Pseudomonas aeruginosa pneumonia

INTRODUCTION — Pseudomonas aeruginosa is one of the most important and most commonly considered pathogens in the differential diagnosis of gram-negative infections. Consideration of this organism is important because it causes severe hospital-acquired infections, especially in immunocompromised hosts, is often antibiotic resistant, complicating the choice of therapy, and is associated with a high mortality rate.

The clinical manifestations, diagnosis, and treatment of P. aeruginosa pneumonia will be reviewed here.

The general principles of antimicrobial treatment of infections caused by P. aeruginosa, including antibiotic options and decisions on combination therapy, are discussed in detail elsewhere. (See "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections".)

The clinical manifestations and management of other P. aeruginosa infections and the epidemiology and pathogenesis of infection with this organism are also discussed separately.

●(See "Epidemiology, microbiology, and pathogenesis of Pseudomonas aeruginosa infection".)

●(See "Pseudomonas aeruginosa bacteremia and endocarditis".)

●(See "Pseudomonas aeruginosa skin and soft tissue infections".)

●(See "Pseudomonas aeruginosa infections of the eye, ear, urinary tract, gastrointestinal tract, and central nervous system".)

●(See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Pseudomonas aeruginosa' and "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations".)

EPIDEMIOLOGY

Hospital-acquired pneumonia — P. aeruginosa is a common cause of gram-negative hospital-acquired (nosocomial) pneumonia [1-6]. This was illustrated in a prospective series of 556 patients in which P. aeruginosa was the most common gram-negative pathogen implicated in both hospital-acquired and ventilator-associated pneumonia (VAP) [1]. In a large multicenter survey of gram-negative aerobic bacteria isolated from patients in intensive care units (ICUs) in the US, P. aeruginosa was the most commonly isolated gram-negative aerobic bacterium (23 percent) and was the most common bacterium recurrently isolated from the respiratory tract (32 percent) [7]. Hospital-acquired pneumonia (HAP) can occur via aspiration of endogenous oral flora or via aspiration of organisms from contamination of ventilator tubing or other health care devices [8,9]. Pulmonary infections due to P. aeruginosa may also arise hematogenously [10]. P. aeruginosa is also an important cause of nosocomial tracheobronchitis [2]. (See "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired and ventilator-associated pneumonia in adults".)

Several risk factors for HAP due to P. aeruginosa have been identified. In one study, a higher probability of P. aeruginosa pneumonia was associated with increased age, length of mechanical ventilation, antibiotics at admission, transfer from a medical unit or ICU, and admission in a ward with higher incidence of patients with P. aeruginosa infections [11]. A lower probability of P. aeruginosa was associated with trauma and admission in a ward with high patient turnover.

P. aeruginosa is a common cause of secondary bacterial pneumonia in individuals hospitalized with COVID-19. (See "Epidemiology, microbiology, and pathogenesis of Pseudomonas aeruginosa infection", section on 'Secondary infections in patients with COVID-19'.)

Community-acquired pneumonia — In general, community-acquired P. aeruginosa pneumonia is a rare occurrence. While its exact incidence is unknown, multi-national studies show its prevalence to be around 4 percent [12]. Community-acquired P. aeruginosa pneumonia is occasionally reported in otherwise healthy hosts [13]. In a recent review of the literature on immunocompetent individuals who did develop community-acquired P. aeruginosa, identified risk factors were [14]:

●Advanced age

●Smoking

●Alcohol use

●Exposure to contaminated liquids

Most patients have an identifiable risk factor for disease. Community-acquired P. aeruginosa pneumonia occurs mainly in individuals who have [12,15-17]:

●A compromised immune system (eg, patients with HIV, solid organ or hematopoietic cell transplant recipients, neutropenic hosts, and those on immunosuppressive or immunomodulatory agents such as TNF-alfa inhibitors)

●Recent prior antibiotic use

●Structural lung abnormalities such as cystic fibrosis or bronchiectasis

●Repeated exacerbations of chronic obstructive pulmonary disease requiring frequent glucocorticoid and/or antibiotic use

As an example, P. aeruginosa causes 5 to 7 percent of cases of community-acquired pneumonia in patients with HIV [18,19]. In another retrospective study of over 10,000 patients hospitalized for pneumonia, P. aeruginosa was most highly associated with bronchiectasis (adjusted odds ratio [aOR] = 6.13), lung abscess/empyema (aOR = 3.36), and chronic obstructive pulmonary disease (COPD; aOR = 1.84), although the rate of P. aeruginosa in patients with COPD but no other comorbidities was similar to the rate in the general population [20]. Additional risk factors for community-acquired pneumonia due to P. aeruginosa include cirrhosis [21], history of recent hospitalization [16], intubation [22], or enteral tube feeding [23]. In one study, P. aeruginosa pneumonia was responsible for 39 out of 559 cases of community-acquired pneumonia; previous hospital admission and pulmonary comorbidity were predictive of the occurrence of this infection [16].

Person-to-person transmission of P. aeruginosa in the community is rare, but has been reported in a few isolated instances. As an example, household spread was documented when a daughter passed a P. aeruginosa strain to her mother, causing cavitary pneumonia and lung abscess; the two isolates were confirmed to be identical using pulsed-field gel electrophoresis [24].

Other rare risks for P. aeruginosa include environmental exposures. As an example, one report described an isolated case of necrotizing P. aeruginosa pneumonia in an immunocompetent patient that was attributed to contact with a contaminated hot tub filter. This case highlights the importance of following the United States Centers for Disease Control and Prevention (CDC) guidelines for hot tub maintenance to prevent Pseudomonas overgrowth [25].

Equipment-related outbreaks — Outbreaks of P. aeruginosa infection linked to contaminated health care equipment such as endoscopes have been occasionally reported [26-28].

Bronchoscope contamination has been linked to defective design, bronchoscope damage, and inadequate disinfection [29]. One outbreak related to defective bronchoscopes led to 32 cases of P. aeruginosa infections and three deaths prior to a voluntary recall of the endoscopes by the manufacturer [27].

CLINICAL FEATURES

Signs and symptoms — Signs and symptoms of pneumonia caused by P. aeruginosa are similar to those caused by other pyogenic bacteria and Legionella. No features can reliably distinguish infection with P. aeruginosa from pneumonia caused by those other pathogens. Acute P. aeruginosa pneumonia is usually characterized by cough productive of purulent sputum, dyspnea, fever, chills, confusion, and severe systemic toxicity. Patients with ventilator-associated P. aeruginosa pneumonia may also present with increased tracheobronchial secretions and decreased ventilator performance that can develop suddenly or gradually.

Although P. aeruginosa is typically associated with severe pneumonia, this is not a distinguishing feature. In a study of 343 patients with hospital-acquired pneumonia, the severity of illness was not associated with or predictive of microbial etiology [30].

The general clinical features of community- and hospital-acquired pneumonia (HAP) are discussed elsewhere. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults", section on 'Clinical evaluation' and "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired and ventilator-associated pneumonia in adults", section on 'Diagnosis' and "Clinical presentation and diagnostic evaluation of ventilator-associated pneumonia".)

Radiology — Radiographic findings are variable and no single finding is predictive or characteristic of P. aeruginosa pneumonia. Diffuse bilateral infiltrates, with or without pleural effusion, may be present. Many patients have multifocal airspace consolidation. Other radiographic features include nodular infiltrates, tree-in-bud opacities, and necrosis [31]. Occasionally, areas of radiolucency suggestive of cavitary disease may be present. Classic lobar consolidation is uncommon.

When P. aeruginosa pneumonia arises from hematogenous spread of the organism, early radiographic findings may include pulmonary congestion and interstitial edema. However, diffuse interstitial and alveolar infiltrates often develop 24 to 48 hours later in such patients. Large hemorrhagic nodules with central necrosis or cavities may rarely occur later in the course.

Radiographic findings in certain hosts may also have particular characteristics. As an example, in a small study of 16 HIV-infected patients with P. aeruginosa pneumonia, of whom the majority had low CD4 cell counts, 11 presented with or subsequently developed cavitary infiltrates [32].

Pathology — Histopathologic changes in patients with pneumonia due to P. aeruginosa typically include microabscesses with focal hemorrhage and necrosis of the alveolar septae without evidence of bacterial invasion of vessel walls or vascular necrosis. Pathologic changes in patients with pneumonia due to hematogenous spread usually include intra-alveolar hemorrhage and necrosis around pulmonary vessels. Small (2 to 15 mm), firm, yellow-brown necrotic nodules with dark red hemorrhagic parenchyma may also be present along with liquefactive necrosis or bacterial invasion of the alveolar cell walls.

One autopsy study of eight infants with P. aeruginosa pneumonia revealed two distinct histopathological patterns. Seven cases demonstrated evidence of a distinctive paucicellular coagulative confluent bronchopneumonia with perivascular bacillary infiltration. These changes occurred in immunocompromised patients with sepsis and rapid deterioration. The eighth case, a patient with an unusually protracted clinical course, had pathologic changes typical of bacterial pneumonia without evidence of perivascular organisms [33].

DIAGNOSIS — The diagnosis of P. aeruginosa pneumonia is made following the growth of P. aeruginosa on culture of expectorated sputum, bronchoscopically obtained samples, or other respiratory specimens in a patient with clinical and radiographic findings consistent with pneumonia. The diagnostic evaluation for pneumonia is discussed in detail elsewhere. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults" and "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired and ventilator-associated pneumonia in adults", section on 'Diagnosis' and "Clinical presentation and diagnostic evaluation of ventilator-associated pneumonia", section on 'Diagnostic evaluation'.)

In some cases, particularly in the settings of intubation or chronic bronchiectasis, which can be associated with chronic growth of P. aeruginosa in the airways, the distinction between respiratory infection and colonization with P. aeruginosa may be difficult to make. Changes in clinical status such as new fever, new leukocytosis, new abnormality on chest imaging, and worsened respiratory status are suggestive of pneumonia in patients chronically colonized with P. aeruginosa. The use of quantitative cultures on sputum specimens from ventilated patients may also be helpful in distinguishing between infection and colonization [34], but these techniques are not widely available and their use in clinical practice is uncommon. (See "Clinical presentation and diagnostic evaluation of ventilator-associated pneumonia", section on 'Diagnostic evaluation'.)

MANAGEMENT

Empiric antimicrobial therapy — Until antimicrobial susceptibility results are available, we initially treat known or suspected cases of P. aeruginosa pneumonia with a single antimicrobial agent, unless the patient has sepsis or risk factors for a drug resistant infection, in which case we use two antibiotics from different classes to which the isolate is likely to be susceptible (table 1).

Specifically, we agree with the guidelines from the Infectious Diseases Society of America and the American Thoracic Society on the empiric management of community-acquired and hospital-acquired pneumonia (HAP) that recommend the following antimicrobial combinations for patients who have risk factors for both P. aeruginosa infection as well as drug resistance [15,35]:

●An antipseudomonal beta-lactam PLUS an antipseudomonal quinolone

●An antipseudomonal beta-lactam PLUS an aminoglycoside

●An antipseudomonal quinolone PLUS an aminoglycoside

Antipseudomonal beta-lactams include piperacillin-tazobactam, ceftazidime, cefepime, imipenem, and meropenem. Aztreonam may be substituted for one of these in the setting of penicillin allergy. Antipseudomonal quinolones include ciprofloxacin and levofloxacin (750 mg dose).

Antimicrobial selection should also include consideration of local epidemiology and local antimicrobial resistance patterns, particularly in patients at risk for multidrug-resistant P. aeruginosa. In settings where multidrug resistance is common, novel expanded-spectrum beta-lactam agents (such as ceftolozane-tazobactam) may be appropriate for empiric therapy [36-44]. Additional details, including dosing, on antibiotic regimens for the treatment of P. aeruginosa infections are found in the table (table 1) and are elaborated on elsewhere. (See "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections", section on 'Intravenous antibiotics'.)

Risk factors for P. aeruginosa among patients presenting with hospital- or community-acquired pneumonia are discussed elsewhere, as are risk factors for antimicrobial resistance. (See 'Epidemiology' above and "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections", section on 'Antimicrobial resistance'.)

The evidence for combination versus monotherapy is also discussed separately. (See "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections", section on 'Role of combination antimicrobial therapy'.)

Directed antimicrobial therapy

Regimen choice — We suggest streamlining empiric combination therapy to a single active antibiotic once susceptibility results are available (table 1). We typically use a beta-lactam, reserving carbapenems for treating polymicrobial infections or organisms resistant to other agents. Advanced beta-lactams, such as ceftolozane-tazobactam, ceftazidime-avibactam, and imipenem-cilastatin-relebactam, can be used as monotherapy, if active, for isolates of P. aeruginosa that are resistant to the traditional antipseudomonal drugs [45]. In general, aminoglycosides should not be used as monotherapy for pneumonia because they perform poorly in an acidic environment.

Ceftolozane-tazobactam's efficacy in treating nosocomial pneumonia has been demonstrated in the ASPECT-NP trial where it proved to be noninferior to meropenem in terms of 28-day mortality [37]. In addition, the supplementary analysis to the ASPECT-NP trial showed that ceftolozane-tazobactam prevented the emergence of resistance in P. aeruginosa as opposed to the meropenem group, where 22.4 percent of the isolates became resistant [46].Furthermore, its ability to enable shorter ICU stays and duration of mechanical ventilation was demonstrated in separate studies [47]. Ceftolozane-tazobactam has also proven superiority in terms of mortality with less risk of adverse effects when compared to polymyxin or aminoglycoside-based regimens [48-50].

Real-world data have consistently shown ceftolozane-tazobactam's effectiveness and safety [43,51-53].

In a multi-center, retrospective analysis of 206 patients with HAP/ventilator-associated pneumonia (VAP) secondary to MDR or extensively drug-resistant (XDR) P. aeruginosa where ceftolozane-tazobactam was compared to the best available therapy, treatment with ceftolozane-tazobactam was independently associated with a 73.3 percent reduction in clinical failure, compared to those who received best available therapy, along with a lower rate of adverse events (10 versus 33 percent). Nephrotoxicity (85 percent) and Clostridioides difficle infection (5 percent) were the most commonly side effects [52]. In another multicenter study in which ceftolozane-tazobactam was used as outpatient therapy, where 18 percent of infections were respiratory infections and 23 percent were secondary to P. aeruginosa, 95 percent of infections clinically resolved [53].

Ceftazidime-avibactam has also proven its efficacy in treating nosocomial pneumonia in the REPROVE trial where it was found to be noninferior to meropenem [54].

Real-world data published so far for the treatment of HAP/VAP confirmed the high efficacy and tolerability of this novel beta-lactam beta-lactamase inhibitor (BL-BLI) [55-58]. In the largest cohort to date, ceftazidime-avibactam was assessed for severe pulmonary infections due to carbapenem-resistant and difficult-to-treat P. aeruginosa; 63 percent achieved clinical cure with bacterial eradication in 80 percent of the cases and an all-cause mortality of 19 percent by day 30 [57].

There are only a few studies that compared ceftolozane-tazobactam to ceftazidime-avibactam. A recent multi-center retrospective cohort study compared both of these BL-BLIs in treating P. aeruginosa infections and looked at overall in-hospital mortality, 30-day mortality, and clinical cure, 28 percent of which were diagnosed with HAP and 21 percent with VAP. The three outcomes were comparable in both groups. In addition, no difference was found in other outcomes, including infection-related mortality, 30-day readmission, 30-day recurrence, 90-day recurrence, microbiologic eradication, length of stay, or duration of mechanical ventilation [59].

Imipenem-cilastatin-relebactam's safety and efficacy was evaluated in the RESTORE-IMI 1 study where it was compared to an imipenem/colistin combination in the treatment of multiple infections, 35.5 percent of which were HAP/VAP, with the most common pathogen being P. aeruginosa (77.4 percent) [60]. Its efficacy was re-affirmed in RESTORE IMI 2 where imipenem-cilstatin-relebactam was compared to piperacillin-tazobactam in the treatment of HAP/VAP [61].

Real-world data evaluating imipenem-cilastatin-relebactam is scarce [62,63]. However, studies done so far have also demonstrated the high efficacy and safety of this BL-BLI. In a multi-center observational study of 21 patients, where the most commonly evaluated infection was respiratory tract infection (52 percent HAP/VAP) and the most common pathogen was MDR P. aeruginosa (76 percent), 30-day mortality was 33 percent, which was attributed to patients having comorbidities, whereas clinical cure was 62 percent. As for side effects, only gastrointestinal symptoms and one case of encephalopathy were reported, neither leading to drug discontinuation [62].

Cross-resistance remains an issue in regard to ceftolozane-tazobactam and ceftazidime-avibactam because of high structural similarities. Accordingly, the IDSA recommended in their recent guidance to always repeat antimicrobial susceptibility testing for newer BL-BLIs when a previously infected patient with difficult-to-treat P. aeruginosa presents with new or relapsed infection, with the consideration of the use of imipenem-cilastatin-relebactam or cefiderocol if the patient was recently treated with ceftolozane-tazobactam or ceftazidime-avibactam [64].

Cefiderocol, a new siderophore cephalosporin, has also demonstrated noninferiority in the treatment of nosocomial pneumonia due to MDR GNB, 16 percent of which were secondary to P. aeruginosa when compared to meropenem in terms of all-cause mortality at 14 days [65].

Real-world data on cefiderocol use remains scarce [66-68]. In the largest recently performed retrospective multi-center cohort study to date that included 142 patients, 51.1 percent of who were diagnosed with pneumonia with 21.1 percent of all isolates being identified as P. aeruginosa, 30-day mortality was shown to be 37 percent, with a higher absolute rate of death in patients diagnosed with pneumonia (43 percent) [68].

Interestingly, in a study evaluating cross-resistance in P. aeruginosa isolates from patients treated with the new BL-BLIs, cross-resistance between cefiderocol and ceftolozane-tazobactam was evident, unlike with ceftazidime-avibactam and imipenem-relebactam [69].

Cefepime-enmetazobactam, a novel BL-BLI with in vitro activity against P. aeruginosa [70], has received approval by the US Food and Drug Administration (FDA) for use in complicated urinary tract infections (UTIs) [70-72]. Data on this novel combination's efficacy in the treatment of nosocomial pneumonia is yet to be published. It is, however, noteworthy that in vitro studies have not demonstrated enhanced potency compared to cefepime against P. aeruginosa [70].

Multiple antibiotics are currently in the pipeline, such as cefepime-taniborbactam, cefepime-zidebactam,  sulbactam durlobactam, and murepavadin [73]. All of these antibiotics, despite variable activity against carbapenemases, have demonstrated in vitro activity against drug-resistant P. aeruginosa [74-78], with cefepime-taniborbactam amd cefepime-zidebactam demonstrating in vivo bactericidal activity in murine lung infection models [79,80]. These antibiotics are yet to be assessed for nosocomial pneumonia.

Murepavadin is a new class antibiotic that selectively inhibits the lipopolysaccharide (LPS) protein D, a vital outer membrane protein involved in LPS biogenesis in Gram negative bacteria. It has demonstrated specific antimicrobial activity against multiple Pseudomonas spp including P. aeruginosa [81]. It was being evaluated in two clinical trials, PRISM-MDR and PRISM-UDR; however, both trials were stopped due to significant nephrotoxicity with further investigation of the molecule's safety required [82,83].

Although some experts continue a combination regimen as directed therapy in order to minimize the emergence of antimicrobial resistance, there is little clinical evidence that clearly demonstrates a benefit to directed combination therapy.

In a multicenter study of 183 patients with VAP due to P. aeruginosa, use of combination therapy or monotherapy tailored to susceptibility results did not influence mortality, length of stay, recurrent infection rate, or development of resistance [84]. In addition, a recent study based on the patients included in the iDIAPASON trial, a multi-center randomized controlled trial comparing 8- to 15-day antibiotic therapy for VAP secondary to P. aeruginosa, assessed the outcomes of using mono- versus combination therapy and no difference was found [85]. Moreover, real-world data on the use of novel BL-BLIs and cefiderocol as part of combination therapy have shown no difference in clinical outcomes [57,58,68]. In their latest update of guidelines for the treatment of resistant organisms, the IDSA recommended against using directed combination therapy in the treatment of difficult-to-treat P. aeruginosa, especially if the organism is susceptible to one of the new BL-BLIs [64]. (See "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections", section on 'Role of combination antimicrobial therapy'.)

Duration of therapy — The optimal duration of antimicrobial therapy for P. aeruginosa pneumonia is uncertain. We individualize the duration based on the underlying comorbidities and condition of the patient, the initial response to therapy, and the susceptibility of the infecting isolate. Patients who have no significant comorbidities, defervesce, and improve clinically within the first week of therapy, and those who have infection with a susceptible P. aeruginosa isolate, can be treated with regimens as short as 7 to 10 days. However, longer treatment durations (eg, from 10 to 21 days) may be warranted for patients with serious underlying conditions (eg, neutropenia), concurrent blood stream infection, a poor or slow response to therapy, and/or a partially susceptible or multidrug-resistant strain. If the isolate is susceptible to fluoroquinolones and there are no concerns about gastrointestinal absorption of oral medications, the patient can transition to oral ciprofloxacin or levofloxacin to complete the course.

Support for a relatively abbreviated course of antibiotics comes from several trials on treatment of VAP, in which short (seven- to eight-day) courses of antibiotics resulted in similar clinical cure and mortality rates and lower rates of recurrence with multidrug-resistant organisms compared with longer (10- to 15-day) courses [86,87]. However, in some studies, the recurrence rate for pneumonias caused by nonfermenting gram-negative bacilli (such as P. aeruginosa) was higher with short courses. This finding was re-demonstrated in the iDIAPASON study, a prospective multi-center randomized controlled open-label trial where the percentage of recurrence of ventilator-associated P. aeruginosa during the ICU stay was 9.2 percent in the 15-day group versus 17 percent in the 8-day group [88]. However, the duration of therapy remains a matter of debate. In a recent editorial, panelists who participated in the 2016 IDSA/ATS guidelines on ventilator-associated/HAP responded to a viewpoint by Albin et al [89] arguing against the last IDSA/ATS guidelines recommending a short course of VAP secondary to P. aerguinosa. Metersky et al argued that both major studies that reported increased recurrence in short duration therapy were fully or partially open-label; both studies did not account for the differential time-at-risk bias, leading to patients in the short-course group being observed for recurrence at least 7 to 10 days more than the opposing group. In addition, recurrence was not adequately assessed as both studies showed no difference in length of stay, mechanical ventilator duration, or mortality [90]. Thus, while a short course may be appropriate for some patients with P. aeruginosa pneumonia, we favor a more conservative approach with a longer course of therapy in patients who may have an especially high mortality because of comorbidities or according to the clinical course.

The airway may remain colonized with P. aeruginosa even in the setting of clinical response. Symptomatic improvement is a more important indicator than organism eradication for decisions regarding timing of antibiotic discontinuation.

Inhaled antibiotics for selected patients — We do not routinely use inhaled antibiotics for the treatment of P. aeruginosa pneumonia.

In their latest guidance on the management of antibiotic-resistant organisms, the IDSA did not recommend the use of nebulized antibiotics for the treatment of difficult-to-treat P. aeruginosa [64]. This is mainly due to the lack of evidence suggesting improved outcomes or higher survival rates even in subgroup analysis of resistant isolates, regardless of the medication used (colistin, amikacin, fosfomycin) [91-93], in addition to concerns that these medications may be causing damage to lung tissue. Similarly, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) did not recommend inhaled antibiotic therapy due to the lack of strong evidence of efficacy [94]. Nevertheless, inhaled antibiotics can be used as an adjunct to intravenous therapy (IV) in cases of infection due to multidrug-resistant strains.

Specifically, inhaled polymyxins have been used successfully in the management of multidrug-resistant P. aeruginosa pneumonia failing to improve on IV therapy [95-98]. In a retrospective study from Italy of patients with VAP due to gram-negative organisms sensitive only to colistin, clinical cure rates were higher (69 versus 55 percent, p = 0.03) and duration of post-VAP mechanical ventilation shorter (median 8 versus 12 days) among 104 patients (24 with P. aeruginosa) who received nebulized and IV colistin compared with 104 matched patients (28 with P. aeruginosa) who received only IV colistin [98]. Nebulized colistin in treatment of pneumonia due to multidrug-resistant Acinetobacter baumannii and P. aeruginosa was evaluated in a retrospective study of 21 patients in Singapore [96]. Overall clinical and microbiological response rates were 57 and 86 percent, respectively. Most patients received 1 million units (approximately 80 mg) of colistin twice daily. There was no significant change in renal function or observed neurotoxicity. (See "Polymyxins: An overview".)

Colistin is approved by the FDA only for IV or intramuscular use; it is not approved as a liquid to be inhaled via nebulizer. When the drug is mixed into a liquid form, the product can break down into other chemicals that can damage lung tissue [99]. Instructions regarding preparation of nebulized colistin are discussed separately. (See "Polymyxins: An overview".)

Other strategies for drug-resistant isolates — Drug-resistant P. aeruginosa infections should be managed with the assistance of an expert in the treatment of multidrug-resistant pathogens. Strategies for such infections include the use of inhaled antibiotics, alternative intravenous agents, and certain combination regimens. These are discussed elsewhere. (See 'Inhaled antibiotics for selected patients' above and "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections", section on 'Management of multidrug-resistant organisms'.)

Bacteriophage therapy has been described as potential treatment for extensively drug-resistant P. aeruginosa infections in scattered case reports, including cases of lung infection [100-102]. In one case report, it was used for seven days in addition to prolonged antibiotic therapy in a woman with extensive necrotizing P. aeruginosa pneumonia, with subsequent resolution of infection and microbiologic clearance; bacteriophage therapy was well tolerated without adverse events detected during or after therapy [100]. Its use in the literature has been mainly described as an adjunct to antibiotics with various formulations used [103]. For instance, in their article describing three case reports of bacteriophage therapy in lung transplant patients, Aslam et al mention a 67-year male who had two episodes of MDR P. aeruginosa pneumonia post-transplant treated with IV and nebulized phage therapy, used both therapeutically and as suppressive therapy [104]. In another report by Chen et al, a 68-year-old man with broncho-pleural fistula-associated empyema and pneumonia secondary to carbapenem-resistant P. aeruginosa was treated with both nebulized and intrapleural phage therapy for 24 days in addition to IV antibiotics. The pathogen was cleared, the patient clinically improved, and phage therapy was well tolerated [105].

Other potential strategies under investigation for control of P. aeruginosa pneumonia include immunotherapy and vaccination. These are discussed elsewhere. (See "Epidemiology, microbiology, and pathogenesis of Pseudomonas aeruginosa infection", section on 'Investigational interventions based on pathogenesis'.)

OUTCOME AND PROGNOSIS — P. aeruginosa pneumonia is associated with high in-hospital mortality rates and prolonged lengths of stay [4,29]. Injury to the alveolar epithelium allows the release of proinflammatory mediators into the circulation that are primarily responsible for septic shock [106]. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis".)

P. aeruginosa pneumonia accompanied by P. aeruginosa bacteremia is associated with a particularly poor prognosis, with death occurring three to four days after the first signs of infection in the majority of cases.

Other factors significantly associated with a poor prognosis include [4,107-109]:

●Advanced age

●Serious underlying disease

●Septic shock

●Acute respiratory distress syndrome

●Previous surgery

●Comorbidities, such as diabetes mellitus

●Inadequate initial antibiotic therapy

●Use of broad-spectrum antibiotics in previous six months

●Multidrug-resistant organisms

As an example, in a study of 110 ICU patients with culture confirmed P. aeruginosa pneumonia, inadequate initial antibiotic therapy, diabetes mellitus, disease severity (high Simplified Acute Physiology Score [SAPS] II), and older age were independently associated with ICU mortality [109]. Among survivors, inappropriate initial antibiotic therapy and infection with multidrug-resistant P. aeruginosa infection were each associated with longer post-pneumonia mechanical ventilation time.

In one retrospective study of patients with hospital-acquired P. aeruginosa pneumonia, receipt of inadequate initial antibiotic therapy was associated with a substantially higher mortality rate compared with adequate therapy (64 versus 25 percent) [109].

PSEUDOMONAS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE — Isolation of P. aeruginosa from sputum samples of adult patients with COPD is associated with advanced pulmonary disease [110].

●In one cross-sectional study, patients with a predicted FEV1 of less than 50 percent were more likely to have H. influenzae or P. aeruginosa isolated from sputum during exacerbations than patients with less severe impairment of pulmonary function [111].

●Another study demonstrated that in patients who had FEV1 less than 35 percent the predicted value, Enterobacterales and Pseudomonas species were the predominant isolated bacteria from sputum [112].

●In a separate study, the presence of enteric gram-negative bacilli and P. aeruginosa in the sputum of patients during exacerbations could be predicted by severe airflow obstruction [113].

●Furthermore, exacerbations in the presence of P. aeruginosa in the sputum are linked to respiratory failure and the need for mechanical ventilation. These interpretations may suggest that P. aeruginosa is a more frequent cause of infection as COPD progresses.

There exists a subset of patients with COPD who become chronically colonized with P. aeruginosa, but whether such patients benefit from antimicrobial therapy is still unclear.

SUMMARY AND RECOMMENDATIONS

●Hospital-acquired pneumonia – P. aeruginosa is a common cause of gram-negative hospital-acquired pneumonia, which can occur via aspiration of endogenous oral flora, via aspiration of organisms from contaminated ventilator tubing or other health care devices, or through hematogenous spread. (See 'Hospital-acquired pneumonia' above.)

●Community-acquired pneumonia – Community-acquired P. aeruginosa pneumonia occurs mainly in immunocompromised patients (eg, HIV-infected patients, solid organ or stem cell transplant recipients, or neutropenic hosts), those with recent prior antibiotic use, and those with structural lung abnormalities such as cystic fibrosis, bronchiectasis, or repeated exacerbations of chronic obstructive pulmonary disease requiring frequent glucocorticoid and/or antibiotic use. (See 'Community-acquired pneumonia' above.)

●Clinical manifestations – P. aeruginosa pneumonia is usually characterized by cough productive of purulent sputum, dyspnea, fever, chills, confusion, and severe systemic toxicity. None of these manifestations firmly distinguish this infection from pneumonia caused by other pyogenic organisms or Legionella. Radiographic findings are variable and no single finding is predictive or characteristic of P. aeruginosa pneumonia. (See 'Clinical features' above.)

●Diagnosis – The diagnosis of P. aeruginosa pneumonia is made following the growth of P. aeruginosa on culture of expectorated sputum, bronchoscopically-obtained samples, or other respiratory specimens in a patient with clinical and radiographic findings consistent with pneumonia. (See 'Diagnosis' above and "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired and ventilator-associated pneumonia in adults".)

●Empiric antibiotic selection – Until antimicrobial susceptibility results are available, suspected cases of P. aeruginosa pneumonia can be empirically treated with a single antimicrobial agent, unless the patient has sepsis or risk factors for a drug resistant infection, in which case we use two antibiotics from different classes to which the isolate is likely to be susceptible (table 1). The rationale for combination versus monotherapy is discussed elsewhere. (See 'Empiric antimicrobial therapy' above and "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections", section on 'Role of combination antimicrobial therapy'.)

●Targeted antibiotics – Once susceptibility testing results are available, we suggest use of a single active antibiotic for directed therapy of susceptible infections instead of combination therapy (Grade 2B). Patients who have no significant comorbidities, defervesce and improve clinically within the first week of therapy, and those who have infection with a susceptible P. aeruginosa isolate can be treated with regimens as short as 7 to 10 days. Longer treatment durations (eg, from 10 to 21 days) may be warranted for other patients. (See 'Directed antimicrobial therapy' above.)

●Management of multidrug resistance – Multidrug-resistant P. aeruginosa infections should be managed with the assistance of an expert in the treatment of such infections. Alternative agents such as colistin may be necessary. Other possible strategies for resistant infections include the use of inhaled antibiotics, combination regimens, and alternative dosing strategies. (See 'Inhaled antibiotics for selected patients' above and "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections", section on 'Management of multidrug-resistant organisms'.)

●Prognosis – P. aeruginosa pneumonia is associated with high in-hospital mortality rates and prolonged lengths of stay. (See 'Outcome and prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Daniel Sexton, MD, who contributed to earlier versions of this topic review.