Community-Acquired MRSA and Influenza — A Lethal Combination
Community-Acquired MRSA and Influenza — A Lethal Combination
Abstract & Commentary
By Stan Deresinski, MD, FACP, Clinical Professor of Medicine, Stanford, Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor for Infectious Disease Alert.
Source: CDC. Severe methicillin-resistant Staphylococcus aureus community-acquired pneumonia associated with influenza - Louisiana and Georgia, December 2006 - January 2007.
After a 2 year lull with few such reports, the CDC was informed of 10 cases of severe community-acquired pneumonia (CAP) due to MRSA in previously generally healthy individuals in Louisiana and Georgia in just the 2 months of December 2006 and January 2007. The age of the patients ranged from 4 months to 48 years, with 8 being < 30 years of age; the sexes were equally represented. Two patients were current smokers and, other than one patient with hypertension and chronic hepatitis C virus infection, none suffered from chronic disease. Four of the patients either lived with someone with a history of skin infection due to MRSA or had recently had such an infection themselves. None of the 6 patients for whom the information was available had received the 2006-2007 influenza vaccine. Six had laboratory confirmed influenza, while the remainder had compatible prodromal illnesses. MRSA was isolated from sputum of 7, blood of 6, and pleural "rind" of one. Seven of the 10 had radiographic evidence of multilobar infiltrates. The median interval from the onset of respiratory symptoms to death in the 6 fatal cases was 3.5 days, with a range of 2 to 25 days.
Further testing was performed on the 5 isolates available to CDC. These 5 isolates, all from Louisiana, besides being resistant to beta-lactam antibiotics, were also resistant to erythromycin, with 2 having inducible resistance to clindamycin and 2 being resistant to levofloxacin. All carried SCCmec type IVa, consistent with their community origin, and belonged to the prevalent USA 300-0114 strain. All also carried genes encoding the Panton-Valentine leukocidin (PVL).
Commentary
The CDC previously described 17 patients with severe CAP due to S. aureus reported to them during the 2003-2004 influenza season.1 Only one had documented receipt of influenza vaccine during 2003-2004. Twelve (93%) of 13 patients for whom data was available were hypotensive. One-fourth of patients had involvement of multiple lobes of the lung and one-fourth had radiographic evidence of cavitation or necrosis; 31% had effusions/empyema. ICU admission was required by 81%, 62% required mechanical ventilation, and 46% required chest tube placement. Five (29%) died, a median of 7 days (range, 3 to 73 days) after the onset of symptoms; one was dead on arrival at hospital. Three-fourths of the isolates tested were MRSA, and all of these carried SCCmec types consistent with community-acquired MRSA (CA-MRSA), and all also carried PVL genes. During that 2003-2004 influenza season, S. aureus was recovered from 11 (11%) of 102 children with influenza-associated deaths reported to CDC and from whom specimens for bacterial culture had been obtained; most of the children had CAP.2
The occurrence of CAP as a complication of influenza has in the past usually been described as presenting as a biphasic illness, a characteristic not observed in these cases. The rapidity of progression of disease has been repeatedly reported as being characteristic of pneumonia due to CA-MRSA and has been attributed to the frequent carriage of a variety of virulence factors by these strains, in particular PVL. Recent data, using molecular techniques, including the creation of isogenic strains with and without PVL in a murine model of pneumonia due to CA-MRSA provide strong evidence that this toxin plays a key role in causing severe necrotizing pneumonia as well as in sepsis-related mortality.3 It should be noted, however, that other investigators using similar techniques but with a subcutaneous route of infection, were unable to demonstrate that PVL was of critical importance to the virulence of CA-MRSA.4
Reports such as this one should reinforce in the clinician the need for obtaining specimens for microbiologic diagnosis in patients admitted to hospital with severe and/or complicated CAP or who have failed an initial course of antibiotic therapy. Since there is an inevitable delay in identifying the presence of the infecting pathogen and determining its antibiotic susceptibility, a high index of suspicion for MRSA infection must be maintained in order to ensure the timely administration of appropriate antibiotic therapy. It generally requires 36-48 hours to identify an isolate as being methicillin-resistant. Waiting for this data in a disease in which, as reported in this series, the median duration from onset of symptoms to death is only 3.5 days is likely to represent a fatal delay. Only 4 of the patients in this report initially received antibiotics with reasonably reliable activity against MRSA (vancomycin in 3, each with other antibiotics, and trimethoprim-sulfamethoxazole in one). Nonetheless, while the single recipient of trimethoprim-sulfamethoxazole survived, 2 of the 3 vancomycin recipients died, with the single exception among vancomycin recipients being a patient who was also given gentamicin. Thus, it is critical that clinical clues on presentation be recovered in order to institute appropriate antibiotic therapy immediately. Suspicion of MRSA infection should be foremost in patients with risk factors for healthcare- associated infection, skin infections or exposure to someone with MRSA skin infections, and the presence of severe illness manifested by such things as multilobar pneumonia, necrotizing pneumonia or shock. While the current recommendation for both healthcare-associated and community-associated pneumonia due to MRSA is to administer either vancomycin or linezolid, accumulating information suggests that vancomycin is a relatively ineffective agent against S. aureus.5,6 Furthermore, although the scientific validity of the analysis has been questioned, a retrospective post hoc subset analysis of 2 randomized clinical therapeutic trials in patients with healthcare-associated MRSA pneumonia reported improved survival in linezolid recipients relative to those treated with vancomycin.7
The 2 fatalities in vancomycin recipients also received ceftriaxone, as did most of the patients receiving initial regimens not containing vancomycin.8 Evidence, unfortunately, indicates that exposure of S. aureus to subinhibitory concentrations of another beta-lactam antibiotic, nafcillin, induced mRNA for PVL, alpha-toxin, and toxic shock syndrome toxin 1 and increased toxin production. Exposure to either of the protein synthesis inhibitors, linezolid or clindamycin, on the other hand, suppressed translation of the toxin genes. Thus, administration of beta-lactam antibiotics to patients with MRSA infection could theoretically worsen outcome, making the initial therapeutic choice even more crucial.
While earlier CA-MRSA isolates were mostly susceptible to respiratory fluoroquinolones, resistance to these agents is becoming increasingly common. Thus, the 2 most commonly utilized empiric regimens for hospitalized patients with CAP of unknown etiology, a fluoroquinolone (usually levofloxacin or moxifloxacin) or ceftriaxone plus azithromycin, lack activity against many or all, respectively, CA-MRSA.
References:
- Hageman JC, et al. Severe community-acquired pneumonia due to Staphylococcus aureus, 2003-04 influenza season. Emerg Infect Dis 2006; 12:894-899.
- Bhat N, et al. Influenza-associated deaths among children in the United States, 2003-2004. N Engl J Med. 2005; 353:2559-2567.
- Labandeira-Rey M, et al. Staphylococcus aureus Panton-Valentine leukocidin causes necrotizing pneumonia. Science. 2007; 315:1130-1133.
- Voyich JM, et al. Is Panton-Valentine leukocidin the major virulence determinant in community-associated methicillin-resistant Staphylococcus aureus disease? J Infect Dis. 2006; 194:1761-1770.
- Deresinski SC. Vancomycin: does it still have a role as an antistaphylococcal agent? Expert Rev Anti-Infect Ther, in press.
- Deresinski SC. Vancomycin and Staphylococcus aureus: An Antibiotic Enters Obsolescence. Clin Infect Dis, in press.
- Wunderink RG, et al. Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia. Chest. 2003; 124:1789-1797.
- Stevens DL, et al. Impact of antibiotics on expression of virulence-associated exotoxin genes in methicillin-sensitive and methicillin-resistant Staphylococcus aureus. J Infect Dis. 2007; 195:202-211.
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