What are the key principles of preventing Gram negative bacteria – Pseudomonas aeruguinosa?

Pseudomonas aeruginosa is a common pathogen in healthcare-associated infections, often associated with a high mortality in vulnerable populations. A review of the National Nosocomial Infections Surveillance System from 1986-2003 revealed that P. aeruginosa was the third most common cause of nosocomial urinary tract infections, the second most common cause of nosocomial pneumonia, the fifth most common cause of surgical site infections, and the eighth most common cause of nosocomial bloodstream infections.

According to the Global SENTRY Antimicrobial Surveillance Program from 1997-1999, P. aeruginosa was most commonly isolated from the respiratory tract, followed by wounds, urine, and then bloodstream. Rates of antimicrobial resistance have increased worldwide, and the number of isolates resistant to multiple antibiotics has also increased. Adequate infection control measures are necessary to prevent the development of resistance to multiple antibiotics, as well as spread of multidrug resistant (MDR) P. aeruginosa to other patients. Prevention of infection is complex and standards of care continue to evolve. A multi-faceted approach targeting environmental contamination, judicious use of antimicrobials, and minimization of invasive lines and devices, will likely be necessary.

What are the key conclusions of clinical trials and meta-analyses regarding Gram negative bacteria – Pseudomonas aeruguinosa?

Infection control trials for P. aeruginosa have covered the role of active surveillance, eradication of biofilms from environmental sources, and the role of synergistic antibiotic combinations to prevent resistance. Many of the results from these studies have not been confirmed by large, randomized, studies on human subjects, so it is difficult to draw evidenced-based conclusions. In general:

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a) Active surveillance may help guide appropriate antibiotic therapy for patients with MDR P. aeruginosa infections, but cost effectiveness is a major concern.

b) Eradiation of P. aeruginosa from hospital sinks and drains is challenging due to biofilm formation, and may therefore serve as a potential reservoir for transmitting the pathogen to patients; however, the exact role of these exogenous sources is less clear.

c) Combination therapy for P. aeruginosa infections to reduce antibiotic resistance has been demonstrated by in vitro studies, but has not been supported by available meta-analyses. Employing pharmacodynamic data to determine the optimal dosing for various antipseudomonal antibiotics may also help reduce the risk for resistance.

What are the consequences of ignoring the control of Gram negative bacteria – Pseudomonas aeruguinosa?

Inadequate infection control measures may result in an increase in multidrug resistant (MDR) P. aeruginosa isolates. Resistance is commonly attributed to antibiotic selective pressure in the setting of broad-spectrum antibiotics, but exogenous transmission of resistant isolates from the environment may also contribute. MDR P. aeruginosa has been associated with an increased mortality, increased risk for secondary bacteremia, and an increase in hospital stay.

Summary of current controversies regarding Gram negative bacteria – Pseudomonas aeruguinosa.

Although it is generally accepted that patients with MDR P. aeruginosa should be isolated with contact precautions, the duration of contact precautions and the means of surveillance is not well-defined.

The Global SENTRY Antimicrobial Surveillance Program concluded that no single agent could successfully cover over 90% of the P. aeruginosa isolates worldwide. Empiric use of a combination of antibiotics from two different classes is often recommended when severe infections from P. aeruginosa are suspected, to ensure that patients are covered by at least one active drug. However, the continued use of combination therapy for treatment of P. aeruginosa infections, instead of narrowing coverage to a single agent based on the susceptibility profile, is controversial.

What is the role of and impact of Gram negative bacteria – Pseudomonas aeruguinosa and the need for control relative to infections at other sites or from other specific pathogens?

Most MDR P. aeruginosainfections are healthcare-associated. P. aeruginosais rarely considered part of the normal flora and tends to occur after several days in the hospital. Immunocompromised populations, individuals with recent antibiotic exposure, and invasive devices are associated with an increased risk for infection.

P. aeruginosa thrives in moist environments, such as hospital sinks and respiratory equipment. In one review, P. aeruginosa persisted from 6 to 16 hours on inanimate surfaces. Biofilms also play a key role in the resistance of P. aeruginosa in the environment by shielding the pathogen from antibiotics and disinfectants. Of note, most environmental isolates are found to be different strains than clinical isolates. As such, most infection control practices rely on preventing person-to-person transmission.

P. aeruginosa is inherently resistant to some antibiotics that are unable to penetrate the cell wall. P. aeruginosa can acquire resistance while on antibiotic therapy, particularly fluoroquinolone exposure. Multiple factors are responsible for acquired resistance, including enzyme inactivation, efflux systems, and changes in porin structures. Of particular concern is the potential for P. aeruginosa to develop resistance to available beta-lactams, carbapenems, fluoroquinolones, and aminoglycosides, by multidrug efflux pumps.

Overview of important clinical trials, meta-analyses, case control studies, case series, and case reports related to infection control and Gram negative bacteria – Pseudomonas aeruguinosa.

Table I provides a summary of relevant research.

Table I.
Meta-analysis Number of studies included Description of meta-analysis Antimicrobials used Conclusions from meta-analysis
Paul 2003 47 (sub-group analysis for all cause fatality with P. aeruginosa- 7 studies) Beta lactam monotherapy v. beta lactam-aminoglycoside combination therapy in neutropenic fever Monotherapy beta lactam could be the same or different than the combination beta lactam – No significant difference in all-cause fatality, rate of superinfection or colonization- Significantly increased number of adverse events in combination group
Safdar 2004 17 (5 studies focused exclusively on P. aeruginosa) Gram-negative bacteremia Varied; majority of monotherapy studies used aminoglycosides – Trend toward reduced mortality in combination group for P. aeruginosa bacteremia
Bliziotis 2005 8 Use of beta-lactam monotherapy v. beta-lactam/aminoglycoside therapy to prevent the emergence of resistance Monotherapy beta lactam could be the same or different than the combination beta lactam – No significant difference in mortality or emergence of resistance- statistically decreased rate of superinfections in monotherapy group
Elphick 2005 8 Cystic fibrosis pulmonary infections Beta lactam was same in monotherapy and combination therapy; second drug was aminoglycoside – No significant difference in resistance at baseline compared with end of treatment
Paul 2006 64 (18 studies with P. aeruginosa) Beta-lactam monotherapy v. beta-lactam/aminoglycoside therapy in patients with sepsis (excluding neutropenic fever) Monotherapy beta lactam could be the same or different than the combination beta lactam – No significant difference in mortality, rate of superinfections or colonization- higher rate of adverse events in combination group
Aarts 2008 41 – 11 trials compared empiric combination therapy v. monotherapy (13.8% with P. aeruginosa) Empiric therapy for suspected ventilator-associated pneumonia Monotherapy group included beta lactam or fluoroquinolone; combination groups had same or different beta lactam combined with a fluoroquinolone or aminogylcoside – No significant difference in mortality, superinfections, or adverse effects
Kumar 2010 50 (12 studies exclusively with P. aeruginosa) Patients with serious bacterial infections leading to sepsis or septic shock, excluding neutropenic fevers, infective endocarditis, and meningitis Same drug (beta-lactam or fluoroquinolone) in monotherapy and combination therapy – Reduced mortality with combination therapy with beta-lactam, aminoglycosides, or quinolone in those patients at higher risk for mortality.- Resistance not evaluated
Marcus 2011 52 (5 trials specifically with P. aeruginosa) Use of beta-lactams v. same beta-lactams plus aminoglycoside in randomized trials Variable – No significant change in all cause mortality- Combination therapy significantly decreased need to modify antibiotic regimen during treatment- No significance in rate of bacterial and fungal superinfections- significantly increased risk for adverse events in combination therapy

Controversies in detail.

The utility of combination therapy, rather than culture-directed monotherapy, to prevent resistance during treatment of P. aeruginosa infections remains controversial. Although combination therapy has been demonstrated to reduce the incidence of resistance in in vitro studies, this has not been adequately studied in large, prospective, randomized trials. Few studies have specifically addressed resistance, and the rate of superinfections or colonization has often been used as a surrogate marker for emerging resistance.

In addition, there are considerable differences among antimicrobial combinations used and the patient populations studied. Most meta-analyses include P. aeruginosa infections as a small subgroup analysis. One of the criticisms of older studies is that most monotherapy regimens included newer, broad-spectrum beta-lactams, while combination therapy tended to use older, narrow-spectrum beta-lactams. In meta-analyses suggesting combination therapy had a survival advantage in P. aeruginosa bacteremia; the monotherapy group was typically aminoglycosides which is probably not sufficient. Disadvantages to combination therapy include an increased potential for adverse effects, as well as acquisition of additional multi-drug resistant organisms due to selective antibiotic pressure.

Some authorities advocate continuous infusion of beta-lactams and higher doses of aminoglycosides and fluoroquinolones to capitalize on time-dependent and concentration-dependent pharmacodynamics, respectively. Aminoglycosides, fluoroquinolones, and carbapenems also demonstrate a postantibiotic effect. In vitro studies suggest that sub-optimal dosing of beta-lactams relative to the density of P. aeruginosagrowth can result in the development of resistant subpopulations. In theory, dosing antipseudomonal antibiotics in a manner that optimizes pharmacodynamic principles may enhance eradication of resistant subpopulations. Optimal dosing strategies for beta-lactams, aminoglycosides, and fluoroquinolones have been described. One Monte Carlo simulation suggested that using fluoroquinolones as monotherapy, despite optimal antipseudomonal dosing, was unable to fully suppress resistance in high inoculum infections, such as with P. aeruginosa pneumonia.

The role for active surveillance of MDR P. aeruginosa is controversial and relies on several variables, including the undetected ratio, duration of colonization, and colonization pressure. Proponents cite that knowledge of colonizing pathogens can help guide empiric therapy, as colonization often precedes infection. In addition, active surveillance might allow for earlier contact isolation and hence less person-to-person transmission. The cost effectiveness of active surveillance has not been established.

Selective digestive tract decontamination (SDD) has been suggested as one method to reduce decolonization, however SDD with 4 days of intravenous cefotaxime and topical application of tobramycin, colistin, and amphotericin B in the oropharynx and stomach, did not decrease P. aeruginosa respiratory tract colonization in one randomized study.

What national and international guidelines exist related to Gram negative bacteria – Pseudomonas aeruguinosa?

There are no national or international guidelines specific to infection control and P. aeruginosa. Although contact precautions are advocated for patients with multidrug resistant gram negative bacteria such as P. aeruginosa, the means of surveillance, decolonization, and the duration of contact isolation has not been established. The Healthcare Infection Control Practices Advisory Committee (HIPAC) advises cleaning these with EPA-approved hospital disinfectants.

What other consensus group statements exist and what do key leaders advise?

According to the Infectious Diseases Society of America and American Thoracic Society guidelines for hospital-acquired pneumonia, patients who are at high risk for pneumonia secondary to MDR P. aeruginosa, initial broad-spectrum empiric therapy with an anti-pseudomonal beta-lactam or carbapenem plus a flouroquinolone or aminoglycoside, is recommended followed by de-escalation to monotherapy based on culture results after 5 days if there is clinical improvement. Broad coverage with de-escalation once culture results become available in patients with gram-negative VAP did not lead to antimicrobial resistance.

Empiric therapy with an antipseudomonal beta-lactam has also been advocated for neutropenic fever, with the addition of a fluoroquinolone or aminoglycoside with any complications or with suspected antimicrobial resistance. Combination therapy with an antipseudomonal beta-lactam and aminoglycoside should also be considered for meningitis and endocarditis secondary to P. aeruginosa. According to the Infectious Diseases Society of America Antimicrobial Stewardship guidelines there is insufficient data to justify combination therapy for the sole purpose of preventing resistance.


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