Thursday, January 9, 2025
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Nearly 5 decades have passed since the initial reports of methicillin-resistant Staphylococcus aureus (MRSA) infections.[1,2] Since then, the epidemiology of MRSA infections has changed dramatically.[3] Initially, MRSA was almost exclusively a nosocomial pathogen, and even today healthcare-associated MRSA (HA-MRSA) infections remain a significant challenge. The proportion of nosocomial S aureus infections demonstrating methicillin resistance nearly doubled, increasing from 36% to 64% between 1992 and 2003.[4-6] Although prevention, control, and management of HA-MRSA infections remain problematic, community-associated MRSA (CA-MRSA) infections have emerged as an increasingly prevalent and serious problem. Skin and soft-tissue infections are the most common type of CA-MRSA infection in the United States.[7,8] Although it has garnered appropriate attention as a troublesome cause of serious cutaneous disease, CA-MRSA infections also cause invasive disease, including pneumonia.[9] Indeed, although S aureus was historically an infrequent cause of community-acquired pneumonia (CAP), a number of reports from the past decade suggested that the incidence and prevalence of CA-MRSA-related CAP may be increasing.[10-15]
This case highlights the potential virulence of S aureus, and its ability to cause life-threatening, hemorrhagic, and necrotizing CAP. Although he was an active smoker and a heavy drinker, this patient was otherwise well until he developed respiratory symptoms that rapidly progressed over a very short period of time, requiring endotracheal intubation, mechanical ventilation, and aggressive supportive care in the intensive care unit. Given his dramatically abnormal radiographic findings and an overwhelming acute illness of uncertain etiology, he was scheduled for exploratory surgical evaluation. Upon exploration, it was found that pulmonary parenchymal necrosis had progressed to the extent that pneumonectomy was necessary. Although the patient eventually recovered completely, his hospital course was protracted, and the medical expense of his care was assuredly significant.
Fortunately, CA-MRSA-related CAP remains relatively rare. Nevertheless, this case shows that CA-MRSA-related CAP can affect otherwise healthy persons who have none of the "classic" risk factors for MRSA infections. The challenge to the busy clinician is to identify people with epidemiologic risk factors, signs, symptoms, and laboratory and radiographic findings suggestive of possible CA-MRSA-related CAP so that appropriate empiric therapy and supportive care interventions can be promptly implemented.
Invasive methicillin-resistant Staphylococcus aureus (MRSA) infections, including bacteremia, pneumonia, endocarditis, osteomyelitis, septic arthritis, and meningitis, are relatively common and have been well described. Indeed, Klevens and colleagues found that the standardized incidence rate of invasive MRSA infections for calendar year 2005 was 31.8 cases per 100,000 Americans, suggesting that MRSA causes more invasive disease than Streptococcus pneumoniae, Streptococcus pyogenes, Neisseria meningitidis, and Haemophilus influenzae combined.[9,16] Aside from bacteremia, pneumonia was the most common (13.3%) type of invasive disease.[9] Although 85% of the cases of pneumonia in Klevens' report were healthcare-associated pneumonia (HAP), 15% were community-associated pneumonia (CAP), suggesting that community-associated MRSA (CA-MRSA) has emerged as a worrisome cause of CAP.[3] Further, whereas recent hospitalization, residence within a long-term care facility, chronic hemodialysis, recent surgery, and the presence of an indwelling foreign body have been identified as risk factors for MRSA infection, as many as 80% of patients with S aureus CAP have no apparent underlying risk factors for severe pulmonary disease or MRSA infection.[9,12,17]
From an epidemiologic perspective, an interesting question to consider is whether the increased incidence of CA-MRSA pneumonia is due to the finding that the majority of isolates of the most common CA-MRSA genotype within the United States carry the gene for Panton-Valentine leukocidin (PVL).[7,15] PVL is a toxin that forms pores in leukocyte membranes, resulting in the release of inflammatory mediators and, ultimately, cell death. Whether PVL is a MRSA virulence factor, or whether it is simply a marker of virulent MRSA strains, is a matter of ongoing and fierce debate that is beyond the scope of this article, although PVL has been shown to cause necrotizing pneumonia in experimental models.[18-21]
However, the role of PVL in S aureus pneumonia is of clinical interest because Gillet and colleagues showed that some cases of pneumonia caused by PVL-positive S aureus strains are more likely to be associated with severe disease (eg, sepsis and hemorrhagic necrosis) and death compared with pneumonia caused by PVL-negative S aureus strains, regardless of whether the S aureus isolate is methicillin sensitive or methicillin resistant.[22] Gillet and colleagues also reviewed a series of 50 cases of necrotizing CAP due to PVL-positive S aureus and found that only 6 of the 50 isolates demonstrated methicillin-resistance.[17]
As noted above, in the United States the vast majority of isolates of the most prevalent CA-MRSA genotype carry the gene for PVL. Thus, to some extent, the term "CA-MRSA" in the United States implies the presence of PVL. This most common genotype is the most common cause of both CA-MRSA skin and soft-tissue infections (SSTI) and CA-MRSA pneumonia in the United States.[7,12]
Clinicians should keep in mind, however, that the presence of PVL (and/or other bacterial virulence factors) -- and not methicillin resistance per se -- may be the primary risk factor for severe CA-MRSA pneumonia. Further, as the distinct lines between CA-MRSA and healthcare-associated MRSA (HA-MRSA) continue to blur, clinicians should also note that many patients who would be defined as having HA-MRSA on the basis of the epidemiologic risk factors noted above are, in fact, found to have S aureus isolates with molecular characteristics commonly associated with CA-MRSA strains.[23] In addition to being of epidemiologic interest, these points may have significant implications for treatment.
Another clinically relevant epidemiologic finding is that influenza virus infection can predispose to the development of a secondary bacterial (S aureus) pneumonia.[24-31] Indeed, the cases of severe S aureus CAP reported in the largest American series to date were collected during the influenza season, and up to 71% of patients in these series had laboratory-confirmed influenza.[12,14] As such, secondary CA-MRSA pneumonia should be considered a diagnostic possibility in any patient seeking medical attention after experiencing a recent upper respiratory tract infection, regardless of whether a diagnosis of influenza virus infection has been objectively confirmed.
Two additional related points are of interest. First, clinicians should note that many of the patients in the recently reported case series of CA-MRSA pneumonia demonstrated a rapidly progressive, monophasic clinical deterioration within days of symptom onset, much like the patient discussed in the video vignette shown earlier.[13,14] Although questions in regard to a history of an influenza-like illness should be asked, clinicians should be aware that, unlike what is classically described, the viral syndrome may occur concurrent with -- not prior to -- CA-MRSA pneumonia.[13] Second, it is worth noting that Klevens and colleagues found no seasonal clustering of cases in the subset of patients with CA-MRSA pneumonia.[9] Consistent findings from a single-center case series have been published.[32] Together, these findings suggest that an antecedent or concurrent viral infection is not a sine qua non for CA-MRSA pneumonia.
Another point of potential interest is whether there is any personal history of SSTI consistent with or confirmed as a CA-MRSA infection, and any such history among intimate contacts may be of interest as well. Neither of the largest American case series of S aureus pneumonia systematically collected data on the prevalence of SSTI among study participants (or their intimate contacts), although both reported some history of SSTI among participants.[12,14] The extent to which comorbid medical conditions increase the risk for S aureus CAP is unknown, although, as noted earlier, S aureus pneumonia among persons with no apparent medical comorbidities has been well described.[12,14]
Describing the most common clinical features of CA-MRSA pneumonia in 2010 is challenging, partly because this is not a reportable illness. Therefore, information in regard to common clinical presentations must be gleaned from published case reports, which may be subject to a bias of reporting only the most severe cases. Further, clinicians should remember that S aureus is an uncommon cause of pneumonia, and traditional pathogens should be strongly considered as the most likely causes of CAP until culture data suggest otherwise. Nevertheless, given the recent reports documenting CA-MRSA as a cause of severe pneumonia, CA-MRSA should be included in the differential diagnosis for any patient seeking medical attention for what appears to be a moderate-to-severe CAP.
Fever is the most common presenting sign, although other signs of sepsis (eg, tachycardia, hypotension, tachypnea) may be present. Other symptoms vary, with cough, dyspnea, myalgia, and sore throat being among the most common.[12,14] The majority of patients described in published case series developed respiratory failure necessitating endotracheal intubation and mechanical ventilation. Whether this is true of all cases of CA-MRSA pneumonia, or whether it reflects reporting bias, is not clear. Hemoptysis is not uncommon. It was present in 44% of cases in one series, but was found to be a poor prognostic sign.[17] No pathognomonic physical examination findings have otherwise been described. Any patient presenting for medical care with some combination of these findings should undergo prompt evaluation to identify the culprit organism. In addition to routine laboratory and radiologic evaluations, blood and sputum should be collected for culture. If the patient has an endotracheal tube, a deep endotracheal specimen and/or bronchoalveolar lavage fluid should be collected for Gram stain and culture.[10]
No laboratory findings are particularly suggestive of severe CA-MRSA pneumonia. Patients are equally likely to manifest leukocytosis as leukopenia, although leukopenia has been shown to be a very poor prognostic sign in multiple series.[14,17] Radiographic findings are variable. Although cavitary disease was reported as a common radiographic finding in both early and more recent case series, other series have suggested that multilobar infiltrates may be the most common radiographic manifestation.[14,17,24,32] Therefore, although cavitary disease should raise concern for the possibility of staphylococcal pneumonia, its absence should not preclude consideration of this possibility. Pleural effusions are detected in roughly 30%-50% of cases and should prompt thoracentesis to exclude empyema, given the frequency of this complication.[12,14,17]
The Infectious Diseases Society of America and American Thoracic Society (IDSA/ATS) consensus guidelines on the management of CAP in adults recommend that persons with CA-methicillin-susceptible S aureus pneumonia be treated with an antistaphylococcal penicillin (eg, oxacillin or nafcillin); recommended alternative agents include cefazolin and clindamycin.[10] Empiric therapy for possible CA-MRSA in persons with severe pneumonia is also recommended, particularly during the influenza season and/or when there is evidence of gram-positive cocci in clusters on the Gram stain of an endotracheal aspirate or an adequate sputum specimen.[10] Optimal treatment of CA-MRSA pneumonia is an area of active investigation. The IDSA/ATS guidelines recommend empiric treatment with vancomycin or linezolid when CA-MRSA is suspected, and that one of these agents be prescribed if MRSA is confirmed as the culprit pathogen. Sulfamethoxazole/trimethoprim is recommended as an alternative agent, and the author recommends clindamycin when susceptibility is confirmed.[10]
Whether vancomycin or linezolid is superior for the treatment of CA-MRSA pneumonia is not known. Concerns have been raised about the effectiveness of vancomycin for the treatment of MRSA pneumonia because of the potential for poor tissue penetration and the relatively high rates of treatment failure.[33-35] A randomized, double-blind, multicenter study comparing vancomycin with linezolid for the treatment of HAP showed that both agents, when combined with aztreonam, achieved equivalent cure rates.[36,37] A subsequent retrospective, post hoc analysis of the subset of patients with HA-MRSA showed that linezolid (plus aztreonam) achieved better survival and a higher clinical cure rate than vancomycin (plus aztreonam).[38] These findings must be considered in the context of the inherent limitations of post hocsubgroup analyses. Further, whether they apply to persons with S aureus CAP is not clear.[39] A more recent study showed no significant differences between linezolid and vancomycin for the treatment of MRSA ventilator-associated pneumonia.[40] Clinical trials of the comparative effectiveness of vancomycin and linezolid for the treatment of MRSA HAP are ongoing.[41]
Limited data are available in regard to the effectiveness of alternative antimicrobial agents for treatment of MRSA. Daptomycin should not be used for the treatment of pneumonia because it is inactivated by pulmonary surfactant.[42] Unpublished studies of telavancin demonstrated it to be noninferior to vancomycin for the treatment of gram-positive HAP, although this agent does not have US Food and Drug Administration (FDA) approval for treatment of respiratory tract infections.[43] Tigecycline achieves good tissue concentrations in the lung and has FDA approval for the treatment of CAP caused by S pneumoniae, H influenzae, and Legionella pneumophila.[44] Although it is active against MRSA, it is not approved for the treatment of S aureus pneumonia, and one single-center review found tigecycline to be less effective in treating pneumonia than other infections.[45]
Recently published data from an open-label, single-center clinical trial of patients with MRSA HAP suggest that the combination of vancomycin and rifampin may be associated with superior clinical outcomes and lower long-term mortality compared with treatment with vancomycin alone, although subsequent rates of rifampin resistance were high in the subgroup treated with combination therapy.[46] As noted above, if in vitro susceptibility is demonstrated for alternative agents, such as clindamycin, then use of one of these agents should be considered. Clinicians should note, however, that if the S aureus isolate appears susceptible to clindamycin but resistant to macrolide antibiotics (eg, erythromycin), then clindamycin susceptibility should be confirmed with the D-test before this agent is used.
Use of linezolid and clindamycin may be attractive for reasons other than their antimicrobial properties. As mentioned above, data have suggested that some of the pathogenicity of S aureus is rendered by its toxins, including PVL. As such, use of agents, such as linezolid or clindamycin, with antitoxin synthesis effects may be associated with clinical benefit in patients with CA-MRSA pneumonia.[47-50] Vancomycin seems to have no impact on toxin production; for this reason, if vancomycin is used for treatment of a seriously ill patient with CA-MRSA pneumonia, then the clinician might consider adding an agent, such as clindamycin, for its antitoxin synthesis effect.[51] Of interest, subinhibitory concentrations of beta-lactam antibiotics have been shown to increase toxin production.[49,50] Whether additional interventions, such as using intravenous immunoglobulin (IVIg) to try to bind PVL and render it inactive, should be pursued is not known, although in vitro studies and anecdotal clinical reports have suggested a potential benefit of this approach.[52,53]
Given the association between S aureus pneumonia and influenza virus infection, diagnostic testing for concurrent influenza infection should be performed during the influenza season, and antiviral treatment should be provided as indicated. The association between S aureus pneumonia and influenza also highlights the importance of seasonal influenza vaccination for all patients. Some investigators believe that a history of MRSA SSTI is an indication for influenza vaccination, given the possible association between this condition and subsequent respiratory tract infection.[54]
The care of patients with S aureus pneumonia complicated by bacteremia should include the usual evaluations (eg, careful physical examination looking for metastatic foci of infection, echocardiography) pursued as part of the evaluation of persons with S aureus bacteremia. Although antimicrobial management of these patients should be individualized on the basis of the complete clinical scenario, clinicians should keep in mind that vancomycin is the only agent that has FDA approval for treatment of MRSA bacteremia and has demonstrated clinical success in treating MRSA pneumonia. As such, use of vancomycin (with or without an additional agent, such as clindamycin) is recommended for these patients. The patient presented in the video vignette also highlights the critical role that surgeons play in managing infectious complications, such as empyema or extensive pulmonary parenchymal necrosis.
In part, because of these kinds of complicated infections, mortality rates for patients with CA-S aureus pneumonia are high, ranging from 29% to 51% in published case series; a more recent series, however, reported a mortality rate of 13%.[12,14,32]S aureus pneumonia can rapidly progress to critical illness. In addition to implementing the measures discussed above, clinicians might also consider consulting an infectious diseases expert, particularly because improved adherence to standards of care and lower mortality rates have been demonstrated when such consultations are obtained for management of patients with S aureus bacteremia.[51,55]
This case demonstrates the potential severity and rapid clinical progression of CA-MRSA pneumonia that can occur in an otherwise healthy person. Making a diagnosis of CA-MRSA pneumonia is challenging; although microbiological confirmation of the diagnosis is clearly required, a combination of epidemiologic, historical, physical examination, laboratory, and radiographic findings may suggest this diagnosis, particularly in a critically ill patient with rapidly progressive disease. In addition to appropriate supportive care, prompt initiation of antibiotic therapy with activity against CA-MRSA is warranted. Use of either vancomycin or linezolid is appropriate, although strong consideration should be given to an agent with antitoxin synthesis effects (eg, clindamycin) if vancomycin is to be used. Treatment for concurrent influenza should also be provided. Enhanced surveillance and reporting of cases of S aureus pneumonia, combined with the results of clinical trials that are already under way, will provide a more complete picture of the magnitude of this problem and the optimal ways of treating it.
Supported by independent educational grants from Astellas and Genentech Inc.
