Franklin D. Lowy

Antimicrobial resistance: the example of Staphylococcus aureus

In the early 1970s, physicians were finally forced to abandon their belief that, given the vast array of effective antimicrobial agents, virtually all bacterial infections were treatable. Their optimism was shaken by the emergence of resistance to multiple antibiotics among such pathogens as Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa, and Mycobacterium tuberculosis. The evolution of increasingly antimicrobial-resistant bacterial species stems from a multitude of factors that includes the widespread and sometimes inappropriate use of antimicrobials, the extensive use of these agents as growth enhancers in animal feed, and, with the increase in regional and international travel, the relative ease with which antimicrobial-resistant bacteria cross geographic barriers (1–3). The irony of this trend toward progressively more resistant bacteria is that it coincides with a period of dramatically increased understanding of the molecular mechanisms of antimicrobial resistance. Unfortunately, while this insight has resulted in the identification of novel drug targets, it has not yet resulted in effective new chemotherapeutic agents. This paradox stands in sharp contrast to the dramatic progress made in antiviral (notably antiretroviral) therapy in the past ten years, where a number of newly discovered molecular targets have resulted in clinically effective therapeutic agents. Nowhere has this issue been of greater concern than with the Gram-positive bacteria pneumococci, enterococci, and staphylococci. Multidrug resistance is now the norm among these pathogens. S. aureus is perhaps the pathogen of greatest concern because of its intrinsic virulence, its ability to cause a diverse array of life-threatening infections, and its capacity to adapt to different environmental conditions (4, 5). The mortality of S. aureus bacteremia remains approximately 20–40% despite the availability of effective antimicrobials (6). S. aureus is now the leading overall cause of nosocomial infections and, as more patients are treated outside the hospital setting, is an increasing concern in the community (7, 8). S. aureus isolates from intensive care units across the country and from blood culture isolates worldwide are increasingly resistant to a greater number of antimicrobial agents (4, 8). Inevitably this has left fewer effective bactericidal antibiotics to treat these often life-threatening infections (Figure ​(Figure1).1). As rapidly as new antibiotics are introduced, staphylococci have developed efficient mechanisms to neutralize them (Table ​(Table11). Figure 1 S. aureus infections in intensive care units in the National Nosocomial Infections Surveillance System. Data include the total number of infections from 1987 to 1997. Isolates were tested for sensitivity to the following antimicrobial agents: gentamicin, ... Table 1 Mechanisms of S. aureus resistance to antimicrobialsA Recent reports of S. aureus isolates with intermediate or complete resistance to vancomycin portend a chemotherapeutic era in which effective bactericidal antibiotics against this organism may no longer be readily available (9, 10). This review will focus on the emergence of antimicrobial resistance in S. aureus. It will review the historical evolution of resistant strains, their spread, the molecular mechanisms of resistance for selected antibiotics, and progress toward the development of alternative drug targets or novel approaches for therapeutic or prophylactic intervention.

Pathogenesis of Methicillin-Resistant Staphylococcus aureus Infection

Staphylococcus aureus is a versatile pathogen capable of causing a wide range of human diseases. However, the role of different virulence factors in the development of staphylococcal infections remains incompletely understood. Some clonal types are well equipped to cause disease across the globe, whereas others are facile at causing disease among community members. In this review, general aspects of staphylococcal pathogenesis are addressed, with emphasis on methicillin-resistant strains. Although methicillin-resistant S. aureus (MRSA) strains are not necessarily more virulent than methicillin-sensitive S. aureus strains, some MRSA strains contain factors or genetic backgrounds that may enhance their virulence or may enable them to cause particular clinical syndromes. We examine these pathogenic factors.

What determines nasal carriage of Staphylococcus aureus

Nasal carriage of Staphylococcus aureus is an important risk factor for infection by this organism in both community and hospital settings; this article reviews the role of host and bacterial factors in carriage. A host genetic influence appears likely but the phenotypic determinants are unknown. Possibilities include variability in host adhesins, immune response or secretion of antimicrobial molecules. Colonization resistance by S. aureus, together with the observation that persistent carriers often carry a single strain whereas intermittent carriers can be colonized with unrelated strains over time, suggests that bacterial factors could also be involved.

Antimicrobial-resistant bacteria in the community setting

Over the past decade, antimicrobial resistance has emerged as a major public-health crisis. Common bacterial pathogens in the community such as Streptococcus pneumoniae have become progressively more resistant to traditional antibiotics. Salmonella strains are beginning to show resistance to crucial fluoroquinolone drugs. Community outbreaks caused by a resistant form of Staphylococcus aureus, known as community-associated meticillin (formerly methicillin)-resistant Staphylococcus aureus, have caused serious morbidity and even deaths in previously healthy children and adults. To decrease the spread of such antimicrobial-resistant pathogens in the community, a greater understanding of their means of emergence and survival is needed.

Staphylococcus epidermidis Infections

Staphylococcus epidermidis, an organism routinely found on the skin and in the hospital environment, has become a primary pathogen in infections associated with prosthetic devices. Because these infections are indolent and often clinically silent, diagnosis and therapy are often difficult. Pathogens are often misidentified as contaminants. Their variable, often resistant antibiotic susceptibility pattern and the uncertain correlation of in-vitro beta-lactam sensitivity testing with therapeutic efficacy make selection of an effective antibiotic regimen difficult. Vancomycin combined with rifampin, gentamicin, or both, is recommended for empiric therapy of these infections. Usually, removal of the prosthetic device is also necessary and may contribute equally to a successful therapeutic outcome.

Is Staphylococcus aureus an intracellular pathogen

I am grateful to A. Zuger and J. Chan for their helpful suggestions concerning this manuscript. F.D.L. is supported by grants from the American Heart Association and the National Institute on Drug Abuse (DA09656 and DA11868).

Ventricular assist device-related infections

Heart failure is a leading cause of death in developed nations despite medical management. Cardiac transplantation is a potentially lifesaving intervention for approximately 4000 advanced heart failure patients per year; however, the demand for donor hearts far exceeds the supply. Ventricular assist devices provide temporary support for patients with severe heart failure until myocardial recovery occurs or a donor heart becomes available. For those ineligible for transplantation, ventricular assist devices may be used permanently and have demonstrated reduced mortality and an improved quality of life compared with continued medical therapy. Nonetheless, these devices are under-used, in part due to the frequency of complications. Device-related infections are one of the most frequent sequelae of ventricular assist device placement and occur in 18-59% of cases. Infections can involve any part of the device and confer substantial morbidity and mortality. Here, we provide an introduction to ventricular assist devices, explore the nature and pathogenesis of ventricular assist device-related infections, discuss problems with diagnosis, and present treatment and prevention strategies.

Identification of a Highly Transmissible Animal-Independent Staphylococcus aureus ST398 Clone with Distinct Genomic and Cell Adhesion Properties

ABSTRACT A methicillin-resistant Staphylococcus aureus (MRSA) clone known as ST398 has emerged as a major cause of acute infections in individuals who have close contact with livestock. More recently, the emergence of an animal-independent ST398 methicillin-sensitive S. aureus (MSSA) clone has been documented in several countries. However, the limited surveillance of MSSA has precluded an accurate assessment of the global spread of ST398 and its clinical relevance. Here we provide evidence that ST398 is a frequent source of MSSA infections in northern Manhattan and is readily transmitted between individuals in households. This contrasts with the limited transmissibility of livestock-associated ST398 (LA-ST398) MRSA strains between humans. Our whole-genome sequence analysis revealed that the chromosome of the human-associated ST398 MSSA clone is smaller than that of the LA-ST398 MRSA reference strain S0385, due mainly to fewer mobile genetic elements (MGEs). In contrast, human ST398 MSSA isolates harbored the prophage φ3 and the human-specific immune evasion cluster (IEC) genes chp and scn. While most of the core genome was conserved between the human ST398 MSSA clone and S0385, these strains differed substantially in their repertoire and composition of intact adhesion genes. These genetic changes were associated with significantly enhanced adhesion of human ST398 MSSA isolates to human skin keratinocytes and keratin. We propose that the human ST398 MSSA clone can spread independent of animal contact using an optimized repertoire of MGEs and adhesion molecules adapted to transmission among humans. IMPORTANCE Staphylococcus aureus strains have generally been considered to be species specific. However, cross-species transfers of S. aureus clones, such as ST398 methicillin-resistant S. aureus (MRSA), from swine to humans have been reported. Recently, we observed the emergence of ST398 methicillin-susceptible S. aureus (MSSA) as a colonizing strain of humans in northern Manhattan. Here we report that ST398 is a frequent cause of MSSA infections in this urban setting. The ST398 MSSA clone was readily transmitted within households, independent of animal contact. We discovered that human ST398 MSSA genomes were smaller than that of the LA-ST398 strain S0385 due to fewer mobile genetic elements. Human and LA-ST398 strains also differed in their composition of adhesion genes and their ability to bind to human skin keratinocytes, providing a potential mechanism of S. aureus host adaptation. Our findings illustrate the importance of implementing molecular surveillance of MSSA given the evidence for the rapid and clinically undetected spread of ST398 MSSA. Staphylococcus aureus strains have generally been considered to be species specific. However, cross-species transfers of S. aureus clones, such as ST398 methicillin-resistant S. aureus (MRSA), from swine to humans have been reported. Recently, we observed the emergence of ST398 methicillin-susceptible S. aureus (MSSA) as a colonizing strain of humans in northern Manhattan. Here we report that ST398 is a frequent cause of MSSA infections in this urban setting. The ST398 MSSA clone was readily transmitted within households, independent of animal contact. We discovered that human ST398 MSSA genomes were smaller than that of the LA-ST398 strain S0385 due to fewer mobile genetic elements. Human and LA-ST398 strains also differed in their composition of adhesion genes and their ability to bind to human skin keratinocytes, providing a potential mechanism of S. aureus host adaptation. Our findings illustrate the importance of implementing molecular surveillance of MSSA given the evidence for the rapid and clinically undetected spread of ST398 MSSA.

Prospective, Multicenter Study of Ventricular Assist Device Infections

Background— Ventricular assist devices (VADs) improve survival and quality of life in patients with advanced heart failure, but their use is frequently complicated by infection. There are limited data on the microbiology and epidemiology of these infections. Methods and Results— One hundred fifty patients scheduled for VAD implantation were enrolled (2006–2008) at 11 US cardiac centers and followed prospectively until transplantation, explantation for recovery, death, or for 1 year. Eighty-six patients (57%) received HeartMate II devices. Data were collected on potential preoperative, intraoperative, and postoperative risk factors for infection. Clinical, laboratory, and microbiological data were collected for suspected infections and evaluated by an infectious diseases specialist. Thirty-three patients (22%) developed 34 VAD-related infections with an incidence rate of 0.10 per 100 person-days (95% confidence interval, 0.073–0.142). The median time to infection was 68 days. The driveline was the most commonly infected site (n=28); 18 (64%) were associated with invasive disease. Staphylococci were the most common pathogen (47%), but pseudomonas or other Gram-negative bacteria caused 32% of infections. A history of depression and elevated baseline serum creatinine were independent predictors of VAD infection (adjusted hazard ratio=2.8 [P=0.007] and 1.7 [P=0.023], respectively). The HeartMate II was not associated with a decreased risk of infection. VAD infection increased 1-year mortality (adjusted hazard ratio=5.6; P<0.0001). Conclusions— This prospective, multicenter study demonstrates that infection frequently complicates VAD placement and is a continuing problem despite the use of newer, smaller devices. Depression and renal dysfunction may increase the risk of VAD infection. VAD infection is a serious consequence because it adversely affects patient survival. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01471795.

The Clonality of Staphylococcus aureus Nasal Carriage

Nasal carriage of Staphylococcus aureus is often a prelude to infection with the same strain. The prevailing assumption has been that colonized individuals carry a single strain. The present study investigated the frequency of simultaneous nasal carriage of multiple strains of S. aureus. Three bacterial colonies from plated samples from colonized subjects were initially compared by pulsed-field gel electrophoresis. Fourteen of 148 S. aureus-positive samples demonstrated at least a difference of a single band; 7 of these 14 samples contained different strains, and 3 of these 7 also belonged to different accessory gene regulator (agr) types. The remaining 7 samples contained clonally related isolates; 3 of these 7 contained pairs that differed by the presence or absence of the staphylococcal chromosomal cassette mec type IV. A mathematical model that we developed predicted that approximately 6.6% of S. aureus-colonized individuals carry >1 strain. The present study demonstrates that carriage of discordant S. aureus strains in individuals with nasal colonization occurs regularly and suggests that the nares are likely sites for horizontal genetic exchange among strains.