Frequency of small-colony variants and antimicrobial susceptibility of methicillin-resistant Staphylococcus aureus in cystic fibrosis patients

Highlights

• A significant proportion of MRSA isolates recovered from individuals with cystic fibrosis have small-colony variant morphology.

• Small-colony variant MRSA has more antibiotic resistance compared to normal MRSA isolates.

• A significant number of individuals with small-colony variant MRSA have evidence of persistent infection.

• Individuals with cystic fibrosis and small-colony variant MRSA infection have lower lung function and higher rates of previous antibiotic use compared to those with normal-colony variant MRSA infection.

Abstract

Background

Small-colony variants (SCVs) are a distinct phenotype of Staphylococcus aureus, known for their role in chronic, difficult to treat infections, including cystic fibrosis (CF) lung disease. The goal of this study was to characterize SCV MRSA infection in an adult and pediatric CF population and to identify antibiotic susceptibility patterns unique to SCV MRSA.

Methods

We recovered methicillin-resistant S. aureus (MRSA) from respiratory culture samples from CF patients at the Johns Hopkins Hospital during a 6 month study period.

Results

Of 1161 samples, 200 isolates (17%) were identified as MRSA, and 37 isolates from 28 patients were identified as SCV MRSA. A higher proportion of MRSA was found among SCV isolates (37/66, 56%) compared to normal colony variant (NCV) isolates (163/417, 39%), p = 0.02. All SCV MRSA isolates from individual patients were susceptible to vancomycin and ceftaroline, but they demonstrated higher rates of antibiotic resistance to trimethoprim/sulfamethoxazole, moxifloxacin, and erythromycin, compared to NCV MRSA isolates. Additionally, individuals with SCV MRSA had lower lung function, higher rates of persistent MRSA infection, and higher rates of previous antibiotic use, compared to individuals with NCV MRSA.

Conclusions

A significant proportion of MRSA isolates recovered from patients with CF have the SCV morphology. Compared to individuals with NCV MRSA, those with SCV MRSA have higher rates of persistent MRSA infection and lower lung function. SCV MRSA isolates were more resistant than NCV, but they are highly susceptible to vancomycin, linezolid and ceftaroline.

Introduction

Cystic fibrosis (CF) is the most common lethal autosomal recessive disorder in Caucasians (Boyle, 2007). Over the last two decades, tremendous progress has been made in the management of CF, with median predicted survival now approaching 40 years of age (Cystic Fibrosis Foundation, 2015). Despite this progress, morbidity and mortality in CF is driven by the presence of chronic bacterial lung infection (Boyle, 2007, Anonymous, 2015). Methicillin-susceptible (MSSA) and Methicillin-resistant (MRSA) Staphylococcus aureus are two of the most important infectious pathogens in CF, with 71% of CF patients having lung infection with MSSA or MRSA in the last year (Cystic Fibrosis Foundation, 2015). The prevalence of MRSA pulmonary infection in the United States CF population has demonstrated a dramatic increase, from less than 5% 20 years ago to now 26% of patients, whereas MSSA prevalence has remained about 50% (Cystic Fibrosis Foundation, 2015). Chronic MRSA infection has clinically significant effects on outcomes in CF, resulting both in a more rapid decline in lung function and decreased survival among patients with persistently positive MRSA respiratory cultures (Dasenbrook et al., 2008, Dasenbrook et al., 2010). Small-colony variants (SCVs) are a specific morphologic subtype of S. aureus that have been recognized for the ability to contribute to persistent infection in different clinical settings (Besier et al., 2007). This may be attributable to the ability of SCV MRSA to persist intracellularly, as well as to their increased antibiotic resistance, when compared to normal-colony MRSA (NCVs) (Besier et al., 2007, Kahl et al., 1998, Kahl, 2014). In addition, there is evidence that SCV S. aureus plays a unique role in CF pulmonary infections. Wolter and colleagues examined a cohort of children with CF and found that infection with SCV S. aureus was independently associated with worse clinical outcomes (Wolter et al., 2013).

The goal of this study was to characterize SCV S. aureus lung infection in an adult and pediatric cystic fibrosis patient population (~ 550 patients) at a large tertiary care medical center in Baltimore. A second aim was to determine the resistance pattern of SCVs compared with NCVs to a broad range of antimicrobial agents, including ceftaroline.