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Persistent Infection Because of Pandoraea sputorum in a Young Cystic Fibrosis Patient Resistant to Antimicrobial Treatment

Pugès, Mathilde MD*; Debelleix, Stéphane MD, PhD†‡; Fayon, Michael MD, PhD†‡; Mégraud, Francis MD, PhD§; Lehours, Philippe PharmD, PhD§

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The Pediatric Infectious Disease Journal: October 2015 - Volume 34 - Issue 10 - p 1135-1137
doi: 10.1097/INF.0000000000000843
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Abstract

CASE REPORT

A 13-year-old boy with cystic fibrosis (CF) was hospitalized for a pulmonary exacerbation. He had been diagnosed with CF (homozygous for the δ-F508 mutation) at age 8 years when he was hospitalized for pneumonia attributed to Staphylococcus aureus, Haemophilus influenzae and Pseudomonas aeruginosa. He had recurrent ear, nose and throat and bronchial infections, with a failure to thrive since age 2 years. From then on, he was chronically colonized with methicillin-susceptible S. aureus (MSSA) and had several exacerbations associated with H. influenzae, P. aeruginosa, Achromobacter xylosoxidans and Serratia marcescens infections. He also had an exocrine pancreatic insufficiency but no failure to thrive. He was admitted in July 2014 to the Pediatric CF Center of the University Pellegrin Hospital in Bordeaux for a pulmonary exacerbation with increased bronchial congestion. Computed tomography images showed mucoid impaction in the lingual of the left upper lobe. Culture of the respiratory specimens was positive for Pandoraea sputorum (1 × 104 CFU/mL), as well as for MSSA (5 × 104 CFU/mL but there had been a prior colonization), Candida albicans (6 × 10² CFU/mL) and non-C. albicans yeasts (1 × 10² CFU/mL). P. sputorum colonies grew on the Burkholderia cepacia-selective agar plate (Thermo Scientific, Oxoid SA, Dardilly, France) after 48 hours of incubation at 36°C. The bacterial identification was performed with a matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) method using a MALDI Biotyper System (Bruker Daltonics, Microflex system), with the Bruker Daltonics database 4.0. The identification score was high (score > 2), therefore, allowing a firm identification. The strain was sent to the Cepacia Observatory in Toulouse, France, which confirmed the identification of P. sputorum with an amplified ribosomic DNA restriction analysis for the primary detection, and then a 16S ribosomal DNA-based polymerase chain reaction, specific to P. sputorum as already described.1 Antibiotic susceptibility testing was performed according to the recommendations of the committee of the French National Society for Microbiology (CA-SFM 2014)2 using a disk diffusion method (0.5 McFarland inoculum, Mueller-Hinton agar plate, 18-hour incubation at 35 ± 1°C). The organism was resistant to ampicillin, ticarcillin, cefalotin, cefepime, aztreonam, meropenem, aminoglycosides, colistin and fosfomycin; intermediate to ciprofloxacin and susceptible to ticarcillin–clavulanate, piperacillin, piperacillin–tazobactam, cefotaxime, imipenem, tigecycline, levofloxacin and trimethoprim–sulfamethoxazole. Minimum inhibitory concentrations (MIC) were estimated by E-test for meropenem (MIC > 32 mg/L) and imipenem (MIC, 1 mg/L), which confirms the susceptibility profile. The possible involvement of P. sputorum in this exacerbation prompted us to treat. As the patient was allergic to piperacillin–tazobactam, treatment with intravenous imipenem (80 mg/kg/d in 3 injections) was prescribed for 2 weeks. As he was chronically colonized, it was decided not to consider MSSA. He was placed under respiratory isolation during hospitalization. No clinical improvement was observed after the treatment: bronchial congestion persisted and lung function worsened, as shown by 2 successive lung function tests. The forced expiratory volume in 1 second (FEV1) and the maximum mid-expiratory flow rate (MMEF 25–75) decreased between April and September 2014 (April 2014: FEV1, 1790 mL, 81% and MMEF 25–75, 2210 mL, 82%; September 2014: FEV1, 1640 mL, 69% and MMEF 25–75, 1480 mL, 51%). The MMEF 25–75 decreased by 31% in 3 months. In September 2014, a new respiratory sample was still positive for P. sputorum (1 × 105 CFU/mL) on the B. cepacia-selective agar plate and also on the cetrimide selective agar plate (Thermo Scientific, Oxoid SA). Identification was again confirmed by MALDI-TOF MS. The antibiotic susceptibility profile was identical to that of the first isolate. Aspergillus fumigatus was also isolated in the sputum sample (4 × 105 CFU/mL). Treatment with imipenem and sulfamethoxazole–trimethoprim also failed to eradicate P. sputorum. Concomitantly, the serum immunoglobulin E concentration increased from 515 kUI/L on June 4, 2014 to 1213 kUI/L on June 20, 2014, and to 1450 kUI/L in September 2014. Radioallergosorbent tests for mites, grasses and mold were at high levels, despite antihistaminic medication and inhaled corticosteroids. We decided to treat with omalizumab (a humanized monoclonal antibody that selectively binds to immunoglobulin E) twice a month. His lung function has not improved since the second antibiotic treatment, and bronchial congestion and infection with P. sputorum remain. The last respiratory sample in May 2015 was still positive for P. sputorum (1.2 × 107 CFU/mL). Therefore, these 2 successive treatments failed to eradicate P. sputorum.

DISCUSSION

The Pandoraea genus is a relatively recently described group (described by Coenye et al),3 which remains poorly understood, particularly in terms of natural resistance, mechanisms of acquired resistance and impact on the prognosis of the disease and lung function. The availability of MALDI-TOF MS in clinical microbiology diagnosis allows a better identification of bacterial species, especially Pandoraea sp. which is difficult to identify with conventional methods. Therefore, descriptions of infections due to Pandoraea sp. in CF patients should increase. Cases of misidentification between Pandoraea sp. and other non-fermenting Gram-negative bacilli from Burkholderia cepacia Complex (BCC) may also decrease.4,5 Indeed, BCC colonization can lead to a contraindication for lung transplantation. Until now, no colonization with Pandoraea sp. ever persisted after a lung transplantation, or only in the first posttransplant bronchial washing.6 This may be linked to the inability of Pandoraea species to produce a biofilm in the respiratory tract.7 Persistent or intermittent colonization with Pandoraea sp. that sometimes coincides with a deterioration in lung function has been reported.6,8 In France, BCC infections or colonizations are followed up by the Cepacia Observatory in collaboration with the CF French Registry. The last epidemiology report in 2011 reported 10 cases of Pandoraea infection in France, including 6 new cases in 2011, a prevalence of 0.17 and an incidence of 0.1 for 100 CF patients. The median age of patients infected with Pandoraea sp. was 20 years (14–51), with the first colonization at age 18 years (14–48). All 4 patients identified with Pandoraea sp. before 2011 were chronically colonized (based on at least 4 positive samples over 12 months, more than half were positive). Among these 10 CF patients, the clinical status was documented in 5 cases. In 3 cases, Pandoraea sp. was associated with a clinical deterioration, and the last 2 were stable. The particular case in this study was unusual because of the young age of our patient; indeed he is younger than all of the cases infected with Pandoraea sp. (colonization or infection) notified to the Cepacia Observatory. Moreover, the infection occurred early in the course of the CF disease. The isolation of P. sputorum in our patient also coincided with a decline in lung function, which has already been noticed in other case reports. It may be explained by Pandoraea sp. virulence factors. Indeed, the main pathogenicity factor of Pandoraea sp. seems to be the trigger of a proinflammatory response, particularly by the secretion of proinflammatory cytokines, especially interleukin-8 (IL-8) and IL-6. This response may amplify the proinflammatory state in lungs of CF patients. IL-6 and IL-8 seem to play a special role in CF. Indeed they are found early in respiratory secretions and may be upregulated in the early stages of the disease. BCC and P. aeruginosa are also known to stimulate IL-6 and IL-8 production. This may worsen the inflammatory state in CF, accelerating the decline in lung function, which is observed in certain cases including our patient.

Our patient was placed under respiratory isolation during the hospitalization to avoid transmission to the other patients. Indeed, an epidemic spread of Pandoraea apista has already been described from 1 patient to 5 other patients exposed during winter camps or hospitalization.8

The Pandoraea genus is resistant to many antibiotics and treatment may be problematic. It has a natural resistance to colistin. Acquired resistances vary between the different species; however, in the different case reports published, Pandoraea sp. was almost always susceptible to piperacillin, piperacillin–tazobactam, trimethoprim–sulfamethoxazole and tetracyclines including tigecycline. On the other hand, some resistances are often found: aminoglycosides, amoxicillin, amoxicillin–clavulanic acid, ticarcillin, aztreonam, meropenem, cephalosporins except cefotaxime, which seems to be spared, and fluoroquinolones. In our case, P. sputorum was susceptible to imipenem and resistant to meropenem. This discrepancy has already been described by several authors and is because of meropenem-hydrolyzing β-lactamases. Some strains are resistant to both imipenem (MIC up to 64 mg/L) and meropenem (MIC up to 1024 mg/L), and an imipenem-hydrolyzing oxacillinase named OXA-62 has been identified in Pandoraea pnomenusa.9 In this particular case, MIC of imipenem was low and does not explain the treatment failure. The optimal antibiotherapy is not yet well established. In our case, despite sensitivity to imipenem and trimethoprim–sulfamethoxazole, the treatment failed. In other case reports, a β-lactamin is often used in monotherapy or bitherapy with a generally favorable outcome. This is the first reported case of treatment failure against Pandoraea sp., which, along with BCC infections, suggests underestimated properties of this species to chronically persist and to accelerate the decline of lung function in CF patients.

REFERENCES

1. Coenye T, Liu L, Vandamme P, et al. Identification of Pandoraea species by 16S ribosomal DNA-based PCR assays. J Clin Microbiol. 2001;39:4452–4455
2. Jehl F. Comité de l’Antibiogramme de la Société Française de Microbiologie Communiqué. 2014 Available at: http://www.sfm-microbiologie.org. Accessed August 24, 2015
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9. Schneider I, Queenan AM, Bauernfeind A. Novel carbapenem- hydrolyzing oxacillinase OXA-62 from Pandoraea pnomenusa. Antimicrob Agents Chemother. 2006;50:1330–1335
Keywords:

Pandoraea; cystic fibrosis; MALDI-TOF MS; multidrug-resistant nonfermenting Gram negative bacteria

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