Richard R. Watkins

Current concepts on the virulence mechanisms of meticillin-resistant Staphylococcus aureus

Meticillin-resistant Staphylococcus aureus (MRSA) strains are prevalent bacterial pathogens that cause both health care and community-associated infections. Increasing resistance to commonly prescribed antibiotics has made MRSA a serious threat to public health throughout the world. The USA300 strain of MRSA has been responsible for an epidemic of community-associated infections in the US, mostly involving skin and soft tissue but also more serious invasive syndromes such as pneumonia, severe sepsis and endocarditis. MRSA strains are particularly serious and potentially lethal pathogens that possess virulence mechanisms including toxins, adhesins, enzymes and immunomodulators. One of these is Panton-Valentine leukocidin (PVL), a toxin associated with abscess formation and severe necrotizing pneumonia. Earlier studies suggested that PVL was a major virulence factor in community-associated MRSA infections. However, some recent data have not supported this association while others have, leading to controversy. Therefore, investigators continue to search for additional mechanisms of pathogenesis. In this review, we summarize the current understanding of the biological basis of MRSA virulence and explore future directions for research, including potential vaccines and antivirulence therapies under development that might allow clinicians to more successfully treat and prevent MRSA infections.

Evaluation of a Pulsed Xenon Ultraviolet Disinfection System for Reduction of Healthcare-Associated Pathogens in Hospital Rooms

OBJECTIVE To determine the effectiveness of a pulsed xenon ultraviolet (PX-UV) disinfection device for reduction in recovery of healthcare-associated pathogens. SETTING Two acute-care hospitals. METHODS We examined the effectiveness of PX-UV for killing of Clostridium difficile spores, methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE) on glass carriers and evaluated the impact of pathogen concentration, distance from the device, organic load, and shading from the direct field of radiation on killing efficacy. We compared the effectiveness of PX-UV and ultraviolet-C (UV-C) irradiation, each delivered for 10 minutes at 4 feet. In hospital rooms, the frequency of native pathogen contamination on high-touch surfaces was assessed before and after 10 minutes of PX-UV irradiation. RESULTS On carriers, irradiation delivered for 10 minutes at 4 feet from the PX-UV device reduced recovery of C. difficile spores, MRSA, and VRE by 0.55±0.34, 1.85±0.49, and 0.6±0.25 log10 colony-forming units (CFU)/cm2, respectively. Increasing distance from the PX-UV device dramatically reduced killing efficacy, whereas pathogen concentration, organic load, and shading did not. Continuous UV-C achieved significantly greater log10CFU reductions than PX-UV irradiation on glass carriers. On frequently touched surfaces, PX-UV significantly reduced the frequency of positive C. difficile, VRE, and MRSA culture results. CONCLUSIONS The PX-UV device reduced recovery of MRSA, C. difficile, and VRE on glass carriers and on frequently touched surfaces in hospital rooms with a 10-minute UV exposure time. PX-UV was not more effective than continuous UV-C in reducing pathogen recovery on glass slides, suggesting that both forms of UV have some effectiveness at relatively short exposure times.

Colistin Versus Ceftazidime-Avibactam in the Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae

Background The efficacy of ceftazidime-avibactam-a cephalosporin-β-lactamase inhibitor combination with in vitro activity against Klebsiella pneumoniae carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CRE)-compared with colistin remains unknown. Methods Patients initially treated with either ceftazidime-avibactam or colistin for CRE infections were selected from the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE), a prospective, multicenter, observational study. Efficacy, safety, and benefit-risk analyses were performed using intent-to-treat analyses with partial credit and the desirability of outcome ranking approaches. The ordinal efficacy outcome was based on disposition at day 30 after starting treatment (home vs not home but not observed to die in the hospital vs hospital death). All analyses were adjusted for confounding using inverse probability of treatment weighting (IPTW). Results Thirty-eight patients were treated first with ceftazidime-avibactam and 99 with colistin. Most patients received additional anti-CRE agents as part of their treatment. Bloodstream (n = 63; 46%) and respiratory (n = 30; 22%) infections were most common. In patients treated with ceftazidime-avibactam versus colistin, IPTW-adjusted all-cause hospital mortality 30 days after starting treatment was 9% versus 32%, respectively (difference, 23%; 95% bootstrap confidence interval, 9%-35%; P = .001). In an analysis of disposition at 30 days, patients treated with ceftazidime-avibactam, compared with those treated within colistin, had an IPTW-adjusted probability of a better outcome of 64% (95% confidence interval, 57%-71%). Partial credit analyses indicated uniform superiority of ceftazidime-avibactam to colistin. Conclusions Ceftazidime-avibactam may be a reasonable alternative to colistin in the treatment of K. pneumoniae carbapenemase-producing CRE infections. These findings require confirmation in a randomized controlled trial.

Overview: Global and Local Impact of Antibiotic Resistance

The rapid and ongoing spread of antibiotic resistance poses a serious threat to global public health. The indiscriminant use of antibiotics in agriculture and human medicine along with increasingly connected societies has fueled the distribution of antibiotic-resistant bacteria. These factors together have led to rising numbers of infections caused by multidrug-resistant and pan-resistant bacteria, with increases in morbidity and mortality. This article summarizes the trends in antibiotic resistance, discusses the impact of antibiotic resistance on society, and reviews the use of antibiotics in agriculture. Feasible ways to tackle antibiotic resistance to avert a post-antibiotic era are suggested.

The role of vitamin D deficiency in sepsis and potential therapeutic implications

Recent studies have shown that vitamin D has important functions besides bone and calcium homeostasis. Cells of the innate and adaptive immune system express vitamin D receptors and respond to stimulation by 1, 25-dihydroxyvitamin D. Patients with sepsis have a high mortality rate as well as a high prevalence of vitamin D deficiency. In addition, septic patients have decreased vitamin D binding protein levels which further exacerbates vitamin D deficiency. Therapy with vitamin D in animal models of sepsis improves blood coagulation parameters in disseminated intravascular coagulation and modulates levels of systemic inflammatory cytokines including TNF-α and IL-6. Vitamin D can enhance the induction of the antimicrobial peptides cathelicidin and β-defensin which are found on mucosal and epithelial surfaces and act as the bodys first line of defense against viral and bacterial pathogens. Vitamin D is potentially an attractive therapeutic agent for sepsis given its low cost and low risk of toxicity and side effects. Further prospective, randomized, controlled clinical trials of adjunctive vitamin D therapy in patients who are deficient are needed in the management of human sepsis syndrome.

Update on Cytomegalovirus Infections of the Gastrointestinal System in Solid Organ Transplant Recipients

Cytomegalovirus (CMV) infection of the gastrointestinal tract is the most common manifestation of tissue-invasive CMV disease, and is a significant cause of morbidity and mortality in the solid organ transplantation (SOT) recipient. In addition to the direct effects of the infection, its indirect effects on allograft function, risk for other opportunistic infections, and mortality are significant in this population. The most common clinical syndromes are esophagitis, colitis, and hepatitis; however, infection can occur anywhere in the gastrointestinal tract. Diagnosis is usually by histopathology or viral culture of tissue specimens; molecular assays also often have a role. Antivirals are the cornerstone of therapy for gastrointestinal tract CMV disease and complications such as recurrent infection and antiviral resistance are not uncommon. Prevention with antiviral prophylaxis or preemptive therapy is important. This review summarizes recent data regarding the clinical manifestations, diagnosis, treatment, and prevention of gastrointestinal tract CMV infection in the SOT population.

An update on the association of vitamin D deficiency with common infectious diseases 1

Vitamin D plays an important role in modulating the immune response to infections. Deficiency of vitamin D is a common condition, affecting both the general population and patients in health care facilities. Over the last decade, an increasing body of evidence has shown an association between vitamin D deficiency and an increased risk for acquiring several infectious diseases, as well as poorer outcomes in vitamin D deficient patients with infections. This review details recent developments in understanding the role of vitamin D in immunity, the antibacterial actions of vitamin D, the association between vitamin D deficiency and common infections (like sepsis, pneumonia, influenza, methicillin-resistant Staphylococcus aureus, human immunodeficiency virus type-1 (HIV), and hepatitis C virus (HCV)), potential therapeutic implications for vitamin D replacement, and future research directions.

Treatment of Giardiasis: Current Status and Future Directions

Giardiasis is a common yet neglected cause of diarrheal illness worldwide. Antimicrobial therapy is usually but not always effective and drug resistance has become an increasing concern. Several promising drug candidates have been recently identified that can overcome antibiotic resistance in Giardia. These include derivatives of 5-nitroimidazoles and benzimidazoles, as well as hybrid compounds created from combinations of different antigiardial drugs. High-throughput screening of large compound libraries has been a productive strategy for identifying antigiardial activity in drugs already approved for other indications, e.g. auranofin. This article reviews the current treatment of giardiasis, mechanisms of resistance, advances in drug and vaccine development, and directions for further research on this significant human pathogen.

An evidence-based review of linezolid for the treatment of methicillin-resistant Staphylococcus aureus (MRSA): place in therapy

Methicillin-resistant Staphylococcus aureus (MRSA), including community-associated and hospital-associated strains, is a major cause of human morbidity and mortality. Treatment options have become limited due to the emergence of MRSA strains with decreased sensitivity to vancomycin, which has long been the first-line therapy for serious infections. This has prompted the search for novel antibiotics that are efficacious against MRSA. Linezolid, an oxazolidinone class of antibiotic, was approved by the Food and Drug Administration in 2000 for treatment of MRSA infections. Since then, there have been a multitude of clinical trials and research studies evaluating the effectiveness of linezolid against serious infections, including pneumonia (both community- and hospital-acquired), skin and soft-tissue infections such as diabetic foot ulcers, endocarditis, osteomyelitis, prosthetic devices, and others. The primary aim of this review is to provide an up-to-date evaluation of the clinical evidence for using linezolid to treat MRSA infections, with a focus on recently published studies, including those on nosocomial pneumonia. Other objectives are to analyze the cost-effectiveness of linezolid compared to other agents, and to review the pharmokinetics and pharmacodynamics of linezolid, emphasizing the most current concepts.

Staphylococcus aureus pyomyositis compared with non-Staphylococcus aureus pyomyositis

OBJECTIVES Pyomyositis is an acute bacterial infection of skeletal muscle not arising from contiguous infection. It is often hematogenous in origin and typically associated with abscess formation. Our objective was to determine if there were any differences in the clinical presentation of disease between Staphylococcus aureus (SA) and non-Staphylococcus aureus pyomyositis. We also sought to determine if methicillin-resistant SA (MRSA) occurred more frequently during the final years of the study period. METHODS A retrospective chart review study at three institutions in two cities. RESULTS Sixty cases of pyomyositis were identified between 1990 and 2010. Twenty-nine patients were infected with SA while 31 had other bacterial etiologies or were culture negative. Those with a traumatic event prior to the onset of infection were more likely to have a SA infection while SA infected patients were younger. Our first documented case of MRSA occurred in 2005, but the frequency of MRSA infection remained static over the following five years. CONCLUSIONS Pyomyositis is an emerging infection that is underappreciated by many physicians. While MRSA has emerged as the foremost cause of SA infections in a majority of clinical conditions, in this series most patients still had methicillin-sensitive SA as their cause of pyomyositis. In light of the severity of pyomyositis and the potential for bacteremia (either as a source or complication of the infection), empiric SA therapy should be initiated in all patients until the culture results are available.