complicated Intra-abdominal Infections in an Era of Multidrug Resistance: Results From a Randomized, Double-Blind, Phase 3 Trial (ASPECT-cIAI). Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 2015, 60, 1462–1471. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Wagenlehner, L.M.; Umeh, O.; Steenbergen, J.; Yuan, G.; Darouiche, R.O. Ceftolozane-TAZOBACTAM Compared with Levofloxacin in the Treatment of Complicated Urinary-Tract Infections, Including Pyelonephritis: A Randomised, Double-Blind, Phase 3 Trial (ASPECT-cUTI). Lancet 2015, 385, 1949–1956. Available online: (accessed on 28 September 2022).
  76. AVYCAZ. Safely and Effectively. Available online:,s006lbl.pdf (accessed on 28 September 2022).
  77. EMA. Zavicefta. Available online: (accessed on 29 September 2022).
  78. 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]
  79. Skoglund, E.; Abodakpi, H.; Rios, R.; Diaz, L.; De La Cadena, E.; Dinh, A.Q.; Ardila, J.; Miller, W.R.; Munita, J.M.; Arias, C.A.; et al. In Vivo Resistance to Ceftolozane/Tazobactam in Pseudomonas aeruginosa Arising by AmpC- and Non-AmpC-Mediated Pathways. Case Rep. Infect. Dis. 2018, 2018, 9095203. [Google Scholar] [CrossRef] [Green Version]
  80. Tamma, P.D.; Beisken, S.; Bergman, Y.; Posch, A.E.; Avdic, E.; Sharara, S.L.; Cosgrove, S.E.; Simner, P.J. Modifiable Risk Factors for the Emergence of Ceftolozane-tazobactam Resistance. Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 2021, 73, e4599–e4606. [Google Scholar] [CrossRef]
  81. Sid Ahmed, M.A.; Hamid, J.M.; Husain, A.A.; Hadi, H.A.; Skariah, S.; Sultan, A.A.; Ibrahim, E.B.; Al Khal, A.L.; Soderquist, B.; Jass, J.; et al. Clinical outcomes, molecular epidemiology and resistance mechanisms of multidrug-resistant Pseudomonas aeruginosa isolated from bloodstream infections from Qatar. Ann. Med. 2021, 53, 2345–2353. [Google Scholar] [CrossRef]
  82. Garazzino, S.; Altieri, E.; Silvestro, E.; Pruccoli, G.; Scolfaro, C.; Bignamini, E. Ceftolozane/Tazobactam for Treating Children With Exacerbations of Cystic Fibrosis Due to Pseudomonas aeruginosa: A Review of Available Data. Front. Pediatr. 2020, 8, 173. [Google Scholar] [CrossRef] [PubMed]
  83. Pfaller, M.A.; Shortridge, D.; Harris, K.A.; Garrison, M.W.; DeRyke, C.A.; DePestel, D.D.; Moise, P.A.; Sader, H.S. Ceftolozane-tazobactam activity against clinical isolates of Pseudomonas aeruginosa from ICU patients with pneumonia: United States, 2015–2018. Int. J. Infect. Dis. IJID Off. Publ. Int. Soc. Infect. Dis. 2021, 112, 321–326. [Google Scholar] [CrossRef] [PubMed]
  84. Nichols, W.W.; Stone, G.G.; Newell, P.; Broadhurst, H.; Wardman, A.; MacPherson, M.; Yates, K.; Riccobene, T.; Critchley, I.A.; Das, S. Ceftazidime-Avibactam Susceptibility Breakpoints against Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2018, 62, e02590-17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Teo, J.Q.-M.; Lim, J.C.; Tang, C.Y.; Lee, S.J.-Y.; Tan, S.H.; Sim, J.H.-C.; Ong, R.T.-H.; Kwa, A.L.-H. Ceftolozane/Tazobactam Resistance and Mechanisms in Carbapenem-Nonsusceptible Pseudomonas aeruginosa. mSphere 2021, 6, e01026-20. [Google Scholar] [CrossRef] [PubMed]
  86. Bassetti, M.; Echols, R.; Matsunaga, Y.; Ariyasu, M.; Doi, Y.; Ferrer, R.; Lodise, T.P.; Naas, T.; Niki, Y.; Paterson, D.L.; et al. Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): A randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect. Dis. 2021, 21, 226–240. [Google Scholar] [CrossRef]
  87. Motsch, J.; Murta de Oliveira, C.; Stus, V.; Köksal, 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. Off. Publ. Infect. Dis. Soc. Am. 2020, 70, 1799–1808. [Google Scholar] [CrossRef] [Green Version]
  88. 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. Off. Publ. Infect. Dis. Soc. Am. 2020, 71, 304–310. [Google Scholar] [CrossRef]
  89. Karlowsky, J.A.; Kazmierczak, K.M.; de Jonge, B.L.M.; Hackel, M.A.; Sahm, D.F.; Bradford, P.A. In Vitro Activity of Aztreonam-Avibactam against Enterobacteriaceae and Pseudomonas aeruginosa Isolated by Clinical Laboratories in 40 Countries from 2012 to 2015. Antimicrob. Agents Chemother. 2017, 61, e00472-17. Available online: (accessed on 22 September 2022).
  90. Lee, M.; Abbey, T.; Biagi, M.; Wenzler, E. Activity of aztreonam in combination with ceftazidime–avibactam against serine- and metallo-β-lactamase–producing Pseudomonas aeruginosa. Diagn. Microbiol. Infect. Dis. 2021, 99, 115227. Available online: (accessed on 22 September 2022). [CrossRef]
  91. 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. Available online: (accessed on 7 September 2022). [CrossRef]
  92. Kallel, H.; Bahloul, M.; Hergafi, L.; Akrout, M.; Ketata, W.; Chelly, H.; Hamida, C.B.; Rekik, N.; Hammami, A.; Bouaziz, M. Colistin as a salvage therapy for nosocomial infections caused by multidrug-resistant bacteria in the ICU. Int. J. Antimicrob. Agents 2006, 28, 366–369. [Google Scholar] [CrossRef] [PubMed]
  93. Hanberger, H.; Giske, C.G.; Ciamarellou, H. When and How to Cover for Resistant Gram-Negative Bacilli in Severe Sepsis and Septic Shock. Curr. Infect. Dis. Rep. 2011, 13, 416. Available online: (accessed on 29 September 2022). [CrossRef] [PubMed]
  94. Pontikis, K.; Karaiskos, I.; Bastani, S.; Dimopoulos, G.; Kalogirou, M.; Katsiari, M.; Oikonomou, A.; Poulakou, G.; Roilides, E.; Giamarellou, H. Outcomes of critically ill intensive care unit patients treated with fosfomycin for infections due to pandrug-resistant and extensively drug-resistant carbapenemase-producing Gram-negative bacteria. Int. J. Antimicrob. Agents 2014, 43, 52–59. [Google Scholar] [CrossRef] [PubMed]
  95. Garnacho-Montero, J.; Sa-Borges, M.; Sole-Violan, J.; Barcenilla, F.; Escoresca-Ortega, A.; Ochoa, M.; Cayuela, A.; Rello, J. Optimal management therapy for Pseudomonas aeruginosa ventilator-associated pneumonia: An observational, multicenter study comparing monotherapy with combination antibiotic therapy. Crit. Care Med. 2007, 35, 1888–1895. [Google Scholar] [CrossRef] [PubMed]
  96. Vardakas, K.Z.; Voulgaris, G.L.; Maliaros, A.; Samonis, G.; Falagas, M.E. Prolonged versus short-term intravenous infusion of antipseudomonal β-lactams for patients with sepsis: A systematic review and meta-analysis of randomised trials. Lancet Infect. Dis. 2018, 18, 108–120. [Google Scholar] [CrossRef]
  97. Gonçalves-Pereira, J.; Póvoa, P. Antibiotics in critically ill patients: A systematic review of the pharmacokinetics of β-lactams. Crit. Care Lond. Engl. 2011, 15, R206. [Google Scholar] [CrossRef] [Green Version]
  98. Carlier, M.; Carrette, S.; Roberts, J.A.; Stove, V.; Verstraete, A.; Hoste, E.; Depuydt, P.; Decruyenaere, J.; Lipman, J.; Wallis, S.C.; et al. Meropenem and piperacillin/tazobactam prescribing in critically ill patients: Does augmented renal clearance affect pharmacokinetic/pharmacodynamic target attainment when extended infusions are used? Crit. Care Lond. Engl. 2013, 17, R84. [Google Scholar] [CrossRef] [Green Version]
  99. De Waele, J.; Carlier, M.; Hoste, E.; Depuydt, P.; Decruyenaere, J.; Wallis, S.C.; Lipman, J.; Roberts, J.A. Extended versus bolus infusion of meropenem and piperacillin: A pharmacokinetic analysis. Minerva Anestesiol. 2014, 80, 1302–1309. [Google Scholar]
  100. Taccone, F.S.; Cotton, F.; Roisin, S.; Vincent, J.; Jacobs, F. Optimal Meropenem Concentrations To Treat Multidrug-Resistant Pseudomonas aeruginosa Septic Shock. Antimicrob. Agents Chemother. 2012, 56, 2129–2131. Available online: (accessed on 16 September 2022). [CrossRef] [Green Version]
  101. Kuti, J.L.; Dandekar, P.K.; Nightingale, C.H.; Nicolau, D.P. Use of Monte Carlo simulation to design an optimized pharmacodynamic dosing strategy for meropenem. J. Clin. Pharmacol. 2003, 43, 1116–1123. [Google Scholar] [CrossRef]
  102. Kothekar, A.T.; Divatia, J.V.; Myatra, S.N.; Patil, A.; Nookala Krishnamurthy, M.; Maheshwarappa, H.M.; Siddiqui, S.S.; Gurjar, M.; Biswas, S.; Gota, V. Clinical pharmacokinetics of 3-h extended infusion of meropenem in adult patients with severe sepsis and septic shock: Implications for empirical therapy against Gram-negative bacteria. Ann. Intensive Care 2020, 10, 4. [Google Scholar] [CrossRef] [PubMed]
  103. Nasomsong, W.; Nulsopapon, P.; Changpradub, D.; Pungcharoenkijkul, S.; Hanyanunt, P.; Chatreewattanakul, T.; Santimaleeworagun, W. Optimizing Doses of Ceftolozane/Tazobactam as Monotherapy or in Combination with Amikacin to Treat Carbapenem-Resistant Pseudomonas aeruginosa. Antibiotics 2022, 11, 517. [Google Scholar] [CrossRef] [PubMed]
  104. Gatti, M.; Giannella, M.; Raschi, E.; Viale, P.; De Ponti, F. Ceftolozane/tazobactam exposure in critically ill patients undergoing continuous renal replacement therapy: A PK/PD approach to tailor dosing. J. Antimicrob. Chemother. 2021, 76, 199–205. [Google Scholar] [CrossRef] [PubMed]
  105. Ruiz, J.; Ferrada, A.; Salavert, M.; Gordon, M.; Villarreal, E.; Castellanos-Ortega, Á.; Ramirez, P. Ceftolozane/Tazobactam Dosing Requirements Against Pseudomonas aeruginosa Bacteremia. Dose-Response Publ. Int. Hormesis Soc. 2020, 18, 1559325819885790. [Google Scholar] [CrossRef] [Green Version]
  106. Xiao, A.J.; Miller, B.W.; Huntington, J.A.; Nicolau, D.P. Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic-derived dose justification for phase 3 studies in patients with nosocomial pneumonia. J. Clin. Pharmacol. 2016, 56, 56–66. [Google Scholar] [CrossRef] [Green Version]
  107. Lodise, T.P.; Lomaestro, B.; Drusano, G.L. Piperacillin-tazobactam for Pseudomonas aeruginosa infection: Clinical implications of an extended-infusion dosing strategy. Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 2007, 44, 357–363. [Google Scholar] [CrossRef]
  108. Bauer, K.A.; West, J.E.; O’Brien, J.M.; Goff, D.A. Extended-infusion cefepime reduces mortality in patients with Pseudomonas aeruginosa infections. Antimicrob. Agents Chemother. 2013, 57, 2907–2912. [Google Scholar] [CrossRef] [Green Version]
  109. Abrar, K.; Thabit, P.D.; Hobbs, A.L.V.; Guzman, O.E.; Shea, K.M. The pharmacodynamics of prolonged infusion blactams for the treatment of Pseudomonas aeruginosa infections: A systematic review. Clin. Ther. 2019, 41, 2397–2415.e8. [Google Scholar] [CrossRef]
  110. Dulhunty, J.M.; Roberts, J.A.; Davis, J.S.; Webb, S.A.R.; Bellomo, R.; Gomersall, C.; Shirwadkar, C.; Eastwood, G.M.; Myburgh, J.; Paterson, D.L.; et al. A Multicenter Randomized Trial of Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis. Am. J. Respir. Crit. Care Med. 2015, 192, 1298–1305. Available online: (accessed on 16 September 2022). [CrossRef] [Green Version]
  111. Shiu, J.; Wang, E.; Tejani, A.M.; Wasdell, M. Continuous versus intermittent infusions of antibiotics for the treatment of severe acute infections. Cochrane Database Syst. Rev. 2013, 2013, CD008481. [Google Scholar] [CrossRef]
  112. Roberts, J.A.; Webb, S.; Paterson, D.; Ho, K.M.; Lipman, J. A systematic review on clinical benefits of continuous administration of beta-lactam antibiotics. Crit. Care Med. 2009, 37, 2071–2078. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Kasiakou, S.K.; Sermaides, G.J.; Michalopoulos, A.; Soteriades, E.S.; Falagas, M.E. Continuous versus intermittent intravenous administration of antibiotics: A meta-analysis of randomised controlled trials. Lancet Infect. Dis. 2005, 5, 581–589. [Google Scholar] [CrossRef]
  114. Abdul-Aziz, M.H.; Sulaiman, H.; Mat-Nor, M.B.; Rai, V.; Wong, K.K.; Hasan, M.S.; Abd Rahman, A.N.; Jamal, J.A.; Wallis, S.C.; Lipman, J.; et al. Beta-Lactam Infusion in Severe Sepsis (BLISS): A prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis. Intensive Care Med. 2016, 42, 1535–1545. Available online: (accessed on 16 September 2022). [CrossRef] [PubMed]
  115. Dulhunty, J.M.; Roberts, J.A.; Davis, J.S.; Webb, S.A.R.; Bellomo, R.; Gomersall, C.; Shirwadkar, C.; Eastwood, G.M.; Myburgh, J.; Paterson, D.L.; et al. Continuous infusion of beta-lactam antibiotics in severe sepsis: A multicenter double-blind, randomized controlled trial. Clin. Infect. Dis. 2013, 56, 236–244. Available online: (accessed on 16 September 2022). [CrossRef] [Green Version]
  116. Chytra, I.; Stepan, M.; Benes, J.; Pelnar, P.; Zidkova, A.; Bergerova, T.; Pradl, R.; Kasal, E. Clinical and microbiological efficacy of continuous versus intermittent application of meropenem in critically ill patients: A randomized open-label controlled trial. Crit. Care 2012, 16, R113. [Google Scholar] [CrossRef] [Green Version]
  117. Li, X.; Liu, C.; Mao, Z.; Li, Q.; Qi, S.; Zhou, F. Short-course versus long-course antibiotic treatment in patients with uncomplicated gram-negative bacteremia: A systematic review and meta-analysis. J. Clin. Pharm. Ther. 2021, 46, 173–180. [Google Scholar] [CrossRef]
  118. Haddad, S.F.; Allaw, F.; Kanj, S.S. Duration of antibiotic therapy in Gram-negative infections with a particular focus on multidrug-resistant pathogens. Curr. Opin. Infect. Dis. 2022, 10, 1097. [Google Scholar] [CrossRef]
  119. Babich, T.; Naucler, P.; Valik, J.K.; Giske, C.G.; Benito, N.; Cardona, R.; Rivera, A.; Pulcini, C.; Fattah, M.A.; Haquin, J.; et al. Duration of Treatment for Pseudomonas aeruginosa Bacteremia: A Retrospective Study. Infect. Dis. Ther. 2022, 11, 1505–1519. [Google Scholar] [CrossRef]
  120. Fabre, V.; Amoah, J.; Cosgrove, S.E.; Tamma, D.P. Antibiotic Therapy for Pseudomonas aeruginosa Bloodstream Infections: How Long Is Long Enough? Clin. Infect. Dis. 2019, 69, 2011–2014. Available online: (accessed on 16 September 2022). [CrossRef]
  121. Olearo, F.; Kronig, I.; Masouridi-Levrat, S.; Chalandon, Y.; Khanna, N.; Passweg, J.; Medinger, M.; Mueller, N.J.; Schanz, U.; van Delden, C.; et al. Optimal Treatment Duration of Pseudomonas aeruginosa Infections in Allogeneic Hematopoietic Cell Transplant Recipients. Open Forum Infect. Dis. 2020, 7, ofaa246. Available online: (accessed on 16 September 2022). [CrossRef]
  122. Chastre, J.; Wolff, M.; Fagon, J.-Y.; Chevret, S.; Thomas, F.; Wermert, D.; Clementi, E.; Gonzalez, J.; Jusserand, D.; Asfar, P.; et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: A randomized trial. JAMA 2003, 290, 2588–2598. [Google Scholar] [CrossRef] [PubMed]
  123. Pugh, R.; Grant, C.; Cooke, R.P.D.; Dempsey, G. Short-course versus prolonged-course antibiotic therapy for hospital-acquired pneumonia in critically ill adults. Cochrane Database Syst. Rev. 2015, 2015, CD007577. [Google Scholar] [CrossRef] [PubMed]
  124. Maharjan, A.; Nepal, R.; Dhungana, G.; Parajuli, A.; Regmi, M.; Upadhyaya, E.; Mandal, D.; Shrestha, M.; Pradhan, P.; Manandhar, K.D.; et al. Isolation and Characterization of Lytic Bacteriophage Against Multi-drug Resistant Pseudomonas aeruginosa. J. Nepal Health Res. Counc. 2022, 19, 717–724. [Google Scholar] [CrossRef] [PubMed]
  125. Dion, M.B.; Oechslin, F.; Moineau, S. Phage diversity, genomics and phylogeny. Nat. Rev. Microbiol. 2020, 18, 125–138. [Google Scholar] [CrossRef]
  126. Waters, E.M.; Neill, D.R.; Kaman, B.; Sahota, J.S.; Clokie, M.R.J.; Winstanley, C.; Kadioglu, A. Phage therapy is highly effective against chronic lung infections with Pseudomonas aeruginosa. Thorax 2017, 72, 666–667. [Google Scholar] [CrossRef] [Green Version]
  127. Fong, S.A.; Drilling, A.; Morales, S.; Cornet, M.E.; Woodworth, B.A.; Fokkens, W.J.; Psaltis, A.J.; Vreugde, S.; Wormald, P.-J. Activity of Bacteriophages in Removing Biofilms of Pseudomonas aeruginosa Isolates from Chronic Rhinosinusitis Patients. Front. Cell. Infect. Microbiol. 2017, 7, 418. [Google Scholar] [CrossRef] [Green Version]
  128. Guo, M.; Feng, C.; Ren, J.; Zhuang, X.; Zhang, Y.; Zhu, Y.; Dong, K.; He, P.; Guo, X.; Qin, J. A Novel Antimicrobial Endolysin, LysPA26, against Pseudomonas aeruginosa. Front. Microbiol. 2017, 8, 293. [Google Scholar] [CrossRef] [Green Version]
  129. Cook, R.; Brown, N.; Redgwell, T.; Rihtman, B.; Barnes, M.; Clokie, M.; Stekel, D.J.; Hobman, J.; Jones, M.A.; Millard, A. INfrastructure for a PHAge REference Database: Identification of Large-Scale Biases in the Current Collection of Cultured Phage Genomes. PHAGE 2021, 2, 214–223. [Google Scholar] [CrossRef]
  130. Nordstrom, H.R.; Evans, D.R.; Finney, A.G.; Westbrook, K.J.; Zamora, P.F.; Hofstaedter, C.E.; Yassin, M.H.; Pradhan, A.; Iovleva, A.; Ernst, R.K.; et al. Genomic characterization of lytic bacteriophages targeting genetically diverse Pseudomonas aeruginosa clinical isolates. iScience 2022, 25, 104372. [Google Scholar] [CrossRef]
  131. Cafora, M.; Deflorian, G.; Forti, F.; Ferrari, L.; Binelli, G.; Briani, F.; Ghisotti, D.; Pistocchi, A. Phage therapy against Pseudomonas aeruginosa infections in a cystic fibrosis zebrafish model. Sci. Rep. 2019, 9, 1527. [Google Scholar] [CrossRef] [Green Version]
  132. Adaptive Phage Therapeutics, Inc. Expanded Access Study of Phage Treatment in COVID-19 Patients on Anti-Microbials for Pneumonia or Bacteremia/Septicemia Due to A. Baumannii, P. Aeruginosa or S. Aureus; Adaptive Phage Therapeutics, Inc.: Gaithersburg, MD, USA, 2021. [Google Scholar]
  133. Jennes, S.; Merabishvili, M.; Soentjens, P.; Pang, K.W.; Rose, T.; Keersebilck, E.; Soete, O.; François, P.-M.; Teodorescu, S.; Verween, G.; et al. Use of bacteriophages in the treatment of colistin-only-sensitive Pseudomonas aeruginosa septicaemia in a patient with acute kidney injury—A case report. Crit. Care 2017, 21, 129. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Bach, M.S.; de Vries, C.R.; Khosravi, A.; Sweere, J.M.; Popescu, M.C.; Chen, Q.; Demirdjian, S.; Hargil, A.; Van Belleghem, J.D.; Kaber, G.; et al. Filamentous bacteriophage delays healing of Pseudomonas-infected wounds. Cell Rep. Med. 2022, 3, 100656. [Google Scholar] [CrossRef] [PubMed]
  135. Wright, A.; Hawkins, C.H.; Anggård, E.E.; Harper, D.R. A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy. Clin. Otolaryngol. 2009, 34, 349–357. [Google Scholar] [CrossRef]
  136. Rhoads, D.D.; Wolcott, R.D.; Kuskowski, M.A.; Wolcott, B.M.; Ward, L.S.; Sulakvelidze, A. Bacteriophage therapy of venous leg ulcers in humans: Results of a phase I safety trial. J. Wound Care 2009, 18, 237–243. [Google Scholar] [CrossRef] [PubMed]
  137. Rubalskii, E.; Ruemke, S.; Salmoukas, C.; Boyle, E.C.; Warnecke, G.; Tudorache, I.; Shrestha, M.; Schmitto, J.D.; Martens, A.; Rojas, S.V.; et al. Bacteriophage Therapy for Critical Infections Related to Cardiothoracic Surgery. Antibiotics 2020, 9, 232. [Google Scholar] [CrossRef] [PubMed]
  138. Oechslin, F.; Piccardi, P.; Mancini, S.; Gabard, J.; Moreillon, P.; Entenza, J.M.; Resch, G.; Que, Y.-A. Synergistic Interaction Between Phage Therapy and Antibiotics Clears Pseudomonas aeruginosa Infection in Endocarditis and Reduces Virulence. J. Infect. Dis. 2017, 215, 703–712. [Google Scholar] [CrossRef] [Green Version]
  139. Holger, D.J.; Lev, K.L.; Kebriaei, R.; Morrisette, T.; Shah, R.; Alexander, J.; Lehman, S.M.; Rybak, M.J. Bacteriophage-antibiotic combination therapy for multidrug-resistant Pseudomonas aeruginosa: In vitro synergy testing. J. Appl. Microbiol. 2022, 133, 1636–1649. [Google Scholar] [CrossRef]
  140. Chan, B.K.; Turner, P.E.; Kim, S.; Mojibian, H.R.; Elefteriades, J.A.; Narayan, D. Phage treatment of an aortic graft infected with Pseudomonas aeruginosa. Evol. Med. Public Health 2018, 2018, 60–66. [Google Scholar] [CrossRef] [Green Version]
  141. Duplessis, C.; Biswas, B.; Hanisch, B.; Perkins, M.; Henry, M.; Quinones, J.; Wolfe, D.; Estrella, L.; Hamilton, T. Refractory Pseudomonas Bacteremia in a 2-Year-Old Sterilized by Bacteriophage Therapy. J. Pediatr. Infect. Dis. Soc. 2018, 7, 253–256. [Google Scholar] [CrossRef] [Green Version]
  142. Simner, P.J.; Cherian, J.; Suh, G.A.; Bergman, Y.; Beisken, S.; Fackler, J.; Lee, M.; Hopkins, R.J.; Tamma, P.D. Combination of phage therapy and cefiderocol to successfully treat Pseudomonas aeruginosa cranial osteomyelitis. JAC-Antimicrob. Resist. 2022, 4, dlac046. [Google Scholar] [CrossRef]
  143. Khawaldeh, A.; Morales, S.; Dillon, B.; Alavidze, Z.; Ginn, A.N.; Thomas, L.; Chapman, S.J.; Dublanchet, A.; Smithyman, A.; Iredell, J.R. Bacteriophage therapy for refractory Pseudomonas aeruginosa urinary tract infection. J. Med. Microbiol. 2011, 60, 1697–1700. [Google Scholar] [CrossRef] [PubMed]
  144. Racenis, K.; Rezevska, D.; Madelane, M.; Lavrinovics, E.; Djebara, S.; Petersons, A.; Kroica, J. Use of Phage Cocktail BFC 1.10 in Combination With Ceftazidime-Avibactam in the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Femur Osteomyelitis-A Case Report. Front. Med. 2022, 9, 851310. [Google Scholar] [CrossRef] [PubMed]
  145. Aslam, S.; Courtwright, A.M.; Koval, C.; Lehman, S.M.; Morales, S.; Furr, C.-L.L.; Rosas, F.; Brownstein, M.J.; Fackler, J.R.; Sisson, B.M.; et al. Early clinical experience of bacteriophage therapy in 3 lung transplant recipients. Am. J. Transplant. 2019, 19, 2631–2639. [Google Scholar] [CrossRef] [PubMed]
  146. Chen, P.; Liu, Z.; Tan, X.; Wang, H.; Liang, Y.; Kong, Y.; Sun, W.; Sun, L.; Ma, Y.; Lu, H. Bacteriophage therapy for empyema caused by carbapenem-resistant Pseudomonas aeruginosa. Biosci. Trends 2022, 16, 158–162. [Google Scholar] [CrossRef]
  147. Hoggarth, A.; Weaver, A.; Pu, Q.; Huang, T.; Schettler, J.; Chen, F.; Yuan, X.; Wu, M. Mechanistic research holds promise for bacterial vaccines and phage therapies for Pseudomonas aeruginosa. Drug Des. Devel. Ther. 2019, 13, 909–924. [Google Scholar] [CrossRef] [Green Version]
  148. Hart, R.J.; Morici, L.A. Vaccination to Prevent Pseudomonas aeruginosa Bloodstream Infections. Front. Microbiol. 2022, 13, 870104. [Google Scholar] [CrossRef]
  149. Adlbrecht, C.; Wurm, R.; Depuydt, P.; Spapen, H.; Lorente, J.A.; Staudinger, T.; Creteur, J.; Zauner, C.; Meier-Hellmann, A.; Eller, P.; et al. Efficacy, immunogenicity, and safety of IC43 recombinant Pseudomonas aeruginosa vaccine in mechanically ventilated intensive care patients—A randomized clinical trial. Crit. Care 2020, 24, 74. [Google Scholar] [CrossRef] [Green Version]
  150. Hauser, A.R. The type III secretion system of Pseudomonas aeruginosa: Infection by injection. Nat. Rev. Microbiol. 2009, 7, 654–665. [Google Scholar] [CrossRef] [Green Version]
  151. Sawa, T.; Shimizu, M.; Moriyama, K.; Wiener-Kronish, J.P. Association between Pseudomonas aeruginosa type III secretion, antibiotic resistance, and clinical outcome: A review. Crit. Care Lond. Engl. 2014, 18, 668. [Google Scholar] [CrossRef] [Green Version]
  152. François, B.; Luyt, C.-E.; Dugard, A.; Wolff, M.; Diehl, J.-L.; Jaber, S.; Forel, J.-M.; Garot, D.; Kipnis, E.; Mebazaa, A.; et al. Safety and pharmacokinetics of an anti-PcrV PEGylated monoclonal antibody fragment in mechanically ventilated patients colonized with Pseudomonas aeruginosa: A randomized, double-blind, placebo-controlled trial. Crit. Care Med. 2012, 40, 2320–2326. [Google Scholar] [CrossRef]
  153. Song, Y.; Baer, M.; Srinivasan, R.; Lima, J.; Yarranton, G.; Bebbington, C.; Lynch, S.V. PcrV antibody-antibiotic combination improves survival in Pseudomonas aeruginosa-infected mice. Eur. J. Clin. Microbiol. Infect. Dis. 2012, 31, 1837–1845. [Google Scholar] [CrossRef] [PubMed]
  154. Lindorfer, M.A.; Nardin, A.; Foley, P.L.; Solga, M.D.; Bankovich, A.J.; Martin, E.N.; Henderson, A.L.; Price, C.W.; Gyimesi, E.; Wozencraft, C.P.; et al. Targeting of Pseudomonas aeruginosa in the Bloodstream with Bispecific Monoclonal Antibodies. J. Immunol. 2001, 167, 2240–2249. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  155. Lee, J.; Zhang, L. The hierarchy quorum sensing network in Pseudomonas aeruginosa. Protein Cell 2015, 6, 26–41. [Google Scholar] [CrossRef] [PubMed]
  156. Le Berre, R.; Nguyen, S.; Nowak, E.; Kipnis, E.; Pierre, M.; Ader, F.; Courcol, R.; Guery, B.P.; Faure, K. Pyopneumagen Group Quorum-sensing activity and related virulence factor expression in clinically pathogenic isolates of Pseudomonas aeruginosa. Clin. Microbiol. Infect. 2008, 14, 337–343. [Google Scholar] [CrossRef]
  157. Wu, H.; Song, Z.; Hentzer, M.; Andersen, J.B.; Molin, S.; Givskov, M.; Høiby, N. Synthetic furanones inhibit quorum-sensing and enhance bacterial clearance in Pseudomonas aeruginosa lung infection in mice. J. Antimicrob. Chemother. 2004, 53, 1054–1061. [Google Scholar] [CrossRef] [Green Version]
  158. Hoffmann, N.; Lee, B.; Hentzer, M.; Rasmussen, T.B.; Song, Z.; Johansen, H.K.; Givskov, M.; Høiby, N. Azithromycin blocks quorum sensing and alginate polymer formation and increases the sensitivity to serum and stationary-growth-phase killing of Pseudomonas aeruginosa and attenuates chronic P. aeruginosa lung infection in Cftr(−/−) mice. Antimicrob. Agents Chemother. 2007, 51, 3677–3687. [Google Scholar] [CrossRef] [Green Version]
  159. Adonizio, A.; Kong, K.-F.; Mathee, K. Inhibition of quorum sensing-controlled virulence factor production in Pseudomonas aeruginosa by South Florida plant extracts. Antimicrob. Agents Chemother. 2008, 52, 198–203. [Google Scholar] [CrossRef] [Green Version]
  160. Smyth, A.R.; Cifelli, P.M.; Ortori, C.A.; Righetti, K.; Lewis, S.; Erskine, P.; Holland, E.D.; Givskov, M.; Williams, P.; Cámara, M.; et al. Garlic as an inhibitor of Pseudomonas aeruginosa quorum sensing in cystic fibrosis—A pilot randomized controlled trial. Pediatr. Pulmonol. 2010, 45, 356–362. [Google Scholar] [CrossRef]
  161. Cotter, P.D.; Ross, R.P.; Hill, C. Bacteriocins—A viable alternative to antibiotics? Nat. Rev. Microbiol. 2013, 11, 95–105. [Google Scholar] [CrossRef]
  162. Al-Mathkhury, H.J.F.; Ali, A.S.; Ghafil, J.A. Antagonistic effect of bacteriocin against urinary catheter associated Pseudomonas aeruginosa biofilm. N. Am. J. Med. Sci. 2011, 3, 367–370. [Google Scholar] [CrossRef]
  163. Snopkova, K.; Dufkova, K.; Klimesova, P.; Vanerkova, M.; Ruzicka, F.; Hola, V. Prevalence of bacteriocins and their co-association with virulence factors within Pseudomonas aeruginosa catheter isolates. Int. J. Med. Microbiol. 2020, 310, 151454. [Google Scholar] [CrossRef] [PubMed]
Scheme 1. Antimicrobial management of P. aeruginosa severe sepsis DTR-PA, difficult to treat Pseudomonas aeruginosa; C/T, ceftolozane-tazobactam; CAZ/AVI, ceftazidime-avibactam; IMI/REL, imipenem-cilastatin-relebactam; AG, aminoglycoside; FQ, fluoroquinolone.
Scheme 1. Antimicrobial management of P. aeruginosa severe sepsis DTR-PA, difficult to treat Pseudomonas aeruginosa; C/T, ceftolozane-tazobactam; CAZ/AVI, ceftazidime-avibactam; IMI/REL, imipenem-cilastatin-relebactam; AG, aminoglycoside; FQ, fluoroquinolone.
Antibiotics 11 01432 sch001
Table 1. Treatment options for Carbapenem-resistant P. aeruginosa according to mechanism of resistance [67,68,69,70,71] C/T, Ceftolozane-Tazobactam; CAZ/AVI, Ceftazidime-avibactam; IMI/REL, Imipenem-cilastatin-relebactam.
Table 1. Treatment options for Carbapenem-resistant P. aeruginosa according to mechanism of resistance [67,68,69,70,71] C/T, Ceftolozane-Tazobactam; CAZ/AVI, Ceftazidime-avibactam; IMI/REL, Imipenem-cilastatin-relebactam.
Class ANoYesYesYesYesYesYes
Class BNoNoNoYesVariableYesYes
Class DNoYesNoYesYesYesYes
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Zakhour, J.; Sharara, S.L.; Hindy, J.-R.; Haddad, S.F.; Kanj, S.S. Antimicrobial Treatment of Pseudomonas aeruginosa Severe Sepsis. Antibiotics 2022, 11, 1432.

AMA Style

Zakhour J, Sharara SL, Hindy J-R, Haddad SF, Kanj SS. Antimicrobial Treatment of Pseudomonas aeruginosa Severe Sepsis. Antibiotics. 2022; 11(10):1432.

Chicago/Turabian Style

Zakhour, Johnny, Sima L. Sharara, Joya-Rita Hindy, Sara F. Haddad, and Souha S. Kanj. 2022. "Antimicrobial Treatment of Pseudomonas aeruginosa Severe Sepsis" Antibiotics 11, no. 10: 1432.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop