A clinical approach to managing Pseudomonas aeruginosa infections.

Authors:

Moore, Luke SP 1,2*

Cunningham, Joel 3

Donaldson, Hugo 2

Affiliations:

1 National Centre for Infection Prevention and Management, Imperial College London, Hammersmith Campus, Du Cane Road, London. W12 0HS. United Kingdom.

2 Imperial College Healthcare NHS Trust, Fulham Palace Road, London.W6 8RF. United Kingdom.

3 Basildon and Thurrock University Hospitals NHS Foundation Trust, Nethermayne, Basildon, Essex. SS16 5NL

*Corresponding author:

Dr Luke SP Moore, National Centre for Infection Prevention & Management, Imperial College

London, Hammersmith Campus, London, W12 0HS. Email: l.moore@imperial.ac.uk, telephone:

02033132732.

Search terms:

Bronchiectasis

Cystic fibrosis

Ventilator associated pneumonia

Microbiology

Burns

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Abstract:

Pseudomonas aeruginosa is a strictly aerobic Gram negative rod, widely found in the

environment, including in and around water sources. It is commonly seen in clinical practice and

reported in clinical microbiological cultures; however this frequently represents colonisation

which often does not necessitate targeted therapy. When specific treatment is indicated choice is

limited, with marked intrinsic and acquired antimicrobial resistance among P.aeruginosa. This

article reviews the clinical presentations associated with P.aeruginosa, particularly acute health-

care associated pulmonary infections, infections in those with pre-existing lung pathology, and

prosthetic device and skin & soft tissue infections. The pertinent clinical and laboratory

investigations are reviewed, as is the evidence around management strategies, and the infection

prevention and control implications.

Key messages:

P.aeruginosa causes acute pulmonary pathology in specific patient cohorts, but also

commonly complicates chronic lung conditions.

P.aeruginosa frequently colonises soft tissue wounds, including diabetic foot ulcers, but

frequently represents colonisation and targeted therapy is not indicated.

The ability of P.aeruginosa to form biofilms, on both biotic and abiotic surfaces, is a key

virulence factor.

Investigation of patients with suspected P.aeruginosa infections should be through

culture of appropriate (and often invasive) specimens, with susceptibility testing playing

a key role in determination of appropriate therapy.

Treatment of patients with P.aeruginosa is complex due to inherent antimicrobial

resistance to many antimicrobials, and increasingly, acquired resistance to the remainder.

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Introduction:

The Pseudomonas genus is a group of more than 140 bacterial species, all strictly aerobic Gram

negative rods, widely found in the environment, including in and around water sources. The

most common species in the context of human colonisation is P. aeruginosa, where estimations

of colonisation vary from 3-5% in healthy individuals, up to 20% among inpatients. However

colonisation does not equal infection, and despite the high rates of colonisation and the potential

for virulence, it is thought that less than 10% of inpatient infections are due to P.aeruginosa.

This colonisation/infection dichotomy can cause confusion in clinical practice, with potential for

both under- and over- treating of clinical conditions in which infection with P.aeruginosa is

suspected, or where it has been confirmed on culture. Clinical management of patients with

P.aeruginosa is further complicated by the complex antimicrobial resistance of this organism.

This article reviews the clinical spectrum of disease caused by this organism, appropriate

investigations and their interpretation, management options, and implications for infection

control and public health.

Clinical spectrum of disease:

Pulmonary:

Acute healthcare-associated infections: Healthcare-acquired pneumonia (HAP) and ventilator-

acquired pneumonia (VAP) (Box 1) are frequently caused by multi-drug resistant bacteria,

among which P.aeruginosa features prominently. Risk factors include not only exposure to

reservoirs within the institutional environment, but also selective antimicrobial pressure, and

compromise of the respiratory tract (for example following endo-tracheal intubation). Mortality

rates from HAP and VAP can be significant (ranging from 7% to 62%), contributed to by

bacterial factors (organism virulence, antimicrobial resistance) and host factors (pre-existing

comorbidities). HAP/ VAP should be suspected when inpatients show signs of sepsis alongside

an increase in oxygen demand or respiratory rate, significant respiratory secretions, or

development of new pulmonary infiltrates on chest radiograph (Rotstein et al., 2008). Although

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the 'CURB65' score is useful in defining severity of community acquired pneumonias, there is

little evidence for robust prognostic scoring tools in HAP/VAP.

[Box 1 here]

Pre-existing lung pathology: Respiratory tract colonisation with P.aeruginosa is not uncommon

among patients with certain chronic pulmonary diseases. The frequent and often early

colonisation of cystic fibrosis (CF) patients with this organism is multifactorial, but includes

aberrant inflammatory responses, increased pathogen adhesion to the endothelium, and altered

host response to biofilm production. Carriage of the organism is often not a cause for clinical

concern until adolescent and early adult years when, at the level of the organism, there is a shift

from a non-mucoid to mucoid phenotype which coincides with worsening respiratory function

(Hewitt, Smeeth, Bulpitt, Tulloch, & Fletcher, 2005).

The other patient group particularly at risk of P.aeruginosa colonisation are those with

bronchiectasis. The characteristic dilated and thickened airways with chronic sputum production

predisposes to chronic and recurrent bacterial infection. There is a general progression during the

disease course from typical respiratory pathogens towards more resilient microbes such as P.

aeruginosa, with colonisation rates of between 12% and 31% (Pappalettera et al., 2009). Similar

to patients with CF, it is difficult to eradicate P.aeruginosa once established, and colonisation is

associated with a decline in respiratory function.

There is increasing evidence to suggest that P.aeruginosa colonisation also has a pathological

role in a subset of patients with chronic obstructive pulmonary disease (COPD), where chronic

biofilm persistence is thought to predispose to 'acute exacerbations' with this organism. There is

a correlation between colonisation and deterioration of lung function, though attribution of

causality is confounded by general disease progression (Holm, Hilberg, Noerskov-Lauritsen, &

Bendstrup, 2013).

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Non pulmonary:

Prosthetic material infections: The ability of P.aeruginosa to form biofilms extends importantly

to abiotic material and is a key virulence factor; colonisation and subsequent infection of

prosthetic devices is a not infrequent complication in clinical practice. This ranges from

intravascular devices (cannula and central lines), to prosthetic joints, through to in-dwelling

intra-thecal/intra-cranial devices in neurology and neurosurgical patients. In

immunocompromised patients (particularly patients undergoing chemotherapy) infection of lines

is of particular concern. All patients with a prosthetic device who develop a fever, or in whom

local clinical signs of infection develop around the device (erythema, pain, pustular discharge),

should have samples taken for culture and a risk/benefit analysis undertaken around device

exchange/removal.

Burns: Infection with P. aeruginosa can be a serious complication of burns. In these patients the

disruption of the tegument, combined with the local immunosuppression that comes with burnt

tissue (reduced T-cell activity, inflammatory cytokines and complement), means colonisation

frequently progresses to infection. Furthermore, non-P.aeruginosa species of Pseudomonas may

also be considered as pathogens, unlike in other patient cohorts. Where there is delayed grafting

of a burn, biofilms may develop in the burn site, and P.aeruginosa is a particular problem in

these cases; difficulty in clearing the infection can make subsequent grafting considerably more

difficult. Early grafting of burns and early antimicrobial therapy where P.aeruginosa is isolated

is advocated.

Diabetic feet and soft tissue wounds: The predilection of P.aeruginosa for moist areas means

wounds, including foot wounds among patients with diabetes, are frequently colonised with this

organism and swab results commonly report its presence. However, the contribution of this

organism to wound infections here is less clear; whilst this organism has the potential to cause

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wound infections, non-pathological colonisation is more commonplace. In intact skin,

P.aeruginosa can also rarely cause a peri-folliculitis - classically reported after sauna and ‘hot

tub’ use and associated with contaminated water.

Investigations:

Investigations of possible pulmonary infections should begin with sputum samples (or in the

case of VAP, endo-tracheal aspirates or bronchoalveolar lavage). In cases of chronic

colonisation, sputum samples should be sought with each new exacerbation to detect

development of new resistance.

Where medical device infections are suspected, and removal is possible, the device should be

sent for culture (e.g. the cannula tip in cases of suspected central line infection). Supporting

samples are also useful (blood culture where central line infections are considered;

cerebrospinal-spinal fluid where intra-thecal/cranial devices are implicated). Exit site swabs for

intravascular lines are poorly correlated to infective organisms, and should be interpreted with

care. Where prosthetic joint infections are considered, multiple samples for culture (four or five;

using separate instruments) should be taken from around the prosthesis. Burns should be

swabbed promptly and acted upon rapidly. In contrast, in diabetic foot infections superficial

swabs can be misleading (as above) - guidelines advocate deep tissue samples in preference

(Lipsky et al., 2012; NICE, 2012). Where there is a suspicion of underlying osteomyelitis, deep

tissue/bone sampling rather than superficial swabbing is key to effective therapy.

In the laboratory, culture using standard methods is usually undertaken on agar based culture

media (Figure 1). Presumptive identification of a Gram negative organism as a Pseudomonas

spp. at the 24 hour mark is based upon it being an oxidase positive non-lactose fermenter with

typical colony morphology. Formal identification to the species level can take several more

hours depending upon laboratory practice. Susceptibility testing usually then follows the next

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day, being available 48hours after the sample was received in the laboratory. Whilst rapid

genotypic based diagnostic tests may become available in the future, currently clinical use is

rare. There are no serological tests available.

[Figure 1 here]

P.aeruginosa, because of its relatively ubiquitous nature, is frequently isolated with other

organisms. In these cases, a clinical decision must be made as to whether (i) the other

organism(s) are causing the disease process (and the P.aeruginosa represents colonisation), (ii)

P.aeruginosa is the pathogen, or (iii) it is a true poly-microbial infection (unusual).

Management:

Antimicrobials: The number of antimicrobials effective against P aeruginosa is limited by the

pathogen's broad range of inherent antibiotic resistance mechanisms. Box 2 lists the commonly

used anti-pseudomonal agents; many are commonly restricted on hospital formularies,

necessitating discussion with infection specialists. Classically, the carbapenem and polymixin

classes have been the least affected by resistance, however there is recent evidence that

resistance to carbapenems is increasing (Moore et al., 2014).

[Box 2 here]

Acute pulmonary infections: Acutely unwell patients with confirmed or suspected P.aeruginosa

infection should be treated with appropriate intravenous agents. There is ongoing debate as to

whether mono- or dual-antimicrobial therapy should be used in acute P.aeruginosa pulmonary

infections, with dual therapy minimising the potential for failure to cover resistant isolates

(Micek et al., 2005) yet well-chosen mono-therapy showing reduction in side effects without

impacting mortality (Damas et al., 2006). Furthermore, optimal duration of antimicrobial therapy

is also contentious, with a shorter course (8 days) producing fewer side effects and less

ecological microbial selectivity, but at the cost of marginally worse clinical outcomes when

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compared to longer courses (15 days) (Chastre et al., 2003). This lack of decisive evidence to

guide treatment reinforces the importance of early discussion with infection specialists to

personalise management strategies.

Chronic pulmonary colonisation:

The role of antibiotics in eradication or suppression of P.aeruginosa to reduce lung damage is

established in patients with CF (Høiby, 2011). There is less evidence base however for the role

of maintenance therapy in bronchiectasis, though many clinicians do support its use to reduce

the frequency of exacerbations (Pappalettera et al., 2009). Bronchiectasis and CF patients should

be managed by a respiratory physician in close liaison with an infection specialist, but several

concepts are clear:

Initial acquisition of P.aeruginosa should be actively treated. Combination therapy with

inhaled/nebulised polymixins (e.g. colistin/colistimethate) or aminoglycosides (e.g.

tobramycin) in conjunction with oral ciprofloxacin for up to three months can be used to

reduce pathogen load in the respiratory tract. Whilst this regime allows patients to be

treated at home, there is insufficient evidence to set this strategy apart from an initial two

week intravenous course of antibiotics (Høiby, 2011).

Acute respiratory exacerbations with suspected or confirmed P.aeruginosa should be

treated with intravenous antimicrobials based on up-to-date culture and susceptibility

testing. Duration of treatment is typically 10-14 days, although evidence for this is not

robust. Ambulatory care may facilitate receipt of intravenous antimicrobials at home.

Oral ciprofloxacin can be used for acute infective exacerbations of CF, however a recent

Cochrane review failed to definitively show that oral agents are more or less effective

than intravenous agents (Remmington, Jahnke, & Harkensee, 2013). The role of

nebulised therapy in acute infections is highly contentious with little evidence to inform

its role and efficacy (El Solh & Alhajhusain, 2009).

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Macrolides such as azithromycin are often used as long term therapy in chronic lung

pathology patients with P.aeruginosa colonisation, likely acting as anti-inflammatories

given the intrinsic resistance of this organism to this antimicrobial class. A recent meta-

analysis focussing on CF patients suggested long term azithromycin may improve lung

function without significant side effects; although evidence on their effect on frequency

of infective exacerbations is less clear (Cai et al., 2011).

Soft tissue infection: Treatment for diabetic foot infections should in the first instance be targeted

against Gram positive organisms and anaerobes, with specific anti-pseudomonal therapy only

instigated where both standard therapy is clinically failing and where P.aeruginosa has been

isolated (Lipsky et al., 2012). Anti-pseudomonal therapy should not be instigated solely on

isolation of P.aeruginosa from a wound swab.

Future: Ongoing research into anti-pseudomonal agents aims to overcome the growing drug-

resistance. Areas of development include next generation carbapenems and cephalosporins, and

more definitive investigation of aerosolized agents to maximise delivery in pulmonary

infections. Monoclonal antibodies targeted against pseudomonal virulence mechanisms are also

in early stage exploration (El Solh & Alhajhusain, 2009).

Infection control and public health:

P.aeruginosa has been of particular concern in relation to clinical sink units in augmented care

(adult, neo-natal, and paediatric intensive care units), with proven transmission from these

environmental sources to patients (Witney et al., 2014). Whilst regulations minimising the risk

from the built environment apply at the institutional level, at the clinical level some units may

advocate applying alcohol gel after hand washing to minimise onwards transmission. Where

multi-drug resistant P.aeruginosa is confirmed, additional precautions may be instigated

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including isolation and glove/gowning. P.aeruginosa is not a notifiable disease, but outbreaks

(particularly of resistant strains) often necessitate public health investigation.

Conclusions:

P.aeruginosa, a ubiquitous environmental organism, is frequently seen in clinical practice and

commonly reported in culture results. However this frequently represents colonisation and

targeted therapy is not indicated. Where specific treatment is indicated choice is limited, and

with antimicrobial resistance increasing at local, national and international levels, careful

consideration and liaison with infection specialists is key.

Word count:

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Acknowledgements:

LSPM is funded by a National Institute of Health Research Imperial Biomedical Research

Centre Clinical Research Training Fellowship and is affiliated with the National Centre for

Infection Prevention & Management which is supported by the UK Clinical Research

Collaboration.

Conflict of interest:

LSPM has consulted for bioMérieux. JC and HD none to declare.

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References:

Cai, Y., Chai, D., Wang, R., Bai, N., Liang, B.-B., & Liu, Y. (2011). Effectiveness and safety of macrolides in cystic fibrosis patients: a meta-analysis and systematic review. Journal of Antimicrobial Chemotherapy, 66(5), 968–78.

Chastre, J., Wolff, M., Fagon, J.-Y., et al. (2003). Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA, 290(19), 2588–98.

Damas, P., Garweg, C., Monchi, M., Nys, M., Canivet, J.-L., Ledoux, D., & Preiser, J.-C. (2006). Combination therapy versus monotherapy: a randomised pilot study on the evolution of inflammatory parameters after ventilator associated pneumonia [ISRCTN31976779]. Critical Care, 10(2), R52.

El Solh, A. A., & Alhajhusain, A. (2009). Update on the treatment of Pseudomonas aeruginosa pneumonia. Journal of Antimicrobial Chemotherapy, 64(2), 229–38.

Hewitt, J., Smeeth, L., Bulpitt, C. J., Tulloch, A. J., & Fletcher, A. E. (2005). Respiratory symptoms in older people and their association with mortality. Thorax, 60(4), 331–4.

Høiby, N. (2011). Recent advances in the treatment of Pseudomonas aeruginosa infections in cystic fibrosis. BMC Medicine, 9(1), 32.

Holm, J. P. Y., Hilberg, O., Noerskov-Lauritsen, N., & Bendstrup, E. (2013). Pseudomonas aeruginosa in patients without cystic fibrosis is strongly associated with chronic obstructive lung disease. Danish Medical Journal, 60(6), A4636.

Lipsky, B. A., Berendt, A. R., Cornia, P. B., et al. (2012). 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clinical Infectious Diseases, 54(12), e132–73.

Micek, S. T., Lloyd, A. E., Ritchie, D. J., Reichley, R. M., Fraser, V. J., & Kollef, M. H. (2005). Pseudomonas aeruginosa Bloodstream Infection: Importance of Appropriate Initial Antimicrobial Treatment. Antimicrobial Agents and Chemotherapy, 49(4), 1306–1311.

Moore, L. S., Freeman, R., Gilchrist, M., et al. (2014). Homogeneity of antimicrobial policy, yet heterogeneity of antimicrobial resistance: antimicrobial non-susceptibility among 108,717 clinical isolates from primary, secondary and tertiary care patients in London. Journal of Antimicrobial Chemotherapy, [In Press].

NICE. (2012). NICE clinical guideline 119. Diabetic foot problems: inpatient management of diabetic foot problems. London.

Pappalettera, M., Aliberti, S., Castellotti, P., Ruvolo, L., Giunta, V., & Blasi, F. (2009). Bronchiectasis: an update. The Clinical Respiratory Journal, 3(3), 126–34.

Remmington, T., Jahnke, N., & Harkensee, C. (2013). Oral anti-pseudomonal antibiotics for cystic fibrosis (Review). Cochrane Database of Systematic Reviews, 10.

Rotstein, C., Evans, G., Born, A., Grossman, R., Light, R. B., Magder, S., … Zhanel, G. G. (2008). Clinical practice guidelines for hospital-acquired pneumonia and ventilator-associated pneumonia in adults. Canadian Journal of Infectious Diseases & Medical Microbiology, 19(1), 19–53.

Witney, A., Gould, K., Pope, C. F., et al. (2014). Genome sequencing and characterization of an extensively drug-resistant sequence type 111 serotype O12 hospital outbreak strain of Pseudomonas aeruginosa. Clinical Microbiology and Infection, [Epub ahead of print].

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Box 1. Classification of acute respiratory tract infections. Modified from Napolitano (2010).

Hospital Acquired Pneumonia (HAP)

Pneumonia occurring >48 hours after hospital admission and not incubating at the time of admission

Ventilator Acquired Pneumonia (VAP)

Pneumonia occurring ≥48 hours following endotracheal intubation

Early HAP/VAP <5 days following admission or intubation. Organisms usually common pathogens; Streptococcus pneumoniae, Haemophilus influenza, methicillin-susceptible Staphylococcus aureus, drug-susceptible Gram-negative bacteria. Low mortality.

Late HAP/VAP ≥5 days following admission or intubation. Organism frequently drug resistant, including Pseudomonas aeruginosa, Acinetobacter species, methicillin-resistant Staphylococcus aureus, multidrug-resistant Gram-negative bacteria. Significant mortality.

Box 2. Antimicrobials most commonly used in Pseudomonas aeruginosa infections

Intravenous agents

Piperacillin-Tazobactam

Ceftazidime / Cefepime

Gentamicin / Amikacin / Tobramycin

Meropenem / Imipenem / Doripenem

Aztreonam

Colistimethate sodium (Polymixin E)

Prescribing notes

This agent is a penicillin, and any history of previous allergy to this class of antimicrobials should be clearly elucidated prior to prescription

Increased risk of Clostridium difficile in the >65 year old population; Cross-allergy in those with penicillin allergy can occur, but is infrequent.

Narrow therapeutic window – plasma trough level monitoring essential; Potential for ototoxity with prolonged use

Cross-allergy in those with penicillin allergy can occur, but is rare; Imipenem-cilastatin has been associated with neurological adverse events

Resistance to this agent among P.aeruginosa is common

Nephro- and neuro-toxicity may occur and should be actively monitored for

Oral agents

Ciprofloxacin / LevofloxacinIncreased risk of Clostridium difficile in the >65 year old population; Ciprofloxacin is a potent inhibitor of the cytochrome P450 pathway

Inhaled/Nebulised agents

Colistimethate sodium (Polymixin E)

Gentamicin / Tobramycin

Bronchospasm may occur on inhalation of antibiotics, but may be ameliorated through use of inhaled beta2-agonists; Sore throats may be

reported, and may be due to either local drug hypersensitivity reactions or Candida spp. infection.

Footnote: Listed agents can be used empirically where there is clinical suspicion of P.aeruginosa as a causative organism, or where culture and susceptibility testing indicate activity

against the organism. Choice of therapy depends upon the individual patient and clinical presentation, and discussion with infection specialists is advocated.

}

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Figure 1. Presumptive laboratory identification of Pseudomonas aeruginosa.

Legend: Laboratory identification of Pseudomonas aeruginosa is typically through use of agar

based culture media, where bacterial production of pyocycanin typically produces a green tint to

colonies (a). Identification is further confirmed through simple bench top biochemistry in a few

seconds where pseudomonads are oxidase positive (b) (negative control (c)). Determination of

drug resistance for pseudomonads is commonly performed using disc susceptibility testing, but

few agents warrant testing given the intrinsic resistance to many agents harboured by

Pseudomonas aeruginosa (as shown). CIP = ciprofloxacin, CAZ = ceftazidime, MEM =

meropenem, CN = gentamicin, TZP = piperacillin-tazobactam, AZ = aztreonam.

(a)

(b)

(c)

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