Copper Resistance Promotes Fitness of Methicillin-Resistant Staphylococcus aureus during Urinary Tract Infection.

Urinary tract infection (UTI) is one of the most common infectious conditions affecting people in the United States and around the world. Our knowledge of the host-pathogen interaction during UTI caused by Gram-positive bacterial uropathogens is limited compared to that for Gram-negative pathogens. Here, we investigated whether copper and the primary copper-containing protein, ceruloplasmin, are mobilized to urine during naturally occurring UTI caused by Gram-positive uropathogens in patients. Next, we probed the role of copper resistance in the fitness of methicillin-resistant Staphylococcus aureus (MRSA) during experimental UTI in a murine model. Our findings demonstrate that urinary copper and ceruloplasmin content are elevated during UTI caused by Enterococcus faecalis, S. aureus, S. epidermidis, and S. saprophyticus. MRSA strains successfully colonize the urinary tract of female CBA mice with selective induction of inflammation in the kidneys but not the bladder. MRSA mutants lacking CopL, a copper-binding cell surface lipoprotein, and the ACME genomic region containing copL, exhibit decreased fitness in the mouse urinary tract compared to parental strains. Copper sensitivity assays, cell-associated copper and iron content, and bioavailability of iron during copper stress demonstrate that homeostasis of copper and iron is interlinked in S. aureus. Importantly, relative fitness of the MRSA mutant lacking the ACME region is further decreased in mice that receive supplemental copper compared to the parental strain. In summary, copper is mobilized to the urinary tract during UTI caused by Gram-positive pathogens, and copper resistance is a fitness factor for MRSA during UTI. IMPORTANCE Urinary tract infection (UTI) is an extremely common infectious condition affecting people throughout the world. Increasing antibiotic resistance in pathogens causing UTI threatens our ability to continue to treat patients in the clinics. Better understanding of the host-pathogen interface is critical for development of novel interventional strategies. Here, we sought to elucidate the role of copper in host-Staphylococcus aureus interaction during UTI. Our results reveal that copper is mobilized to the urine as a host response in patients with UTI. Our findings from the murine model of UTI demonstrate that copper resistance is involved in the fitness of methicillin-resistant S. aureus (MRSA) during interaction with the host. We also establish a critical link between adaptation to copper stress and iron homeostasis in S. aureus.

Methicillin-Susceptible, Vancomycin-Resistant Staphylococcus aureus, Brazil.

We report characterization of a methicillin-susceptible, vancomycin-resistant bloodstream isolate of Staphylococcus aureus recovered from a patient in Brazil. Emergence of vancomycin resistance in methicillin-susceptible S. aureus would indicate that this resistance trait might be poised to disseminate more rapidly among S. aureus and represents a major public health threat.

High prevalence of mupirocin resistance in Staphylococcus aureus isolates from a pediatric population.

Topical mupirocin is used widely to treat skin and soft tissue infections and to eradicate nasal carriage of methicillin-resistant Staphylococcus aureus (MRSA). Few studies to date have characterized the rates of S. aureus mupirocin resistance in pediatric populations. We retrospectively studied 358 unique S. aureus isolates obtained from 249 children seen in a predominantly outpatient setting by the Division of Pediatric Dermatology at a major academic center in New York City between 1 May 2012 and 17 September 2013. Mupirocin resistance rates and the associated risk factors were determined using a logistic regression analysis. In our patient population, 19.3% of patients had mupirocin-resistant S. aureus isolates at the time of their first culture, and 22.1% of patients with S. aureus infection had a mupirocin-resistant isolate at some time during the study period. Overall, 31.3% of all S. aureus isolates collected during the study period were resistant to mupirocin. Prior mupirocin use was strongly correlated (odds ratio [OR] = 26.5; P = <0.001) with mupirocin resistance. Additional risk factors for mupirocin resistance included methicillin resistance, atopic dermatitis (AD), epidermolysis bullosa (EB), immunosuppression, and residence in northern Manhattan and the Bronx. Resistance to mupirocin is widespread in children with dermatologic complaints in the New York City area, and given the strong association with mupirocin exposure, it is likely that mupirocin use contributes to the increased resistance. Routine mupirocin testing may be important for MRSA decolonization strategies or the treatment of minor skin infections in children.