Optimizing therapy for MRSA pneumonia

Optimizing therapy for MRSA pneumonia

Semin Respir Crit Care Med. 2007 Dec

Skrupky LP, Micek ST, Kollef MH.
Department of Pharmacy, Barnes-Jewish Hospital. St. Louis, Missouri.

With its remarkable armamentarium of resistance and virulence factors, STAPHYLOCOCCUS AUREUS has emerged as a dominant pathogen causing pneumonia of all classifications. Rates of methicillin resistance are increasing as clinicians struggle to find ways to prevent the acquisition of methicillin-resistant STAPHYLOCOCCUS AUREUS (MRSA) and to effectively treat MRSA pneumonia. Community-associated MRSA has been identified as an important subset of MRSA with unique characteristics. Vancomycin remains a recommended first-line therapy for MRSA pneumonia, but resistance and therapeutic failures with vancomycin are being increasingly reported. Factors associated with vancomycin success or failure have been identified, including the genetics of the MRSA isolate, vancomycin lung penetration, minimum inhibitory concentration, and pharmacokinetic and pharmacodynamic variables. Retrospective analyses suggest that linezolid may provide improved outcomes compared with vancomycin for MRSA pneumonia, but validation in a prospective trial is currently lacking. Other treatment options are limited, but new prospects are being investigated. This paper reviews the epidemiology and pharmacotherapy of MRSA pneumonia.

Thieme Connect

The Increasing Problem of Wound Bacterial Burden and Infection in Acute and Chronic Soft-Tissue Wounds Caused by Methicillin-Resistant Staphylococcus

The Increasing Problem of Wound Bacterial Burden and Infection in Acute and Chronic Soft-Tissue Wounds Caused by Methicillin-Resistant Staphylococcus aureus.

J Burns Wounds. 2007

Demling RH, Waterhouse B.
Brigham and Women's Hospital, Burn and Trauma Center, Boston, MA.

Methicillin-resistant Staphylococcus aureus (MRSA) has become a leading cause of colonization and infection in both acute and chronic soft-tissue wounds. Objective: Our objective is to define this current epidemic problem caused by both community-acquired MRSA (CA-MRSA) and hospital-acquired MRSA (HA-MRSA), focusing on the similarities and differences between these 2 isolates as well as the impact on wound management decisions. Methods: Methods used include a literature review on the growth of the current MRSA problem and its International scope. In addition, a current up-to-date assessment had been made of the problem and the current approach to management of MRSA in acute soft-tissue and chronic wounds. Burns are not discussed because this injury usually does not fit either categories and is managed quite uniquely. Results: Results included the following: (1) There are very distinct properties of CA-MRSA and HA-MRSA, which must be considered for acute and chronic wound care. Management of both requires rigorous barrier precaution techniques to avoid cross-contamination. The presence of MRSA as a carrier state increases the risk of both a systemic and local wound infection in the carrier. There are large and increasing reservoirs of CA-MRSA and HA-MRSA worldwide leading to more bacteremias and wound problems. Topical antimicrobial therapy has not been addressed in managing MRSA in acute and chronic wounds. Conclusion: Conclusions include the fact that both HA-MRSA and CA-MRSA wound infections are rapidly increasing, especially with CA-MRSA. This high incidence requires appropriate wound prediction and management decisions as well as attempts to avoid further cross-contamination and reservoir growth. Topical antimicrobial therapy would seem to be an important component in controlling this tremendous problem. Yet this topic has yet to be adequately addressed.

PMID: 18091985 [PubMed - in process]

Pharmacokinetics and Pharmacodynamics of Ceftobiprole, an Anti-MRSA Cephalosporin with Broad-Spectrum Activity

Pharmacokinetics and Pharmacodynamics of Ceftobiprole, an Anti-MRSA Cephalosporin with Broad-Spectrum Activity
Clin Pharmacokinet. 2008

Murthy B, Schmitt-Hoffmann A.
Clinical Pharmacology and Experimental Medicine, Johnson & Johnson Pharmaceutical Research & Development, LLC, Raritan, New Jersey, USA.

Ceftobiprole, a beta-lactam, is the first of a new generation of broad-spectrum cephalosporins in late-stage development with activity against methicillin-resistant Staphylococcus aureus (MRSA) in addition to broad-spectrum bactericidal activity against other Gram-positive and Gram-negative pathogens. The prodrug, ceftobiprole medocaril, is converted rapidly and almost completely to the active drug, ceftobiprole, upon infusion by type A esterases. In humans, ceftobiprole binds minimally (16%) to plasma proteins, and binding is independent of the drug and protein concentrations. Its steady-state volume of distribution (18.4 L) approximates the extracellular fluid volume in humans. Ceftobiprole undergoes minimal hepatic metabolism, and the primary metabolite is the beta-lactam ring-opened hydrolysis product (open-ring metabolite). Systemic exposure of the open-ring metabolite accounts for 4% of ceftobiprole exposure following single-dose administration; approximately 5% of the dose is excreted in the urine as the metabolite. Ceftobiprole does not significantly induce or inhibit relevant cytochrome P450 enzymes and is neither a substrate nor an inhibitor of P-glycoprotein. Ceftobiprole is rapidly eliminated, primarily unchanged, by renal excretion, with a terminal elimination half-life of 3 hours; the predominant mechanism responsible for elimination is glomerular filtration, with approximately 89% of the dose being excreted as the prodrug, active drug (ceftobiprole) and open-ring metabolite. The pharmacokinetics of ceftobiprole are linear following single and multiple infusions of 125-1000 mg. Steady-state drug concentrations are attained on the first day of dosing, with no appreciable accumulation when administered three times daily (every 8 hours) and twice daily (every 12 hours) in subjects with normal renal function. Low intersubject variability has been seen across studies. Ceftobiprole exposure is slightly higher (~15%) in females than in males; this difference has been attributed to bodyweight. However, the pharmacodynamics of ceftobiprole are similar in males and females, and dosing adjustments are not required based on gender. In patients with moderate to severe renal impairment, systemic clearance of ceftobiprole correlated well with creatinine clearance. For these patients, dose adjustments for the treatment of infections caused by target pathogens, including MRSA, should be based on creatinine clearance. Ceftobiprole is undergoing clinical evaluation in phase III trials in patients with complicated skin and skin structure infections, patients with nosocomial pneumonia, and community-acquired pneumonia in hospitalized patients.

PMID: 18076216 [PubMed - in process]

Public computer surfaces are reservoirs for methicillin-resistant staphylococci.

Public computer surfaces are reservoirs for methicillin-resistant staphylococci.

ISME J. 2007 Jul

Kassem II, Sigler V, Esseili MA.
1Laboratory for Microbial Ecology, Department of Environmental Sciences, University of Toledo, Toledo, OH, USA.

The role of computer keyboards used by students of a metropolitan university as reservoirs of antibiotic-resistant staphylococci was determined. Putative methicillin (oxacillin)-resistant staphylococci isolates were identified from keyboard swabs following a combination of biochemical and genetic analyses. Of 24 keyboards surveyed, 17 were contaminated with staphylococci that grew in the presence of oxacillin (2 mg l(-1)). Methicillin (oxacillin)-resistant Staphylococcus aureus (MRSA), -S. epidermidis (MRSE) and -S. hominis (MRSH) were present on two, five and two keyboards, respectively, while all three staphylococci co-contaminated one keyboard. Furthermore, these were found to be part of a greater community of oxacillin-resistant bacteria. Combined with the broad user base common to public computers, the presence of antibiotic-resistant staphylococci on keyboard surfaces might impact the transmission and prevalence of pathogens throughout the community.The ISME Journal (2007) 1, 265-268; doi:10.1038/ismej.2007.36; published online 31 May 2007.

PMID: 18043636 [PubMed - in process]

Methicillin-Resistant Staphylococcus Aureus Carriage, Infection and Transmission in Dialysis Patients, Healthcare Workers and their Family Members.

Methicillin-Resistant Staphylococcus Aureus Carriage, Infection and Transmission in Dialysis Patients, Healthcare Workers and their Family Members.

Nephrol Dial Transplant. 2007

Lu PL, Tsai JC, Chiu YW, Chang FY, Chen YW, Hsiao CF, Siu LK.
1Department of Internal Medicine, Kaohsiung Medical University Hospital.

BACKGROUND: Carriage and subsequent infection with methicillin resistant S. aureus (MRSA) and its transmission between hospital and community settings have not been studied in dialysis patients and their contacts.

METHODS: Surveillance for nasal MRSA carriage and infection among dialysis patients, healthcare workers (HCWs) and their family members in a dialysis centre was prospectively undertaken during three time periods within 1 year. Molecular typing was used to determine epidemiological relationship.

RESULTS: Among 1687 samples collected, MRSA colonization rates were 2.41% (2/83) for peritoneal dialysis patients and 2.36% (12/509) for haemodialysis patients. Five (5/14) subjects subsequently had MRSA infection. The clinical MRSA isolates had the same molecular type as the colonized strains of the same person, indicating MRSA colonization preceded clinical infection. Significantly higher MRSA nasal carriage rates were observed among family members of HCWs than family members of dialysis patients (P = 0.0024). Only three major clones were observed. Pulmonary diseases (OR: 4.873, 95% CI: 1.668-14.235), recent admission to a hospital (OR: 2.797, 95% CI: 1.291-6.059) and recent antibiotics usage (OR: 2.319, 95% CI: 1.053-5.104) were also significantly associated with MRSA carriage.

CONCLUSION: Transmission of MRSA among dialysis patients, HCWs and their family members in a dialysis unit could be inferred. Monitoring and eradication of MRSA from patients, HCWs and their family members should be considered to prevent continuous spread between healthcare facilities and the community.

PMID: 18029375 [PubMed - as supplied by publisher]

Most MRSA infections in the United States are health care-associated

Most MRSA infections in the United States are health care-associated
Nov 20, 2007

Community-associated cases not the majority but are still responsible for invasive infections and, rarely, death.
by Michelle StephensonIDN Correspondent

November 2007

Invasive methicillin-resistant Staphylococcus aureus infections are a major public health problem. Recent study results found that although they are primarily health care-associated, they are no longer confined to a particular type of institution.

Researchers from across the country recently participated in a study to describe the incidence and distribution of invasive MRSA. The Active Bacterial Core surveillance system is an ongoing, population-based, active laboratory surveillance system, and it is a part of the Emerging Infections Program of the CDC. For this study, researchers from several Emerging Infections Program sites conducted surveillance for invasive MRSA infections from July 2004 through December 2005.

The sites included the Atlanta metropolitan area; Baltimore City; the state of Connecticut; Davidson County, Tennessee; the Denver metropolitan area; Monroe County, New York; the Portland, Oregon metropolitan area; Ramsey County (the St. Paul area), Minnesota and the San Francisco Bay Area. In 2005, the total population under surveillance was approximately 16.5 million people, or approximately 5.6% of the U.S. population.

Incidence rates

Between July 2004 and December 2005, there were 8,987 reported cases of invasive MRSA. Most were health care-associated, with 5,250 (58.4%) community-onset, health care-associated infections; 2,389 (26.6%) hospital-onset, health care-associated infections; 1,234 (13.7%) community-associated infections and 114 (1.3%) that could not be classified.

In 2005, the standardized incidence rate of invasive MRSA was 31.8 per 100,000, and the standardized mortality rate was 6.3 per 100,000. People who were aged 65 years or older had the highest incidence rates (127.7 per 100,000), followed by blacks (66.5 per 100,000) and men (37.5 per 100,000). Children aged 5 to 17 years had the lowest incidence rates (1.4 per 100,000).

Of the total number of patients with MRSA infection, 1,598 died while they were inpatients.

The unadjusted incidence rates of all types of invasive MRSA infections ranged from approximately 20 to 50 per 100,000; however, rates were remarkably higher in Baltimore City (116.7 per 100,000).

The incidence rate of invasive CA-MRSA was five per 100,000 or fewer in all of the sites, and incidence rates were consistently higher among blacks compared with whites in all age groups.

The rate of health care-associated, community-onset MRSA infections was 17.6 per 100,000, which was greater than either health care-associated, hospital-onset infections (8.9 per 100,000) or community-associated infections (4.6 per 100,000). Among patients with MRSA, the mortality rate for health care-associated, community-onset infections was higher (3.2 per 100,000) than for health care-associated, hospital-onset infections (2.5 per 100,000) or for community-associated infections (0.5 per 100,000).

“For the first time, we have a measurement of the burden and distribution of invasive MRSA infections. Given that the majority [of cases] were health care-associated, we need to step up our prevention efforts in health care facilities. The findings also suggest that, in 2005, community-associated cases had invasive infections at a rate of five per 100,000 and death at a rate of 0.5 per 100,000: not the majority but not trivial,” said Monina Klevens, DDS, from the CDC, who was a researcher of the study. The study results were recently published in the Journal of the American Medical Association.

During 2005, 5,287 MRSA infections were reported in the surveillance areas, and after adjusting for age, race, and sex and applying these numbers to the total U.S. population, the researchers estimated that 94,360 patients had an invasive MRSA infection. During 2005, 988 patients died of invasive MRSA infections. After adjusting these numbers to the total U.S. population, the researchers estimated that there were 18,650 in-hospital deaths due to invasive MRSA infections.

Risk factors for MRSA

During the study period, 4,105 (78.2%) of the 5,250 patients with health care-associated, community-onset infections and 1,993 (83.4%) of the 2,389 patients with health care-associated, hospital-onset infections had more than one health care risk factor for MRSA documented in their medical records. The most common health care risk factors among patients with community-onset infections were a history of hospitalization (76.6%), long-term care residence (38.5%), history of surgery (37.0%) and MRSA infection or colonization (30.3%). The most common health care risk factors among patients with hospital-onset infections were a history of hospitalization (57.7%), history of surgery (37.6%), long-term care residence (21.9%) and MRSA infection or colonization (17.4%).

Of the 8,987 observed cases of invasive MRSA, 8,792 cases had complete information in their charts, and of these, the clinical syndrome associated with invasive MRSA disease included bacteremia (75.2%), pneumonia (13.3%), cellulitis (9.7%), osteomyelitis (7.5%), endocarditis (6.3%) and septic shock (4.3%). Of the patients, 8,304 (92.4%) were hospitalized. Additionally, 1,598 (17.8%) of the patients died during hospitalization, and 1,162 (12.9%) of the patients developed recurrent invasive infections.

Ninety-eight percent of patients had a recorded clinical outcome. Interestingly, mortality rates varied according to MRSA-related diagnosis. Patients with septic shock had a high mortality rate of 55.6%; for patients with pneumonia, 32.4%. Patients with endocarditis had a moderate mortality rate of 19.3%; for patients with bacteremia, 10.2%. Patients with cellulitis had a low mortality rate (6.1%).

Pulsed-field typing

The results of pulsed-field gel electrophoresis were available for 864 (71.9%) of the 1,201 isolates received from eight of the nine study sites. Most (81.6%) of the results were from blood cultures, 4.8% from synovial fluid, 4.7% from bone, 1.9% from pleural fluid, 1.5% from peritoneal fluid and 5.5% from other normally sterile sites. Isolates tested were associated with uncomplicated bacteremia (69.8%), pneumonia (19.3%), cellulitis (11.3%), osteomyelitis (10.4%), endocarditis (8.5%) and septic shock (5.0%).

For two-thirds (66.6%) of the isolates from community-associated cases, USA300 was the strain type identified. It was also identified among 22.2% of the isolates from health care-associated, community-onset cases and among 15.7% of health care-associated, hospital-onset cases. USA100 was the strain type found in 35 (23.0%) of the 150 isolates from community-associated cases.

“One of the interesting findings from this study was the report that the USA300 clone, the most common community-associated MRSA strain, caused not only community-associated infection but also health care-associated infection. The epidemiology of MRSA continues to evolve and becomes more and more complex. The frequency of MRSA in the community and hospital and its effect on poor clinical outcomes will hopefully lead to improved hand and personal hygiene,” said Keith S. Kaye, MD, medical director of the hospital infection control committee, Duke University Medical Center, Durham, N.C., and member of the Infectious Disease News editorial advisory board.

Denise M. Cardo, MD, director of the division of health care quality promotion at the CDC’s National Center for Preparedness, Detection and Control of Infectious Diseases, and member of the Infectious Disease News editorial advisory board, also stressed the importance of infection prevention measures. “MRSA is an important problem in health care settings and is a threat to your patients. Most MRSA invasive infections are health care-associated, and these infections can be prevented with adherence to infection prevention recommendations during all patient encounters,” said Cardo.

Because the main mode of transmission of MRSA is the hands, standard precautions such as hand hygiene and gloving are imperative.

For more information:

Klevens RM, Morrison MA, Nadle J, et al. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA. 2007;298:1763-1771.

Infectious Disease News

Key to MRSA Virulence in Community Discovered

Key to MRSA Virulence in Community Discovered

Bacteria target immune system cells sent to kill them, study finds

Monday, November 12, 2007

MONDAY, Nov. 12 (HealthDay News) -- Researchers have uncovered a cache of molecular weapons that helps make community-associated methicillin-resistant Staphylococcus aureus (MRSA) so virulent.

Though more work must be done, the study "provides a partial explanation of why these strains are so successful in causing infection and gives a starting point in the development of new drug treatments," said Dr. Gregory Moran, a professor of medicine in the departments of emergency medicine and infectious disease at the Olive View-UCLA Medical Center.

Michael Otto, a senior investigator at the National Institute of Allergy and Infectious Disease, Rocky Mountain Laboratories, and his colleagues searched for and found a battery of short, novel peptides that are expressed by community-associated MRSA strains at higher levels than their hospital-associated MRSA cousins.

Deleting the genes encoding these peptides in mouse models of bacterial infection reduced the microbes' ability to kill or induce skin lesions in infected animals, while purified peptides paralyzed -- and paradoxically, activated -- neutrophils, which are the white blood cells whose job it is to prevent bacterial infections and the principal component of pus.

The study was published in the Nov. 11 online issue of Nature Medicine.

According to the U.S. Centers for Disease Control and Prevention, S. aureus, commonly found on the skin and in the nose of healthy individuals, is associated with bacterial skin infections. MRSA, as its name implies, is a particularly nasty strain of S. aureus that is resistant to the class of antibiotics that includes penicillin, amoxicillin and methicillin.

Traditionally, MRSA, which can cause boils, skin necrosis and even death, has been limited to hospital settings and crowded environments such as prisons. Yet, beginning in 1999, community-associated cases of the disease have been on the rise. Last month, a study in the Journal of the American Medical Association found that more people died of MRSA than of AIDS in 2005.

"That [sudden increase] was alarming, and nobody knew why it was happening," said Moran, who co-authored a 2006 study showing that community-associated MRSA accounts for almost 60 percent of skin infections that require a visit to the emergency room. "Something about these strains made them very well-suited to spread throughout the population."

These peptides could explain that virulence, at least in part, said Philip Tierno, director of clinical microbiology & immunology at New York University Medical Center and author of The Secret Life of Germs: Observations and Lessons From a Microbe Hunter."

"Virulence, it seems, is caused by these peptides, which can kill phagocytic cells [neutrophils], which come to your defense when staph is invading your body," he explained.

Staphylococci, Tierno noted, induce pus formation by recruiting and activating white blood cells. "That very induction of phagocytes [neutrophils] is key to your successful eradication of the organisms in the body," he said. However, "Staph has a defense. These peptides that can kill these phagocytic cells, thereby rendering you defenseless."

The genes encoding these toxins are found in the genomes of all sequenced MRSA strains, but community-associated MRSA strains produced the toxins at higher levels than the hospital strains, which typically cannot infect healthy individuals. Thus, they may explain the enhanced virulence of the community-associated strains.

The bacteria would fly under the immune system's radar, so to speak, by not expressing the peptides until the bacteria were either present in very large numbers, or perhaps after being engulfed by neutrophils and enclosed in a small space.

In either case, the mechanism would detect that situation and begin production of the peptides in earnest to fight back against the immune system.

"From the bacterial point of view, the most important thing is to get rid of the neutrophil," Otto said.

According to Moran, these findings suggest new drug possibilities -- antibodies that can remove the peptides from circulation, for instance.

"Any time we can better understand the basic physiology of how infections get around the immune system, it gives a potential target for treatment," he said.

However, Tierno emphasized that focusing exclusively on these peptides would be a mistake, as they represent just one of many mechanisms by which virulent MRSA can harm their hosts; these strains also express toxins that can overwhelm the body in other ways.

"All of these work together to make the organism so deadly," Tierno said. "There is a synergy without question that accounts for a big problem with these organisms."

HealthDay

Subtle genetic changes enhance virulence of methicillin resistant and sensitive Staphylococcus aureus MRSA

Subtle genetic changes enhance virulence of methicillin resistant and sensitive Staphylococcus aureus.

BMC Microbiol. 2007 Nov 6;
ABSTRACT:

BACKGROUND: Community acquired (CA) methicillin-resistant Staphylococcus aureus (MRSA) increasingly causes disease worldwide. USA300 has emerged as the predominant clone causing superficial and invasive infections in children and adults in the USA. Epidemiological studies suggest that USA300 is more virulent than other CA-MRSA. The genetic determinants that render virulence and dominance to USA300 remain unclear.

RESULTS: We sequenced the genomes of two pediatric USA300 isolates: one CA-MRSA and one CA-methicillin susceptible (MSSA), isolated at Texas Children's Hospital in Houston. DNA sequencing was performed by Sanger dideoxy whole genome shotgun (WGS) and 454 Life Sciences pyrosequencing strategies. The sequence of the USA300 MRSA strain was rigorously annotated. In USA300, MRSA 2685 chromosomal open reading frames were predicted and 3.1 and 27 kilobase (kb) plasmids were identified. USA300 MSSA contained a 20 kb plasmid with some homology to the 27 kb plasmid. Two regions found in US300 MRSA were absent in USA300 MSSA. The USA300 sequence was aligned with other sequenced S. aureus genomes and regions unique to USA300 MRSA were identified.

CONCLUSIONS: USA300-MRSA is highly similar to other MRSA strains based on whole genome alignments and gene content, indicating that the differences in pathogenesis are due to subtle changes rather than to large-scale acquisition of virulence factor genes. The USA300 Houston isolate differs from another sequenced USA300 strain isolate, derived from a patient in San Francisco, in plasmid content and a number of sequence polymorphisms. Such differences will provide new insights into the evolution of pathogens.

BioMed Microbiology

Environmental contamination makes an important contribution to hospital infection.

Environmental contamination makes an important contribution to hospital infection.
J Hosp Infect. 2007 Jun;65

Boyce JM.
Infectious Diseases Section, Hospital of Saint Raphael, New Haven, USA.

KEYWORDS: Environmental contamination; MRSA; VRE; Hydrogen peroxide vapour

Meticillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) are capable of surviving for days to weeks on environmental surfaces in healthcare facilities. Environmental surfaces frequently touched by healthcare workers are commonly contaminated in the rooms of patients colonized or infected with MRSA or VRE. A number of studies have documented that healthcare workers may contaminate their hands or gloves by touching contaminated environmental surfaces, and that hands or gloves become contaminated with numbers of organisms that are likely to result in transmission to patients. Pathogens may also be transferred directly from contaminated surfaces to susceptible patients. There is an increasing body of evidence that cleaning or disinfection of the environment can reduce transmission of healthcare-associated pathogens. Because routine cleaning of equipment items and other high-touch surfaces does not always remove pathogens from contaminated surfaces, improved methods of disinfecting the hospital environment are needed. Preliminary studies suggest that hydrogen peroxide vapour technology deserves further evaluation as a method for decontamination of the environment in healthcare settings.

Elsevier

Importance of the environment in meticillin-resistant Staphylococcus aureus acquisition: the case for hospital cleaning

Importance of the environment in meticillin-resistant Staphylococcus aureus acquisition: the case for hospital cleaning
Review

Dr Stephanie J Dancer MDa, , aDepartment of Microbiology, Southern General Hospital, Glasgow, UK Available online 31 October 2007.

Summary

In the UK, we continue to debate the importance of hospital cleaning in relation to increasing numbers of patients acquiring meticillin-resistant Staphylococcus aureus (MRSA). However, there is little direct evidence for the effectiveness of cleaning because it has never been afforded scientific status. Hospital hygiene is usually assessed visually, but this does not necessarily correlate with microbiological risk. A more robust case for hospital cleaning can be presented by considering the evidence for all the stages of the staphylococcal transmission cycle between human beings and their environment. Cleaning has already been accepted as an important factor in the control of other hardy environmental pathogens, such as Clostridium difficile, vancomycin-resistant enterococci, norovirus, and Acinetobacter spp. This Review will show why the removal of dirt might have more impact on the control of MRSA than previously thought. Introduction of additional cleaning services is easier than improvements in hand-hygiene compliance.

The Lancet Infectious Diseases

Invasive methicillin-resistant Staphylococcus aureus infections in the United States.

Invasive methicillin-resistant Staphylococcus aureus infections in the United States.

JAMA. 2007 Oct 17

Klevens RM, Morrison MA, Nadle J, Petit S, Gershman K, Ray S, Harrison LH, Lynfield R, Dumyati G, Townes JM, Craig AS, Zell ER, Fosheim GE, McDougal LK, Carey RB, Fridkin SK; Active Bacterial Core surveillance (ABCs) MRSA Investigators.

Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, USA. rmk2@cdc.gov

CONTEXT: As the epidemiology of infections with methicillin-resistant Staphylococcus aureus (MRSA) changes, accurate information on the scope and magnitude of MRSA infections in the US population is needed.

OBJECTIVES: To describe the incidence and distribution of invasive MRSA disease in 9 US communities and to estimate the burden of invasive MRSA infections in the United States in 2005.

DESIGN AND SETTING: Active, population-based surveillance for invasive MRSA in 9 sites participating in the Active Bacterial Core surveillance (ABCs)/Emerging Infections Program Network from July 2004 through December 2005. Reports of MRSA were investigated and classified as either health care-associated (either hospital-onset or community-onset) or community-associated (patients without established health care risk factors for MRSA).

MAIN OUTCOME MEASURES: Incidence rates and estimated number of invasive MRSA infections and in-hospital deaths among patients with MRSA in the United States in 2005; interval estimates of incidence excluding 1 site that appeared to be an outlier with the highest incidence; molecular characterization of infecting strains.

RESULTS: There were 8987 observed cases of invasive MRSA reported during the surveillance period. Most MRSA infections were health care-associated: 5250 (58.4%) were community-onset infections, 2389 (26.6%) were hospital-onset infections; 1234 (13.7%) were community-associated infections, and 114 (1.3%) could not be classified. In 2005, the standardized incidence rate of invasive MRSA was 31.8 per 100,000 (interval estimate, 24.4-35.2). Incidence rates were highest among persons 65 years and older (127.7 per 100,000; interval estimate, 92.6-156.9), blacks (66.5 per 100,000; interval estimate, 43.5-63.1), and males (37.5 per 100,000; interval estimate, 26.8-39.5). There were 1598 in-hospital deaths among patients with MRSA infection during the surveillance period. In 2005, the standardized mortality rate was 6.3 per 100,000 (interval estimate, 3.3-7.5). Molecular testing identified strains historically associated with community-associated disease outbreaks recovered from cultures in both hospital-onset and community-onset health care-associated infections in all surveillance areas.

CONCLUSIONS: Invasive MRSA infection affects certain populations disproportionately. It is a major public health problem primarily related to health care but no longer confined to intensive care units, acute care hospitals, or any health care institution.

PMID: 17940231 [JAMA]

How staph became drug-resistant threat

How staph became drug-resistant threat

Sunday November 4, 2007

94,000 infections a year, many occurring outside of hospitals

By Jeremy Manier Tribune staff reporter

The evolutionary path of the bacterium called MRSA wound around the globe for decades before a pair of Chicago doctors in 1996 noticed the bug had taken an ominous turn.

Before then, the germ's resistance to antibiotics was of concern mainly in hospitals, where steadily growing numbers of patients were contending with the stubborn staph infection. Reports of healthy people who contracted MRSA outside of a hospital were rare and isolated, the stuff of obscure medical journal articles.

But the bacterium, formally known as methicillin-resistant Staphylococcus aureus, was beginning to depart from the habits it had settled into during years of adaptation to human hosts.

At the University of Chicago Medical Center, pediatric specialists Dr. Robert Daum and Dr. Betsy Herold held an impromptu meeting to discuss a dramatic increase in young patients showing up at the hospital with MRSA infections they'd gotten in the community. Dozens of children were sickened by the resistant bacteria without having contact with hospitals -- an unprecedented outbreak.

"We just looked at each other and said, 'What's going on here?'" said Daum, chief of pediatric infectious diseases at the U. of C.

They were witnessing a pivotal episode in the biography of a bacterial family that is now found widely in hospitals and among the public at large, causing 94,000 severe infections each year with 19,000 deaths, according to a recent federal estimate. From its humble birth at hospitals in Britain, MRSA has transformed itself into a menacing microbe with fewer weaknesses and perhaps more lethal power than its ancestors had.

The germ's years of adaptation did not make it an invulnerable superbug. Some antibiotics still work reliably against MRSA and even severe cases of illness can be treated. But many doctors still do not know how to recognize and properly treat the infection, and experts are concerned potent strains will continue spreading in the community.

The bug's erratic evolutionary story became clear only in the last few years as scientists decoded the full genomes of at least 12 separate staph varieties, making the bacteria among the most intensely studied pathogens in recent memory. Genetic sleuthing has revealed MRSA's family ties and some potential gaps in its armor, as well as the darker corridors of its private life.

Like most successful germs, MRSA has triumphed by constantly changing and adapting to new environments. MRSA does this mostly through an uncanny talent for weird bacterial sex.

It's not sex as humans understand the term, but the effect is the same: a blending of genes from unrelated individuals. MRSA does it with the aid of viruses that siphon DNA from an individual germ and inject it into the next, like microscopic mosquitoes. The bacterium also has the ghoulish ability to suck up genetic material from germs that have died and dissolved.

"This isn't like human biology at all -- after we're born we're stuck with the genes we've got," said MRSA researcher Dr. Henry Chambers, chief of infectious diseases at San Francisco General Hospital. "Staph can take on new genes and share them with friends."

The bacterial ancestors of MRSA have probably stalked humans throughout history. Staph is an ancient, ball-shaped germ that caused skin inflammation and battlefield wound infections long before it encountered the antibiotics that helped spawn MRSA. Scientists identified Staphylococcus aureus as a species in the late 19th Century.

Staph felt the sting of antibiotics before any other bacteria, when British researcher Anthony Fleming discovered penicillin stopped the germ's growth. By the 1950s, however, the bacterium had adapted by making an enzyme that could slice through penicillin. The need for more antibiotics led to a new wave of drugs, including the debut of methicillin in 1959.

Just one year after methicillin hit the market, a young English bacteriologist named Patricia Jevons was testing thousands of bacterial samples and found three strains were resistant to the new drug. Reporting her findings in the British Medical Journal in 1961, Jevons noted calmly, "The fact that the occasional resistant strain does exist should be borne in mind."

No newspaper headlines heralded the birth of MRSA, perhaps because experts already knew it was only a matter of time before staph figured out the new drug. Antibiotics shove bacteria into an evolutionary corner, weeding out the vulnerable varieties and offering an opportunity to strains that have picked up key defensive traits."

We can always expect antibiotic resistance to follow antibiotic use, as surely as night follows day," said Dr. John Jernigan, a medical epidemiologist with the federal Centers for Disease Control and Prevention.

Evolution's answer to methicillin was a gene called mecA that allowed MRSA to evade the antibiotic's molecular weaponry. Scientists searching for its origins have found different versions of the gene in a form of staph that infects rats, as well as in a relatively harmless type of staph that can be found virtually everywhere.

The resistance gene likely hopped repeatedly from one staph species to another, perhaps using the bacterial viruses called phages as its taxi service. The gene "wasn't very common, but it was there in the background, waiting to be amplified," Chambers said.

Landing in the U.S.

MRSA spent its youth in the '60s lurking in the shadows, slowly spreading and gathering force. The bacteria got its U.S. passport in 1968, when the first American cases showed up in Boston. Methicillin fell out of use as a drug because it was toxic to some patients, but MRSA was still resistant to the similar drugs that replaced it.

Then, as today, doctors could still stop the bug with a more powerful antibiotic, vancomycin. But if an infection is not recognized as MRSA, the patient's condition can get dangerously worse while a physician tries to treat it with weaker antibiotics. Doctors typically do not reach first for vancomycin because routine use of the drug could help bacteria build resistance to it as well.

As of 1974 the resistant bug still accounted for only 2 percent of all hospital staph infections. The problem in hospitals grew more quickly in the 1980s before flattening out. MRSA took off first in big-city teaching hospitals, which brought together large numbers of the sickest patients from around the world. Once the bug gained a foothold, it seemed almost impossible to eradicate.

"It's not as though we can point to one organism at one location and say everything emanated from here in logical fashion," said Fred Tenover, acting director of the CDC's office of antimicrobial resistance. "We had progressions, fallbacks; then the bacteria reached a critical mass, got a foothold, and from there you got larger and larger epidemics."

Scattered cases of MRSA cropped up outside of hospitals in Michigan and parts of Australia, but before the 1990s, resistant staph never quite caught on in the community.

Pressures of evolution

The reason may go back to the selective pressures of evolution. Drug resistance doesn't always help bacteria survive. It's vital for germs in a hospital, where the constant use of antibiotics slowly weeds out any bacteria that lack such defenses, but in the community, resistance genes may become a drag.

"Having this extra baggage can take away from the bacteria's fitness, so it's better for the bug not to have it," said Susan Boyle-Vavra, a staph researcher at the University of Chicago.

That's one reason the U. of C. finding of a spike in community-acquired MRSA cases came as such a shock when Daum's team published its results in 1998. Another was that no one had seen this strain of MRSA before. Among other clues, the U. of C. strain could be treated with drugs such as clindamycin, which the common forms of hospital MRSA had learned to resist long before.

Daum began sounding an alarm about the new form of community MRSA, but few people in the media or in the research community took his concern seriously. Community MRSA still seemed rare, and the hospital variety was a bigger problem. Jernigan was one of many experts who argued the new bug had merely escaped from hospitals and posed no unique threat.

"Early on, I wondered if MRSA in the community had its origins in the health-care setting," Jernigan said. "That was wrong. It definitely has its own foothold in the community.

"The unusual properties of MRSA's new form have emerged since 2000 as scientists intensely studied the bug.

Troubling toxin

One of the strain's most potentially troubling features is a gene for a toxin called PVL, which hopped a ride into the staph genome on a bacterial phage. The toxin's role has spurred debate, as some researchers think it's merely a benign passenger. But some studies suggest MRSA with PVL can cause more serious forms of disease, including a severe form of pneumonia.

"If you have bad staph pneumonia, you're likely to have a strain with PVL," Daum said. "It's a convergence of drug resistance and virulence."An even newer strain of community MRSA has swept the country in the last few years and now accounts for nearly all cases. The latest variety appropriated yet another gene from a mostly harmless type of staph that may be helping the new strain spread.

"It can survive inside the cells the body normally uses to kill it," Tenover said. In the latest twist to the story, scientists say the community strain now has begun infecting hospital patients, who may be more vulnerable to it.

Genetic studies of MRSA have brought some good news. Last year researchers from the U. of C. and Rockefeller University in New York reported a successful test in mice of a vaccine that would protect against several forms of MRSA, including one of the community varieties.

It may even be possible to make old antibiotics work against MRSA. Daum's lab has focused on disabling a system of proteins in the bacteria that sense when antibiotics are nearby. Turning off that system makes the bug blind to the drugs that can kill it.

If successful, the approach one day could allow doctors to use standard antibiotics even against germs that possess the resistance gene. For once, MRSA's long evolutionary march could take a welcome step backward.

Avoiding infection

Good hygiene is the best way to avoid infection with MRSA. This staph infection sometimes first appears on the skin as a red, swollen pimple or boil that may be painful or have pus. It can be spread by close, skin-to-skin contact or by touching surfaces contaminated with the germ.

The federal Centers for Disease Control and Prevention advises:

* Keep your hands clean by washing thoroughly with soap and water or using an alcohol-based hand cleaner.

* Keep cuts and scrapes clean and covered with a bandage until healed.

* Avoid contact with other people's wounds or bandages.

* Avoid sharing personal items such as towels or razors.

Tracking MRSA in hospitals and communities

Resistant strains of Staphylococcus aureus have evolved steadily over the years and acquired the ability to spread through the community. Today about 2.3 million Americans carry MRSA in their nose or on their skin.

TIMELINE OF MRSA

Methicillin-resistant Staphylococcus aureus

1959: Methicillin is introduced as an antibiotic.

1961: Bacteriologist Patricia Jevons discovers first methicillinresistant staphylococcus aureus (MRSA) in England hospitals.

1968: First report of MRSA in American hospitals in Boston.

1974: MRSA accounts for 2% of hospital staph infections in U.S.

1981: First reports of MRSA acquired in the community, while MRSA in hospitals rises steadily.

1997: MRSA accounts for 50% of hospital staph infections.

1998: University of Chicago researchers report a 25-fold increase in community-acquired MRSA from 1993 to 1995. During the same period, 35 kids in Chicago are hospitalized with community-acquired MRSA.

1999: CDC reports deaths of four otherwise healthy children from community-acquired MRSA.

2002: U. of C. team finds that new cases of community-acquired MRSA are genetically distinct from hospital strains.

2007: CDC estimates that MRSA causes 94,000 severe infections each year, killing 19,000.

Sources: CDC, University of Chicago, Barry Kreiswirth for The Public Health Research Institute Center

Chicago Tribune

jmanier@tribune.com

MRSA cases higher, but they're still rare

MRSA cases higher, but they're still rare

Posted by the Asbury Park Press on 11/4/07

After days of media hype, the public now knows a lot about Methicillin-resistant Staphylococcus aureus (MRSA), and many of us have come to fear this big bad "superbug."

As an emergency physician, who has successfully treated many types of infections, I feel the need to clarify two common public misconceptions:

There has not been a sudden jump in MRSA cases. Rather, reports of MRSA have been steadily increasing for years.

MRSA is still relatively rare. Only 1 percent of the population carries MRSA, and most of these people do not develop infections — especially if they simply wash their hands. Moreover, most MRSA infections are easily treated, if caught early enough.

What is most alarming about MRSA is its link to the continued inappropriate use of antibiotics. That's why the American College of Emergency Physicians is saying it's important for people to know when — and when not — to seek antibiotics for a range of illnesses. For example, people need to realize they should not be seeking antibiotics for colds or the flu because these illnesses are caused by viruses, which do not respond to antibiotic treatment.

We need to focus less on useless fear-mongering and instead educate the public about why unnecessary use of antibiotics is contributing to a widespread public health problem.

Dr. Laurence DesRochers

TOMS RIVER
PRESIDENT, NEW JERSEY CHAPTER
AMERICAN COLLEGE OF EMERGENCY PHYSICIANS

Ashbury Park Press

Increasing incidence of methicillin-resistant Staphylococcus aureus skin and soft-tissue infections: reconsideration of empiric antimicrobial therapy.

Increasing incidence of methicillin-resistant Staphylococcus aureus skin and soft-tissue infections: reconsideration of empiric antimicrobial therapy.
Am J Surg. 2007 Nov

Awad SS, Elhabash SI, Lee L, Farrow B, Berger DH.
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Michael E. DeBakey Veterans Affairs Hospital, MED VAMC, OCL (112), 2002 Holcombe Blvd, Houston, TX 77030, USA. sawad@bcm.tmc.edu

BACKGROUND: Community-acquired methicillin-resistant Staphylococcus aureus (MRSA) rates are at an all time high. MRSA rates as high as 60% have been reported in patients presenting with skin and soft-tissue infections (SSTIs). Our objectives were to (1) examine the incidence of MRSA over a 7-year period in surgical patients with SSTIs, (2) examine the choice of empiric antibiotic therapy, and (3) evaluate the vancomycin minimum inhibitory concentration (MIC) in MRSA isolates.

METHODS: The medical records of all patients who underwent operative debridement of SSTIs from 2000 to 2006 were retrospectively reviewed. Demographic data such as age, race, and gender as well as co-morbid risk factors were collected. Preoperative American Society of Anesthesiologists (ASA) score, temperature, WBC, creatinine, HgbA1c, albumin, and empiric antimicrobial of choice were also included. Microbiology of all operative cultures was recorded. Available vancomycin MIC data were collected. All data are presented as mean +/- standard error of the mean. A chi-square test was used for statistical analysis.

RESULTS: From 2000 to 2006, 288 patients with operative debridement for SSTIs were identified. The mean age was 54 +/- 11 years. Fifty-two percent of patients had diabetes mellitus, 55% were tobacco users, 34% alcohol users, and 23% had hepatitis C. The mean temperature at presentation was 99.2 degrees +/- 1.5 degrees F. The mean white blood cell count was 13.8 +/- .9. The mean HgbA1c was 8.6 +/- 2.5. The mean body mass index was 30.1 +/- 8. Sixty-seven percent of patients had an ASA > or = 3. There was a significant increase in MRSA SSTIs in 2006 (77%) compared with 2000 (34%, P < .001). Correspondingly, there was a significant increase in empiric administration of vancomycin in 2006 (93%) compared with 2000 (18%, P < .001). The examination of vancomycin MIC shows a shift for MRSA isolates over this time period.

CONCLUSION: Our study shows a significant and ongoing increase in the incidence of MRSA in patients with SSTIs. Empiric coverage with an MRSA antimicrobial should be used as first-line therapy. However, given the observed increase in vancomycin MIC, alternative MRSA antimicrobials should be considered.

Elsevier

Risk factors associated with methicillin-resistant Staphylococcus aureus infection in patients admitted to the ED.

Risk factors associated with methicillin-resistant Staphylococcus aureus infection in patients admitted to the ED.
Am J Emerg Med. 2007 Oct

Viallon A, Marjollet O, Berthelot P, Carricajo A, Guyomarc'h S, Robert F, Zeni F, Bertrand JC.
Emergency and Intensive Care Department, Hôpital de Bellevue, Saint-Etienne, France. alain.viallon@chu-st-etienne.fr

OBJECTIVES: The objective of our study was to define the characteristics of patients admitted to the emergency department (ED) presenting with a methicillin-resistant Staphylococcus aureus (MRSA) infection.

PATIENTS AND METHODS: The study included all patients admitted to the ED between January 2003 and December 2004 in whom a staphylococcal infection was documented. The risk factors associated with carriage of MRSA, the diagnosis made in the ED, and the treatment administered were established from the patients' medical files. The sites from which the bacteria were isolated, the spectrum of resistance of the staphylococci to different antibiotics, and the presence or absence of the gene coding for Panton-Valentin leukocidin for certain S aureus isolates were determined from the reports issued by the bacteriologic department. Two groups of patients were compared: those with an infection caused by MRSA and those with an infection due to methicillin-susceptible S aureus (MSSA).

RESULTS: A total of 238 patients were included, 93 presenting with an infection caused by MRSA and 145 an infection due to MSSA. The patients harboring MRSA had a higher median age than those carrying MSSA (74 vs 61 years, P = .0001), experienced a greater loss of autonomy (according to the Knauss index), and had more comorbidity factors. Nine patients, younger than 40 years, presented with an infection due to MRSA in the absence of any comorbidity factor or any factor associated with carriage of these bacteria. Seven patients in the MRSA group were tested for Panton-Valentine leukocidin genes, and a positive result was obtained in 2 of them. Regardless of whether the infection was caused by MRSA or by MSSA, the bacteria were most frequently isolated from a cutaneous site, in 40% and 65% of the patients, respectively. Irrespective of the group, 28% of the patients presented with bacteremia. The spectrum of resistance of these MRSA strains suggested a hospital rather than community origin. The initial antibiotic therapy was rarely appropriate in the case of an infection due to MRSA.

CONCLUSION: Infections caused by MRSA accounted for a high proportion of the staphylococcal infections diagnosed in the ED, necessitating a rational approach to the prescription of antibiotics for infections of this type.

Elsevier

Antibiotic resistant Staphylococcus aureus: a paradigm of adaptive power.

Antibiotic resistant Staphylococcus aureus: a paradigm of adaptive power.

Curr Opin Microbiol. 2007 Oct 5

de Lencastre H, Oliveira D, Tomasz A.

Laboratory of Microbiology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA; Laboratory of Molecular Genetics, Instituto de Tecnologia Química e Biológica (ITQB) da Universidade Nova de Lisboa (UNL), 2780 Oeiras, Portugal.

Nothing documents better the spectacular adaptive capacity of Staphylococcus aureus than the response of this important human and animal pathogen to the introduction of antimicrobial agents into the clinical environment. The effectiveness of penicillin introduced in the early 1940s was virtually annulled within a decade because of the plasmid epidemics that spread the ss-lactamase gene through the entire species of S. aureus.

In 1960 within one to two years of the introduction of penicillinase resistant ss-lactams (methicillin), methicillin resistant S. aureus (MRSA) strains were identified in clinical specimens. By the 1980s, epidemic clones of MRSA acquired multidrug resistant traits and spread worldwide to become one of the most important causative agents of hospital acquired infections. In the early 2000s, MRSA strains carrying the Tn1546 transposon-based enterococcal vancomycin resistant mechanism were identified in clinical specimens, bringing the specter of a totally resistant bacterial pathogen closer to reality.

Then, in the late 1990s, just as effective hygienic and antibiotic use policies managed to bring down the frequency of MRSA in hospitals of several countries, MRSA strains began to show up in the community.

PMID: 17921044 [PubMed - as supplied by publisher]