New pathogens in cystic fibrosis

Introduction

In people with cystic fibrosis, the accumulation of viscous mucus in the respiratory tract favors the onset of chronic bacterial infections. During childhood, the bacteria that are most often found in bronchial secretions is Staphylococcus aureus, whereas as an adult, Pseudomonas aeruginosa is more common.

Chronic infection with P. Aeruginosa is the main cause of morbidity in cystic fibrosis. It helps accelerate the decline in lung function and increases the risk of mortality. This is why as soon as this bacterium appears in the respiratory tract, a treatment is started to eradicate it. When infection with P. aeruginosa becomes chronic, long-term treatment with inhaled antibiotics is initiated in order to preserve lung function and reduce the risk of acute exacerbations.

In recent years, other bacteria have become more and more prevalent in people with fibrocystic fibrosis. This is the case of Staphylococcus aureus methicillin resistant (MRSA), of Stenotrophomonas maltophilia And ofAchromobacter xylosoxidans. The arrival of these new pathogens raises a lot of questions to which we do not yet have all the answers. Here's what we know so far about these three emerging pathogens.

Staphylococcus aureus methicillin resistant (MRSA)

Epidemiology

SARM was first described in the United Kingdom in 1961. It is part of the gram-positive cocci family and, as its name suggests, it has increased resistance to antibiotics compared to Staphylococcus aureus usual.

MRSA is a pathogen that can be transmitted from one person to another and that is why people carrying this bacteria need to be isolated when they are hospitalized. The majority of SARMs are acquired in the hospital, but since the 1990s, there has been the emergence of community-acquired MRSA (outside the hospital). According to studies, 14 to 32% of SARMs in the fibrocystic population are acquired in community. Taking antibiotics frequently is another risk factor for MRSA infection.

Over the past few years, the prevalence of MRSA in people with cystic fibrosis has increased steadily. In the United States, it increased from 0.1% in 1995 to 25% in 2011. In Canada, MRSA is much less common, but its prevalence is also increasing year by year. In 2011, 5% of people with cystic fibrosis in Canada were infected with MRSA.

Clinical impact

Several cohort studies have sought to determine the impact of MRSA on the course of the disease, with results that are sometimes contradictory. In a study to determine the impact of MRSA on lung function, the results showed that the 593 patients with MRSA initially had a more severe disease than those who were not infected with this bacteria. However, acquiring MRSA did not accelerate the decline in lung function. Another study carried out on a larger number of patients (1732 patients with MRSA) showed opposite results. People who became infected with MRSA had a higher baseline FEV1 than the negative MRSA group, but their FEV1 declined more rapidly after acquiring this bacteria.

What about the impact of MRSA on survival? Another major cohort study looked at this question. In 5759 patients infected with MRSA, the mortality rate was higher than in those who did not have MRSA (relative risk 1.27).

Based on these findings, it can be concluded that MRSA infection in people with fibrocystic fibrosis seems to be associated with an accelerated decline in lung function (FEV1) and a higher mortality rate. Care should be taken in interpreting these data, as they demonstrate an association and not a causal link between the presence of MRSA and a worsening of the disease. MRSA infection may only be a marker of disease severity.

Treatment

Contrary to the case of P. Aeruginosa, there is no consensus in the literature on the therapeutic management of MRSA. No studies have shown that MRSA eradication therapy can prevent chronic infection or improve the course of the disease. There are also no recommendations for the chronic treatment of MRSA and no medication has been developed for this purpose.

In case of acute pulmonary exacerbation (pulmonary superinfection) associated with MRSA, the choice of antibiotics is more limited than for Staphylococcus aureus. Orally, trimethoprim-sulfame-thoxazole (Bactrim) or minocycline may be used, depending on the sensitivity of the bacteria. Zyvoxam is effective in the majority of cases, but it is preferable to use it as a second line when other treatments do not work or for more severe infections, in order to avoid the development of resistance. Intravenously, the possible choices are vancomycin or tygecycline.

Stenotrophomonas maltophilia

Epidemiology

Just like P. aeruginosa, S. maltophilia is part of the gram-negative bacillus family and has intrinsic resistance to several antibiotics. It is found in the environment, mainly in water sources (lakes and rivers), plants and soil. It can also be acquired in hospital settings, but it is not transmitted from one person to another. Frequent use of antibiotics is a risk factor for infection by this bacteria.

The prevalence of S. maltophilia The incidence of cystic fibrosis varies from one country to another, reaching up to 30% in some clinics in Europe. In 2011, 14% of people with cystic fibrosis in the United States had S. maltophilia. Just as with MRSA, the prevalence of S. maltophilia in Canada has increased gradually in recent years, reaching 15% in 2011.

Clinical impact

Several studies on the impact of infection with S. maltophilia in cystic fibrosis have been published, but the results are contradictory. In a cohort study, the presence of this pathogen in sputum cultures did not affect survival at three years. However, it was noted that the bacteria was found in patients with more severe illness compared to the control group. Another study showed that chronic infection with S. maltophilia was associated with an increased risk of mortality and lung transplantation. However, after adjusting the results for confounding factors, the results became insignificant.

With regard to the impact of S. maltophilia on lung function (FEV1), two studies came to the same conclusion. People who acquire S. maltophilia have a more severe basic disease, but the appearance of this microorganism does not accelerate the decline in lung function. Other data indicate that chronic infection with S. maltophilia is associated with an increased risk of acute pulmonary exacerbations (relative risk 1.63).

In summary, these data suggest that infection with S. maltophilia occurs in people with more severe illness and is associated with an increased risk of respiratory exacerbations. The impact of this pathogen on lung function and survival has not been clearly demonstrated to date.

Treatment

There is little data in the literature on the treatment of S. maltophilia in cystic fibrosis. Therefore, there is no guideline for the eradication or chronic treatment of this bacteria. In practice, we treat S. maltophilia only during an exacerbation. The appropriate treatment is selected according to the antibiogram. When the bacteria is very resistant, a combination of antibiotics may be used. The most active agents against S. maltophilia are trimethoprim-sulfamethoxazole, tetracyclines (minocycline, doxy-cycline), fluoroquinolones (mainly levofloxacin), ceftazidime, ticarcillin-clavulanate (timentin) and piperacillin-tazobactam (tazocin).

Achromobacter xylosoxidans

Epidemiology

Achromobacter xylosoxidans also belongs to the family of gram-negative bacilli. It is found in hospitals, but also in the ground and waterways. It is not transmitted from person to person.

1. Xylosoxidans is less common than MRSA and
2. Maltophilia. In 2011, only 3% of people with CF in Canada were infected with A. xylosoxidans while in the United States, the prevalence was 6%.

Clinical impact

Studies on the impact ofA. xylosoxidans in cystic fibrosis are few and are limited to small groups of patients. A study on 13 patients chronically infected with Achromobacter showed no difference between their lung function test scores, nutritional status, and antibiotic treatments and those of the control group (patients without Achromobacter).

In a second study, 15 patients with chronic infection with A. xylosoxidans were compared to control cases. The results indicated a more rapid decline in FEV1 in the infected group. A third study involving only eight patients with chronic infection by A. xylosoxidans has shown no impact of this bacterium on lung function. However, infected patients required more intravenous antibiotics than the control group.

It is difficult to draw conclusions from such limited and contradictory data.

Treatment

As with other emerging pathogens, there are no recommendations that indicate that one should eradicate A. xylosoxidans or treat it over the long term. In practice, it is treated during a respiratory exacerbation, based on the sensitivities determined by the antibiogram. The most active antibiotics against A. xylosoxidans are minocycline, meropenem, piperacillin-tazobactam, and high-concentration Colistin.

CONCLUSION

Chronic bacterial infection of the respiratory tract plays a major role in cystic fibrosis. Pseudomonas aeruginosa remains the main pathogen and its negative impact on the course of the disease is undeniable. The role of emerging bacteria is not as well defined and further studies are needed to clarify this question.

Bibliographical references

1. WATERS,, “New treatments for emerging cystic fibrosis pathogens other than Pseudomonas,” Current Pharmaceutical Design, 2012, vol. 18, no. 5, p. 696-725.
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8. DALBOGE, C.S. and others, “Chronic pulmonary infection with Stenotrophomonas maltophilia and lung function in patients with cystic fibrosis”, Journal of Cystic Fibrosis, 2011, vol. 10, no. 5, p. 318-325.
9. WATERS, et al., “Stenotrophomonas maltophilia in cystic fibrosis: Serologic response and effect on lung disease,” American Journal of Respiratory and Critical Care Medicine, 2011, vol. 183, no. 5, p. 635-640.
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11. RONNE HANSEN, C. and others, “Chronic infection with Achromobacter xylosoxidans in cystic fibrosis patients; a retrospective case control study,” Journal of Cystic Fibrosis, 2006, 5, no. 4, p. 245-251.
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13. CYSTIC FIBROSIS CANADA, Canadian Cystic Fibrosis Registry: 2011 Annual Report.

Lara Bilodeau

M.D., FRCPC

Pulmonologist

Institut Universitaire de Cardiologie et de Pneumologie de Québec

Quebec (Quebec)

Canada

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