Review

Pseudomonas aeruginosa is a Gram-negative bacterium commonly implicated in serious noso-comial infections and often poses great man-agement challenges to clinicians. In this review, we attempt to summarize the latest findings in treatment strategies (Figure 1) and transmission reduction for daily clinical practice.

Treatment considerations & strategiesSource controlIn general, source control is an important strat-egy in the management of infections. Key aspects involve fluid collection drainage, debridement, removal of foreign bodies or devices, and correc-tion of anatomic derangements [1]. If the source of infection is not adequately controlled or removed, it can serve as a reservoir for microor-ganisms to propagate and disseminate through-out the body. Source control is particularly important in infections caused by microorgan-isms that form biofilms, such as P. aeruginosa. Antibiotics have decreased penetration and slower diffusion rates within biofilms that render antibiotics ineffective [2]. In a study of infected orthopedic prosthetic implants due to biofilm-forming organisms, conservative management with surgery or aggressive antibiotics resulted in clinical failure. Device removal or replacement was required in most cases for clinical cure [3].

Risk assessment & diagnosisIn order to effectively treat patients with pseu-domonal infections, the first step is to establish

a correct etiological diagnosis. Two compo-nents to establishing a diagnosis include high clinical suspicion and microbiological confirma-tion. Patients must be accurately identified for increased risk of infection with P. aeruginosa and appropriate cultures obtained as soon as possible.

P. aeruginosa is a common multidrug resistant (MDR) pathogen found in healthcare settings. According to the treatment guidelines for venti-lator-associated pneumonia, hospital-associated pneumonia and healthcare-associated pneumo-nia, risk factors for MDR organisms include: previous antimicrobial therapy within 90 days, current hospitalization of 5 days or greater, high frequency of antimicrobial resistance in a specific hospital unit or community and immunosuppres-sive disease state and/or therapy [4]. In addition, patients with specific risk factors for hospital-associated pneumonia with an MDR pathogen include those with recent contact with hospital personnel such as hospitalization for 2 days or greater within the previous 90 days, residence in a nursing home or extended care facility, home infusion therapy, chronic dialysis within the last 30 days, home wound care or are in close contact with a person with an MDR patho-gen. According to the 2012 Infectious Diseases Society of America diabetic foot infection guide-lines, patients are at risk for pseudomonal diabetic foot infections if they reside in a warm climate or have frequent exposure of the foot to water [5]. Some other risks factors identified for MDR P. aeruginosa bacteremia are presence of a central

Dana R Bowers and Vincent H Tam*University of Houston College of Pharmacy, 1441 Moursund St, Houston, TX 77030, USA*Author for correspondence: Tel.: +1 832 842 8316 Fax: +1 832 842 8383 vtam@uh.edu

Infections caused by Pseudomonas aeruginosa can be difficult to treat and require a coordinated approach for their management. This involves quickly controlling the source of infection, establishing a correct etiologic diagnosis and administering appropriate empiric antimicrobial therapy. Once antimicrobial therapy has been initiated and susceptibilities are available, therapy should be tailored with optimized antibiotic doses for an appropriate duration in order to sufficiently treat the infection and minimize resistance emergence.

Pseudomonas aeruginosa treatment and transmission reductionExpert Rev. Anti Infect. Ther. 11(8), 831–837 (2013)

Expert Review of Anti-infective Therapy

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Keywords: antimicrobial stewardship • Gram-negative bacteria • infection control • nonfermenter • resistance surveillance • therapy

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venous catheter, previous antibiotic exposure and corticosteroid use [6]. It is critical to recognize and stratify at-risk patients, so that the aggressiveness of treatment can be modified accordingly.

As P. aeruginosa can colonize many body sites, proper specimen collection will aid clinicians’ assessment of its clinical relevance. Cultures should be taken promptly, preferably before antibiotics are administered, when there is a clinical suspicion for infection. Cultures should be taken using an aseptic technique to minimize sample contamination. Blood cultures should be drawn simulta-neously, in multiple specimens, to help clinicians determine the clinical relevance of recovered isolates. Unlike other potential contaminants, the presence of P. aeruginosa in a blood culture should be regarded as a true pathogen [7].

Diagnosis of pneumonia through respiratory tract secretions presents its own unique challenges. It is often difficult to distin-guish between lower respiratory tract infection and rhinopharynx colonization. Specifically for ventilator-associated pneumonia, two diagnostic techniques have been evaluated. The ‘invasive technique’, bronchoalveolar lavage with quantitative culture and the ‘noninvasive technique’, nonquantitative endotracheal aspi-rate, have been assessed in randomized trials with conflicting results [8–11]. Current recommendations do not prefer one method over the other as long as prompt antimicrobial therapy is initiated once ventilator-associated pneumonia is suspected [12].

Prompt risk assessment, relevant clinical microbiologic data and establishment of a correct diagnosis are important strategies to the management of P. aeruginosa infections.

Empiric antibiotic selectionAfter establishing a presumed diagnosis, empiric antibiotic selec-tion is the next step in the management of pseudomonal infections.

Many studies have demonstrated the importance of early appropriate therapy in P. aeruginosa bacteremia, showing a higher associated mortality in patients who receive inappropriate therapy (Figure 2) [13–15]. Intrinsic and acquired resistance to many commonly used antimicrobials complicates empiric antimicrobial selection. Due to the complex nature and numerous resistance mechanisms in P. aeruginosa, such as upregulation of multidrug efflux pumps, decreased target site-binding affinity, loss of functional porin chan-nels and production of β-lactamases, the reader is referred for such details elsewhere [16–18]. Therefore, combination therapy is often used empirically to increase the likelihood of achieving appropriate therapy [19]. Common examples of combination therapy include an antipseudomonal β-lactam (e.g., piperacillin, cefepime and mero-penem) combined with either a fluoroquinolone (e.g., ciprofloxacin, levofloxacin) or aminoglycoside (e.g., amikacin, tobramycin). Due to the numerous possible combinations of antibiotics and limited data on many combinations, there are not enough clinical data to support comments on the pros and cons of each potential combination.

The idea of using combination therapy was introduced by the Hilf study in 1989 where there was a significant mortality benefit of using combination therapy over monotherapy for P. aeruginosa bacteremia [20]. The rationales for using combination therapy are to increase the likelihood of achieving appropriate therapy; provide synergy and prevent resistance emergence. While there is enough literature to support combination therapy to increase the likelihood of appropriate therapy, there are limited clinical data on synergy and resistance suppression. To date, there have been no prospec-tive, randomized, controlled clinical trials comparing combination and monotherapy for P. aeruginosa. Bowers et al. retrospectively reviewed 368 patients with P. aeruginosa bacteremia who received appropriate empiric combination or monotherapy. The authors found no difference in 30-day mortality, hospital mortality or time to mortality between patients who received combination and monotherapy. The authors concluded that the number of agents did not affect patient outcomes as long as the therapy was appropri-ate [21]. Furthermore, there is no compelling clinical evidence for continuing combination therapy once susceptibilities are available. Therefore therapy should be de-escalated as soon as possible.

There are a few tools guiding clinicians with empiric antimicro-bial therapy selection. Antibiograms provide institution- and unit-specific in vitro data on antimicrobial susceptibilities. They are usually updated annually and track resistance patterns throughout an institution. A recent study by Anderson et al. found the ability of an antibiogram to predict the susceptibility of P. aeruginosa decreased with a longer length of hospital stay, due to increased isolation of MDR P. aeruginosa [22]. Although designed to guide empirical antimicrobial selection, it is important to understand the limitations of antibiograms and use sound clinical judgment.

The presentation of P. aeruginosa infections is often clinically indistinguishable from other bacterial infections. Therefore, the use of rapid diagnostic tools enables clinicians to identify organ-isms and tailor therapy in a short period of time. Two techniques recently evaluated for detection of P. aeruginosa bacteremia include quantitative PCR [23] and peptide nucleic acid (PNA) FISH [24]. Quantitative PCR was able to identify P. aeruginosa 18–24 h faster

Figure 1. Components of optimal treatment of Pseudomonas aeruginosa infections.

Treatment ofPseudomonas aeruginosa

infections

Antimicrobialdose

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Optimalduration of

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Earlyappropriateantibiotics

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than conventional methods of microbiologic culture and pheno-typic identification. The authors reported this novel technique was 100% specific and 97% sensitive for P. aeruginosa. Another method, PNA FISH has also been evaluated in P. aeruginosa bac-teremia with similar results. These two current rapid diagnostic tests are able to identify the species but are unable to reliably predict antimicrobial susceptibilities. However, their use may prompt a change in antibiotics once the species is determined based on local antibiograms, thus decreasing time to appropriate therapy and unnecessary antibiotic use.

Matrix assisted laser desorption ionization-time of f light (MALDI-ToF) mass spectrometry is another promising new technology that is able to detect antimicrobial susceptibilities; however, more validation studies need to be completed before it can be used routinely [25].

Appropriate, timely empiric antimicrobial selection is crucial to survival in severe pseudomonal infections. There are many different tools to aid clinicians in selecting appropriate antimi-crobials. While selection of combination versus monotherapy for P. aeruginosa infections is a controversial topic, the impact of early appropriate therapy to decrease mortality is well recognized.

Definitive therapyIn order to achieve appropriate empiric therapy, most clinicians would consider it reasonable to initiate combination therapy. However, there are limited clinical data supporting continuing com-bination therapy once susceptibilities are available. Paul et al. evalu-ated β-lactam combination and monotherapy in immunocompetent and immunocompromised hosts in two meta-analyses [26,27]. In both patient populations, the authors found no advantage of combination over monotherapy for all-cause mortality or treatment failures.

Definitive combination therapy was evaluated in a retrospec-tive, multicenter study of patients with ventilator-associated pneu-monia [28]. The authors found a significantly higher mortality in inappropriately treated patients but found no significant differ-ence in mortality with combination or monotherapy as definitive treatment. For bacteremia, no other studies have been able to reproduce the mortality benefits observed by Hilf et al. [20,29,30]. One criticism of the Hilf study is the large number of patients who received monotherapy with an aminoglycoside, which many clinicians would consider as inappropriate therapy.

The strongest evidence supports combination therapy as it applies to early appropriate therapy. As unnecessary antibiotic exposures carry inherit risks such as toxicity and other adverse events, de-escalation of therapy should be considered when possible to minimize these risks.

Antimicrobial dose optimization should be considered for infections due to organisms with reduced susceptibilities (low or intermediate level of resistance). Individual dose optimization can be achieved by understanding the two types of bactericidal activ-ity: concentration-dependent killing and time-dependent killing [31]. Common antibiotics used to treat P. aeruginosa infections include anti-pseudomonal β-lactams (penicillins, cephalospor-ins, carbapenems and monobactams), aminoglycosides, fluoro-quinolones and polymyxins (colistin and polymyxin B). These

antimicrobial agents can be classified according to their pharma-codynamic properties. By optimizing the pharmacokinetics and pharmacodynamics of these agents, there is a potential to increase likelihood of therapeutic success and shorten duration of therapy.

Aminoglycosides are classified as agents with concentration-dependent killing effects. Peak concentration to minimum inhibi-tory concentration (MIC) ratio (C

max: MIC) has been linked to

clinical efficacy. The optimal ratio associated with efficacy is approximately 8–10. Also, aminoglycosides exhibit a postanti-biotic effect where suppression of bacterial growth persists after the concentration drops below the MIC. One dosing strategy for aminoglycosides that optimizes C

max: MIC is administering one

large daily dose [32,33]. Once-daily administration of aminogly-cosides using a population-based nomogram was found to be safe and efficacious in selected patient populations [32].β-lactams, on the other hand, exhibit time-dependent bacte-

ricidal activity; the bacterial killing can be characterized by the time the drug concentration remains above the MIC (%T>MIC). Higher drug concentrations will not produce greater bacterial kill as long as the concentration remains four to five-times above the MIC. This idea has been used clinically by administering β-lactams as an extended or continuous infusion [34–36]. In criti-cally ill patients with P. aeruginosa infections, prolonged infusion of piperacillin/tazobactam (infused over 4 h instead of 30 min) was associated with improved 14-day mortality and a significantly shorter length of hospital stay [34]. Data are limited with extended infusion of other β-lactams (i.e., carbapenems) to case reports or Monte Carlo simulations [37,38]. While this concept is appealing, more clinical data on outcomes are needed.

For definitive treatment of pseudomonal infections, there is lim-ited evidence on using combination therapy once susceptibilities are known. Therefore, it is recommended to de-escalate therapy whenever possible. Combination therapy may be considered for infections with limited treatment options, but robust clinical data are sparse to support this practice. Additionally, antimicrobial

Figure 2. Studies demonstrating the importance of appropriate antimicrobial therapy to reduce mortality in Pseudomonas aeruginosa bacteremia. †30-day mortality. ‡Hospital mortality.

0

10

20

30

40

50

Kang et al. 2003† [13]

Lodise et al. 2007† [14]

Cheong et al. 2008† [15]

Micek et al. 2005‡ [19]

Mo

rtal

ity

(%)

Appropriate empiric therapy Inappropriate empiric therapy

p = 0.049 p = 0.008

p = 0.018

p = 0.046

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dose optimization may be used to increase efficacy in difficult-to-treat infections. Once daily administration strategies may be used for the aminoglycosides and prolonged infusion for the β-lactams to optimize therapeutic efficacy.

Duration of therapyThere are no specific guidelines on the duration of therapy for most infections; the optimal duration must balance sufficient time to cure the infection while not promoting resistance emergence. Duration of therapy is not well defined for many clinical scenarios and is dependent on patient-specific factors. Such factors include source control, susceptibility of organism, comorbid conditions, among others. While considering the overall clinical picture, some clinicians are moving toward shorter courses of antibiotics, in addition to using clinical biomarkers to guide decisions on antimicrobial therapy [39].

For ventilator-associated pneumonia there was no difference in mortality or recurrent infections when 8 days of antibiotics therapy was compared with that of 15 days [40]. The only subset of infec-tions demonstrating a difference was in patients with nonlactose-fermenting Gram-negative bacilli, including P. aeruginosa. These patients tended to have higher relapse rates and increased MDR organisms. Therefore, in order to prevent relapsing infection, longer treatment courses are recommended in patients with P. aeruginosa ventilator-associated pneumonia.

Inflammatory markers are utilized in different algorithms to determine when to start and/or discontinue antibiotics. Procalcitonin is a biomarker that has been shown to be elevated in bacterial infections, but not in viral infections, making it a good surrogate marker in the diagnosis and treatment of bacterial infections. Several strategies using procalcitonin levels have been proposed as an antimicrobial stewardship effort [41]. Algorithms using procalcitonin to initiate or discontinue antibiotics have consistently demonstrated a decrease in antibiotic consumption, mostly for chronic obstructive pulmonary disease. However, data examining its utility specifically in pseudomonal infections are lacking and more clinical data are needed before procalcitonin can be used in routine clinical practice for these types of infections [42].

Appropriate duration of therapy for most pseudomonas infec-tions is not well established in the literature. Therapy should be optimized to treat the infection while preventing further resistance development. Also, using biomarker algorithms to start or discontinue therapy have not been studied extensively in P. aeruginosa infections; they should be used cautiously in conjunction with close patient monitoring.

Adjunct therapyIn addition to traditional therapies, adjunct therapies are used to manage difficult-to-treat P. aeruginosa infections. Aerosolized antibiotics are used to directly deliver drug to the site of infection and limit systemic exposure. Inhaled therapies have been used to both treat an infection and reduce colonization with P. aeruginosa. For example, aminoglycosides have been studied for eradication of P. aeruginosa in cystic fibrosis. The data on aminoglycosides in ventilator-associated pneumonia are limited to small case series but may be beneficial in MDR ventilator-associated pneumonia [43,44].

Polymyxins as a class are of particular interest lately due to the increase in MDR P. aeruginosa infections. They are often reserved as a last-line therapy for systemic use due to their toxicities. The polymyxins are often used in the treatment of urinary tract infec-tions caused by MDR pathogens despite their uncertain urinary disposition [45]. In different case series, colistin was used with var-ied success for ventilator-associated pneumonia [43,46,47]. Currently, both the aminoglycosides and polymyxins may be considered for ventilator-associated pneumonia due to MDR pathogens.

Direct site instillation may also be used in certain types of diffi-cult-to-treat infections. Polymyxins have been used intraventricu-larly or intrathecally for Gram-negative bacterial meningitis. There have been case reports using a polymyxin alone or in combination with systemic antibiotics successfully for central nervous system infections [48]. However, further studies are needed to define their role in therapy and optimal dosages. Topical application could be considered in chronic nonhealing wounds with inadequate blood supply for systemic antibiotics. Topical application of moxifloxa-cin was studied in a porcine wound infection model, resulting in reduction in P. aeruginosa burden and promotion of wound heal-ing [49]. Endophthalmitis is another infection with limited antibi-otic penetration. Intravitreal instillation piperacillin/tazobactam was reported to be safe and effective in three patients with MDR P. aeruginosa infection [50]. Due to the severity of pseudomonal infections, adjunct therapy can be considered in certain types of infection when systemic antibiotics are not feasible or effective.

Additional supportive care for P. aeruginosa infections may improve outcomes for severely ill patients. The importance of glycemic control, administration of corticosteroids and strict hemodynamic control are recommended in patients with sepsis to improve mortality outcomes [51–53]. These strategies should be utilized whenever possible.

Transmission reductionIn order to prevent the spread of resistant P. aeruginosa far and wide, three strategies must work together: antimicrobial steward-ship, antimicrobial resistance surveillance and infection control polices. All three strategies rely on one another for overall effective-ness (Figure 3). For example, antimicrobial stewardship efforts can be negated if infection control measures are not strictly adhered to or antimicrobial surveillance is not conducted diligently.

Antimicrobial stewardshipOne of the keystones of an effective antimicrobial stewardship program is to reduce overall selective pressure on local ecology. According to the Infectious Diseases Society of America, this can be accomplished through different approaches: education, guide-line and clinical pathways, antimicrobial restriction and cycling [54].

Effects of antimicrobial stewardship on P. aeruginosa suscepti-bilities have been reported with varied success [55–57]. In one study, ciprofloxacin and ceftazidime were restricted in an ICU over an 18-month period. While susceptibilities to both of these agents increased, meropenem susceptibilities decreased [55]. In another study, similar findings were reported where there was an increase in carbapenem resistance as a consequence of ciprofloxacin

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restriction [56]. These studies stress that antimicrobial restriction alone is not effective in reducing antimicrobial resistance; it has to be implemented with other policies.

Antimicrobial resistance surveillanceContinuous surveillance for outbreaks of drug-resistant bacte-ria and prospective data collection provide real-time feedback to implement or reinforce infection control policies. Clinical microbiologists play an important role in antimicrobial resist-ance surveillance by monitoring and reporting these trends to the appropriate groups (i.e., antimicrobial stewardship and/or infection control committees). Routine review of antimicrobial susceptibility testing can discover emerging resistance trends throughout an institution and aid in identifying an outbreak.

Infection controlSince P. aeruginosa is a nosocomial pathogen, infection control procedures remain the mainstay to prevent the dissemination of drug-resistant P. aeruginosa infections throughout the hospital. Isolation procedures are often used to separate patients with known colonization or infection with an MDR organism from other non-infected patients. Such procedures include negative pressure single rooms, barrier precautions (gowns and gloves) for hospital staff (and visitors) when entering a patient’s room, among others.

As with prevention with other types of infection, proper and effective hand hygiene is important in preventing the dissemina-tion of drug-resistant P. aeruginosa. In an outbreak in a neonatal intensive care unit, 16 neonates died from P. aeruginosa infections. After further investigations and using a multivariate analysis, two nurses were associated with either colonizing or infecting the neonates [58]. P. aeruginosa is commonly found in water sources, therefore it is recommended to limit multiuse water-based gels or liquids. There was a recent outbreak of respiratory tract infec-tions from contaminated transesophageal echocardiogram gel that resulted in increased respiratory tract infections [59].

Expert commentary & five-year viewP. aeruginosa is a common MDR pathogen which must be promptly identified and treated accordingly. Currently, rapid diagnostic tools being used to reduce the time from organism detection to treatment initiation are yielding promising results [23]. However, further validation of these tools is needed before widespread use can be adopted. Administration of early appropri-ate therapy has been shown to improve patient outcomes [13–15] in P. aeruginosa bacteremia and therefore empiric combination

therapy should be considered in order to increase the likelihood of achieving appropriate therapy. Once antimicrobial therapy has begun, antibiotic de-escalation is recommended whenever pos-sible based on clinical and microbiological data. Limiting anti-biotic exposure may prevent further antimicrobial resistance and other complications. Additionally, adjunct therapies with anti-biotics may be considered in specific patients with severe pseu-domonal infections when systemic antibiotics are not feasible or have limited efficacy. Lastly, in addition to appropriate treatment, antimicrobial stewardship, antimicrobial resistance surveillance and infection control procedures need to be established to reduce the transmission of P. aeruginosa in various settings.

Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Figure 3. Key aspects of prevention of drug-resistant Pseudomonas aeruginosa emergence.

Antimicrobialstewardship

Antimicrobialresistance

survellience

Infectioncontrolpolicies

Preventemergence ofdrug-resistantPseudomonas

aeruginosa

Key issues

• Prompt risk assessment, establishment of a correct diagnosis and source control are important strategies to the management of Pseudomonas aeruginosa infections.

• Empiric combination therapy is recommended to increase the likelihood of appropriate therapy.

• Definitive combination therapy has not been associated with improved outcomes. Therefore, antibiotic de-escalation is recommended once sensitivities are known.

• Adjunct therapies such as aerosolized antibiotics and direct site instillation of antibiotics may be considered in specific patients.

• Antimicrobial stewardship, antimicrobial resistance surveillance and infection control procedures must work in concert to decrease antimicrobial resistance and transmission.

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ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

1 Marshall JC, Maier RV, Jimenez M et al. Source control in the management of severe sepsis and septic shock: An evidence-based review. Crit. Care Med. 32(11 Suppl.), S513–526 (2004).

2 Costerton JW, Stewart PS, Greenberg EP. Bacterial biofilms: A common cause of persistent infections. Science 284(5418), 1318–1322 (1999).

3 Ferreira AS, Silva IN, Oliveira VH et al. Comparative transcriptomic analysis of the burkholderia cepacia tyrosine kinase bcef mutant reveals a role in tolerance to stress, biofilm formation, and virulence. Appl. Environ. Microbiol. 79(9), 3009–3020 (2013).

4 Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am. J. Respir. Crit. Care Med. 171(4), 388–416 (2005).

5 Lipsky BA, Berendt AR, Cornia PB et al. 2012 infectious diseases society of america clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin. Infect. Dis. 54(12), e132–173 (2012).

6 Tumbarello M, Repetto E, Trecarichi EM et al. Multidrug-resistant Pseudomonas aeruginosa bloodstream infections: Risk factors and mortality. Epidemiol. Infect. 139(11), 1740–1749 (2011).

7 Bates DW, Lee TH. Rapid classification of positive blood cultures. Prospective validation of a multivariate algorithm. JAMA. 267(14), 1962–1966 (1992).

8 Sanchez-Nieto JM, Torres A, Garcia-Cor-doba F et al. Impact of invasive and noninvasive quantitative culture sampling on outcome of ventilator-associated pneumonia: A pilot study. Am. J. Respir. Crit. Care Med. 157(2), 371–376 (1998).

9 Ruiz M, Torres A, Ewig S et al. Noninva-sive versus invasive microbial investigation in ventilator-associated pneumonia: Evaluation of outcome. Am. J. Respir. Crit. Care Med. 162(1), 119–125 (2000).

10 Sole Violan J, Fernandez JA, Benitez AB et al. Impact of quantitative invasive diagnostic techniques in the management and outcome of mechanically ventilated patients with suspected pneumonia. Crit. Care Med. 28(8), 2737–2741 (2000).

11 Fagon JY, Chastre J, Wolff M et al. Invasive and noninvasive strategies for management of suspected ventilator-associated

pneumonia. A randomized trial. Ann. Intern. Med. 132(8), 621–630 (2000).

12 Kwon Y, Milbrandt EB, Yende S. Diagnos-tic techniques for ventilator-associated pneumonia: Conflicting results from two trials. Crit. Care 13(3), 303 (2009).

13 Kang CI, Kim SH, Kim HB et al. Pseudomonas aeruginosa bacteremia: risk factors for mortality and influence of delayed receipt of effective antimicrobial therapy on clinical outcome. Clin. Infect. Dis. 37(6), 745–751 (2003).

•• DelayingappropriatetherapyinPseudomonas aeruginosabacteremiawasassociatedwithahighermortality.

14 Lodise TP Jr, Patel N, Kwa A et al. Predictors of 30-day mortality among patients with Pseudomonas aeruginosa bloodstream infections: impact of delayed appropriate antibiotic selection. Antimicrob. Agents Chemother. 51(10), 3510–3515 (2007).

•• Delayingappropriatetherapyformorethan52hsignificantlyincreasedtheriskof30-daymortalityinP. aeruginosabacteremia.

15 Cheong HS, Kang CI, Wi YM et al. Inappropriate initial antimicrobial therapy as a risk factor for mortality in patients with community-onset Pseudomonas aeruginosa bacteraemia. Eur. J. Clin. Microbiol. Infect. Dis. 27(12), 1219–1225 (2008).

16 Livermore DM. Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare? Clin. Infect. Dis. 34(5), 634–640 (2002).

17 Tam VH, Chang KT, Abdelraouf K et al. Prevalence, resistance mechanisms, and susceptibility of multidrug-resistant bloodstream isolates of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 54(3), 1160–1164 (2010).

18 Tam VH, Chang KT, LaRocco MT et al. Prevalence, mechanisms, and risk factors of carbapenem resistance in bloodstream isolates of Pseudomonas aeruginosa. Diagn. Microbiol. Infect Dis. 58(3), 309–314 (2007).

19 Micek ST, Lloyd AE, Ritchie DJ et al. Pseudomonas aeruginosa bloodstream infection: importance of appropriate initial antimicrobial treatment. Antimicrob. Agents Chemother. 49(4), 1306–1311 (2005).

•• CombinationtherapyforP. aeruginosabacteremiacouldminimizeinappropriatetreatmentuntilsusceptibilitiesareknown.

20 Hilf M, Yu VL, Sharp J et al. Antibiotic therapy for Pseudomonas aeruginosa

bacteremia: Outcome correlations in a prospective study of 200 patients. Am. J. Med. 87(5), 540–546 (1989).

21 Bowers DR, Liew YX, Lye DC et al. Outcomes of appropriate empiric combination versus monotherapy for Pseudomonas aeruginosa bacteremia. Antimicrob. Agents Chemother. 57(3), 1270–1274 (2013).

• Therewasnosignificantdifferencebetweenempiricappropriatecombinationtherapyandmonotherapyfor30-daymortalityinP. aeurginosabacteremia.

22 Anderson DJ, Miller B, Marfatia R et al. Ability of an antibiogram to predict Pseudomonas aeruginosa susceptibility to targeted antimicrobials based on hospital day of isolation. Infect. Control. Hosp. Epidemiol. 33(6), 589–593 (2012).

23 Cattoir V, Gilibert A, Le Glaunec JM et al. Rapid detection of Pseudomonas aeruginosa from positive blood cultures by quantitative pcr. Ann. Clin. Microbiol. Antimicrob. 9, 21 (2010).

24 Della-Latta P, Salimnia H, Painter T et al. Identification of escherichia coli, klebsiella pneumoniae, and Pseudomonas aeruginosa in blood cultures: A multicenter perfor-mance evaluation of a three-color peptide nucleic acid fluorescence in situ hybridiza-tion assay. J. Clin. Microbiol. 49(6), 2259–2261 (2011).

25 Schaumann R, Knoop N, Genzel GH et al. A step towards the discrimination of beta-lactamase-producing clinical isolates of enterobacteriaceae and Pseudomonas aeruginosa by MALDI-ToF mass spectrom-etry. Med. Sci. Monit. 18(9), MT71–77 (2012).

26 Paul M, Soares-Weiser K, Leibovici L. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for fever with neutropenia: systematic review and meta-analysis. BMJ. 326(7399), 1111 (2003).

27 Paul M, Benuri-Silbiger I, Soares-Weiser K et al. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analy-sis of randomised trials. BMJ. 328(7441), 668 (2004).

28 Garnacho-Montero J, Sa-Borges M, Sole-Violan J et al. Optimal management therapy for Pseudomonas aeruginosa ventilator-associated pneumonia: An obser-vational, multicenter study comparing monotherapy with combination antibiotic therapy. Crit. Care Med. 35(8), 1888–1895 (2007).

Expert Rev. Anti Infect. Ther. 11(8), (2013)836

Bowers & Tam

Review

29 Bliziotis IA, Petrosillo N, Michalopoulos A et al. Impact of definitive therapy with beta-lactam monotherapy or combination with an aminoglycoside or a quinolone for Pseudomonas aeruginosa bacteremia. PLoS One 6(10), e26470 (2011).

30 Chamot E, Boffi El Amari E, Rohner P et al. Effectiveness of combination antimicrobial therapy for Pseudomonas aeruginosa bacteremia. Antimicrob. Agents Chemother. 47(9), 2756–2764 (2003).

31 Craig WA. Pharmacokinetic/pharmacody-namic parameters: rationale for antibacterial dosing of mice and men. Clin. Infect Dis. 26(1), 1–10; quiz 11–12 (1998).

32 Nicolau DP, Freeman CD, Belliveau PP et al. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob. Agents Chemother. 39(3), 650–655 (1995).

33 Murry KR, McKinnon PS, Mitrzyk B et al. Pharmacodynamic characterization of nephrotoxicity associated with once-daily aminoglycoside. Pharmacotherapy 19(11), 125–1260 (1999).

34 Lodise TP Jr, Lomaestro B, Drusano GL. Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy. Clin. Infect. Dis. 44(3), 357–363 (2007).

35 Felton TW, Hope WW, Lomaestro BM et al. Population pharmacokinetics of extended-infusion piperacillin-tazobactam in hospitalized patients with nosocomial infections. Antimicrob. Agents Chemother. 56(8), 4087–4094 (2012).

36 Yost RJ, Cappelletty DM. The retrospec-tive cohort of extended-infusion piperacil-lin-tazobactam (receipt) study: a multi-center study. Pharmacotherapy 31(8), 767–775 (2011).

37 Taccone FS, Cotton F, Roisin S et al. Optimal meropenem concentrations to treat multidrug-resistant Pseudomonas aeruginosa septic shock. Antimicrob. Agents Chemother. 56(4), 2129–2131 (2012).

38 Roberts JA, Kirkpatrick CM, Roberts MS et al. Meropenem dosing in critically ill patients with sepsis and without renal dysfunction: intermittent bolus versus continuous administration? Monte carlo dosing simulations and subcutaneous tissue distribution. J. Antimicrob. Chemother. 64(1), 142–150 (2009).

39 Hayashi Y, Paterson DL. Strategies for reduction in duration of antibiotic use in hospitalized patients. Clin. Infect. Dis. 52(10), 1232–1240 (2011).

40 Chastre J, Wolff M, Fagon JY et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA. 290(19), 2588–2598 (2003).

41 Christ-Crain M, Opal SM. Clinical review: the role of biomarkers in the diagnosis and management of community-acquired pneumonia. Crit. Care 14(1), 203 (2010).

42 Povoa P, Salluh JI. Biomarker-guided antibiotic therapy in adult critically ill patients: a critical review. Ann. Intensive Care 2(1), 32 (2012).

43 Michalopoulos A, Papadakis E. Inhaled anti-infective agents: emphasis on colistin. Infection 38(2), 81–88 (2010).

44 Palmer LB, Smaldone GC, Chen JJ et al. Aerosolized antibiotics and ventilator-associated tracheobronchitis in the intensive care unit. Crit. Care Med. 36(7), 2008–2013 (2008).

45 Satlin MJ, Kubin CJ, Blumenthal JS et al. Comparative effectiveness of aminoglyco-sides, polymyxin b, and tigecycline for clearance of carbapenem-resistant klebsiella pneumoniae from urine. Antimicrob. Agents Chemother. 55(12), 5893–5899 (2011).

46 Kwa AL, Loh C, Low JG et al. Nebulized colistin in the treatment of pneumonia due to multidrug-resistant acinetobacter baumannii and Pseudomonas aeruginosa. Clin. Infect. Dis. 41(5), 754–757 (2005).

47 Michalopoulos A, Falagas ME. Colistin and polymyxin b in critical care. Crit. Care Clin. 24(2), 377–391, x (2008).

48 Falagas ME, Bliziotis IA, Tam VH. Intraventricular or intrathecal use of polymyxins in patients with gram-negative meningitis: a systematic review of the available evidence. Int. J. Antimicrob. Agents 29(1), 9–25 (2007).

49 Jacobsen F, Fisahn C, Sorkin M et al. Efficacy of topically delivered moxifloxacin against wound infection by Pseudomonas aeruginosa and methicillin-resistant staphylococcus aureus. Antimicrob. Agents Chemother. 55(5), 2325–2334 (2011).

50 Pathengay A, Mathai A, Shah GY et al. Intravitreal piperacillin/tazobactam in the management of multidrug-resistant Pseudomonas aeruginosa endophthalmitis.

J. Cataract. Refract. Surg. 36(12), 2210–2211 (2010).

51 Vincent JL, Gerlach H. Fluid resuscitation in severe sepsis and septic shock: an evidence-based review. Crit. Care Med. 32(11 Suppl.), S451–454 (2004).

52 Keh D, Sprung CL. Use of corticosteroid therapy in patients with sepsis and septic shock: an evidence-based review. Crit. Care Med. 32(11 Suppl.), S527–533 (2004).

53 Dellinger RP, Levy MM, Rhodes A et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit. Care Med. 41(2), 580–637 (2013).

54 Dellit TH, Owens RC, McGowan JE Jr et al. Infectious diseases society of america and the society for healthcare epidemiology of america guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin. Infect. Dis. 44(2), 159–177 (2007).

55 Ntagiopoulos PG, Paramythiotou E, Antoniadou A et al. Impact of an antibiotic restriction policy on the antibiotic resistance patterns of gram-negative microorganisms in an intensive care unit in greece. Int. J. Antimicrob. Agents 30(4), 360–365 (2007).

56 Cook PP, Das TD, Gooch M et al. Effect of a program to reduce hospital ciprofloxa-cin use on nosocomial Pseudomonas aeruginosa susceptibility to quinolones and other antimicrobial agents. Infect. Control. Hosp. Epidemiol. 29(8), 716–722 (2008).

57 Jonas D, Meyer E, Schwab F et al. Genodiversity of resistant Pseudomonas aeruginosa isolates in relation to antimicro-bial usage density and resistance rates in intensive care units. Infect. Control. Hosp. Epidemiol. 29(4), 350–357 (2008).

58 Moolenaar RL, Crutcher JM, San Joaquin VH et al. A prolonged outbreak of Pseudomonas aeruginosa in a neonatal intensive care unit: did staff fingernails play a role in disease transmission? Infect. Control. Hosp. Epidemiol. 21(2), 80–85 (2000).

59 Centers for Disease Control and Prevention. Pseudomonas aeruginosa respiratory tract infections associated with contaminated ultrasound gel used for transesophageal echocardiography – Michigan, December 2011–January 2012. MMWR Morb. Mortal. Wkly. Rep. 61, 262–264 (2012).

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