In the Literature

PULMONARY MYCOBACTERIUM AVIUM COMPLEX (MAC): TREATMENT FAILURE OR REINFECTION?

Jhun BW, Kim SY, Moon SM, et al. Development of macrolide resistance and reinfection in refractory Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 2018. doi:10.1164/rccm.201802-0321OC.

Pulmonary infections due to nontuberculous mycobacteria (NTM), most commonly Mycobacterium avium complex (MAC), are increasing in incidence in the United States [1]. Treatment success of pulmonary MAC is inadequate at approximately 60%, similar to the success rate of treatment of multidrug-resistant tuberculosis [2, 3].

Jhun and colleagues, noting the low frequency of macrolide-resistant MAC among patients with persistent positive cultures, hypothesized that these patients are being reinfected with new MAC strains rather than harboring organisms refractory to therapy. They identified a cohort of 72 patients in their South Korean referral center with refractory MAC, defined as positive cultures after at least 12 months of antibiotic therapy, who had available data on antimicrobial susceptibility testing (AST). Genotyping was performed on isolates from 49 patients with both pre- and posttreatment isolates available for study. The authors also analyzed macrolide resistance mutations along with phenotypic AST results.

Their cohort was approximately evenly divided by sex; more than half of their patients had prior pulmonary tuberculosis. Patients with both nodular bronchiectatic and fibrocavitary disease were treated with standard regimens including macrolides, ethambutol, and rifamycins; more than half were treated with intravenous amikacin or other drugs and 6% underwent lung resection. Overall, 73% of the 49 patients with available pre- and posttreatment isolates acquired infection with new MAC strains. Macrolide resistance was uncommon, occurring in 22% of the 72 total patients, but curiously did not significantly differ among patients with persistent infections, new infections, or mixed infections with persistent and new strains. Mutations in the 23S ribosomal RNA rrl gene were present in most patients who developed macrolide-resistant disease and in none of the patients with macrolide-susceptible MAC, at least among patients with stored isolates. Multiple colonies were analyzed from each isolate, maximizing the likelihood that pretreatment isolates were accurately identified.

This study has important implications for therapy and shaping the research agenda for pulmonary MAC infections. While providers often modify antimicrobial therapy and sometimes pursue surgical resection in patients with so-called refractory pulmonary MAC infection, these interventions may be ineffective in the case of reinfection masquerading as microbial persistence. The importance of reinfection also underlines the need to identify the immunologic mechanisms that underlie the susceptibility of certain people to infection with these ubiquitous organisms. While some individuals with pulmonary NTM infections in the absence of underlying structural lung disease have distinct morphologic features suggesting an underlying syndrome, and cystic fibrosis transmembrane conductance regulator and other genetic mutations have been identified in many patients, we still are unable to fully account for risk factors for NTM infection, which are likely polygenic and also require environmental exposure [4]. Research into prevention is clearly needed. Epidemiologic studies suggest an association between soil exposure and MAC infection, though molecular investigations into the sources of individual patients’ MAC strains have yielded mixed results, perhaps due to the often long delay between infection and diagnosis [5, 6]. Suggested practices to reduce the risk of reinfection have been proposed, though they are not evidence based and some (such as draining and refilling hot water heaters every 2 weeks) are so burdensome as to be impractical for all but the most motivated patients [7].

References

MYCOBACTERIUM LEPRAE INFECTION IN ASYMPTOMATIC HOUSEHOLD CONTACTS

Gama RS, Gomides TAR, Gama CFM, et al. High frequency of M. leprae DNA detection in asymptomatic household contacts. BMC Infect Dis 2018; 18:153. doi:10.1186/s12879-018-3056-2.

Gama and colleagues examined the prevalence of Mycobacterium leprae infection among asymptomatic household contacts in a hyperendemic region of Brazil, utilizing a quantitative polymerase chain reaction (PCR) for amplification of 16S ribosomal RNA specific for the organism. Slit skin smears from the right earlobe and from blood were obtained for study from 43 patients with leprosy, 113 household contacts, and 8 negative controls.

Mycobacterium leprae nucleic acid was detected in 24% of subjects with clinical leprosy (most of whom were on therapy), including 25% with paucibacillary (PB) infection and in 69.6% of those with multibacillary (MB) infection; none of the PB patients had a positive bacterial index (BI), whereas 56.5% of MB patients had a positive BI. A positive PCR of blood and/or earlobe skin smear was present in 19.2% of asymptomatic household contacts of PB cases and in 27.9% of contacts of MB cases. All negative control samples were PCR negative.

These results resemble those found in an earlier study in Brazil that tested blood, nasal swabs, and nasal turbinate biopsy samples from 104 household contacts; these were PCR positive in 49%, 53.8%, and 6.7% [1]. During follow-up periods of 5–7 years, 7 (6.7%) of household contacts developed leprosy. PCR positivity of blood (but not nasal positivity) was a significant risk factor, along with antibody seropositivity, for the development of leprosy.

These studies confirm the remarkably high frequency of M. leprae infection in asymptomatic household contacts of individuals with clinically apparent leprosy. It is this factor that accounts for the difficulty of total elimination of the infection. Thus, both the prevalence and incidence of leprosy plateaued beginning in 2005 without significant overall progress since that time and with continued evidence of infection transmission. Added approaches to efforts that shows promise are chemoprophylaxis and immunoprophylaxis. The authors of a systematic review found that administration of a single dose of rifampin to household contacts reduced their incidence of leprosy by 56.5% at 2 years but to only 34.9% with follow-up of 1–4 years [2]. BCG vaccination has a protective effect similar to that seen 2 years after rifampin administration, while the combination of single-dose rifampin and BCG increased protection to 80%.

References

CASE VIGNETTE: ANOTHER CAUSE OF CULTURE-NEGATIVE ENDOCARDITIS—LYME DISEASE

Paim AC, Baddour LM, Pritt BS, Schuetz AN, Wilson JW. Lyme endocarditis. Am J Med 2018. doi:10.1016/j.amjmed.2018.02.032.

A 68-year-old man presented with a 2-week history of worsening shortness of breath and orthopnea but with no fever, chills, or night sweats. He had a history of extensive outdoor activity in the upper Midwest and had suffered multiple tick bites. He had received a diagnosis of Lyme disease 8 years earlier and received 2 courses of doxycycline.

On examination he was afebrile and was found to be in atrial fibrillation and to have an apical systolic murmur. His white blood cell count was 13900 cells/µL and C-reactive protein was elevated, whereas his erythrocyte sedimentation rate and procalcitonin were normal. Bilateral pleural effusions with bibasilar atelectasis or infiltrates were present and ceftriaxone plus azithromycin was administered. Transesophageal electrocardiography revealed aneurysmal dilatation of the anterior mitral leaflet with a perforation together with severe mitral valve regurgitation and moderate aortic regurgitation.

Blood cultures were negative, as were serological tests for endemic fungi, Bartonella species, Coxiella burnetii, Chlamydia species, Legionella pneumophila, and HV. Serum and urine antigen tests were negative, respectively, for Cryptococcus and Histoplasma. Polymerase chain reaction (PCR) tests on blood were negative for Tropheryma whipplei and Borrelia species.

No gross inflammation or purulence was noted during cardiac surgery when the mitral leaflet perforation was patched with pericardial tissue and the aortic valve was replaced. Despite the gross appearance, histopathological examination of mitral tissue identified evidence of active endocarditis. Multiple histologic stains failed to reveal any organisms, and cultures for bacteria (including mycobacteria) and fungi were negative, as were 4 additional blood cultures. 16S ribosomal RNA PCR and sequencing performed at the University of Washington was also positive, as was a PCR targeting a portion of the oppA2 gene of Borrelia species performed at the Mayo Clinic Research Laboratory. Serological testing for Lyme disease was positive. The patient received ceftriaxone for 6 weeks, after which he had no evidence of infection.

While carditis is a known complication of Lyme disease, the authors indicate that this is only the third report of valvular infection confirmed by molecular means and the first in the United States. Borrelia burgdorferi infection will have to be added to the list of pathogens causing culture-negative endocarditis.