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Is Methicillin-Resistant Staphylococcus aureus Pneumonia Epidemiology and Sensitivity Changing?

      Abstract

      Introduction

      Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia poses a deadly threat due to the pathogen’s remarkable resistance and virulence factors. Evidence suggests that the epidemiology and sensitivity to antibiotics for MRSA pneumonia is changing extremely fast, creating the potential for it to become a “super bug.”

      Objective

      To assess the incidence of community-acquired and hospital-acquired MRSA pneumonia in the community hospital at Christus Spohn during a period of 3 years and its reactivity to antibiotic therapy.

      Methods

      The retrospective study was performed using data collected from Christus Spohn Memorial Hospital Corpus Christi inpatient charts between 2006 and 2008. Patients were identified and selected based on positive sputum cultures for MRSA and using Center of Disease Control, American Thoracic Society and Infectious Diseases Society of America guidelines. Patients were then categorized into 2 groups: community-acquired MRSA (CA-MRSA) pneumonia and hospital acquired MRSA (HA-MRSA) pneumonia.

      Results

      Our results indicated increase resistance to clindamycin among both CA-MRSA and HA-MRSA, whereas the sensitivity to trimethoprim/sulfamethoxazole (TMP/SMX) is preserved for both CA-MRSA and HA-MRSA.

      Conclusions

      Resistance to clindamycin has increased over time, but TMP/SMX has preserved its sensitivity against MRSA. TMP/SMX should be revisited as a viable antibiotic option against CA-MRSA and HA-MRSA, specifically against CA-MRSA.

      Key Indexing Terms

      Methicillin-resistant Staphylococcus aureus (MRSA) infection was almost exclusively associated with acquisition from hospitals, nursing facilities, dialysis units, and other healthcare settings where skilled care was provided.
      • Bradley S.F.
      Staphylococcus aureus pneumonia: emergence of MRSA in the community.
      Historically, MRSA has been considered primarily a nosocomial pathogen. Over the last decade, however, its presence as a colonizer or pathogen in residents of long-term care facilities has been noted with increasing frequency.
      • Johnston B.L.
      Methicillin-resistant Staphylococcus aureus as a cause of community-acquired pneumonia—a critical review.
      As the medical community’s understanding of MRSA has evolved, so has the terminology used to classify MRSA infections. This has given rise to the terms community-acquired MRSA (CA-MRSA) and hospital-acquired MRSA (HA-MRSA).
      • Salgado C.
      • Farr B.
      • Calfee D.
      Community-acquired Methicillin resistant Staphylococcus aureus: a meta-analysis of prevalence and risk factors.
      • Kilbane B.J.
      • Reynolds S.L.
      Emergency department management of community-acquired methicillin-resistant Staphylococcus aureus.
      In the United States, reports of CA-MRSA necrotizing pneumonia in healthy children appeared in the late 1990s and were followed by reports of outbreaks of CA-MRSA skin and soft-tissue infections among prison inmates, homosexual men, Native Americans and sports teams. They now occur widely both in communities and health facilities.
      • Hidran A.I.
      • Low C.E.
      • Honig E.G.
      • et al.
      Emergence of community-associated methicillin-resistant Staphylococcus aureus strain USA300 as a cause of necrotising community-onset pneumonia.
      HA-MRSA pneumonia has been a problem in hospital settings since the 1960s; there has since been a progressive increase in the prevalence of antimicrobial resistance in hospital-acquired Staphylococcus aureus infections. In the United States, isolates with methicillin resistance increased from 22% to 57% between 1995 and 2001.

      Boyce JM. Epidemiology of methicillin-resistant infection in adults, UpToDate Available at: www.uptodate.com/contents/epidemiology-of-methicillin-resistant-staphylococcus-aureus-infection-in-adults. Accessed on June 28, 2011.

      The blurring epidemiology distinction between HA-MRSA and CA-MRSA became evident in the United States when the Bacterial Core Surveillance Network reported invasive MRSA infections in 2005. Of the infections, CA-MRSA was found in hospitals more frequently than HA-MRSA. In addition, CA-MRSA may be replacing traditional nosocomial strains.
      An undeniable difference is the distinct genetic findings in HA-MRSA and CA-MRSA. HA-MRSA is linked to SCCmec (Staphylococcus cassette chromosome) type II and type III that enables resistance to non-β lactamase antibiotics.
      • Kilbane B.J.
      • Reynolds S.L.
      Emergency department management of community-acquired methicillin-resistant Staphylococcus aureus.
      They are typified by a USA100 or USA200 pulse-field electrophoresis pattern.

      Boyce JM. Epidemiology of methicillin-resistant infection in adults, UpToDate Available at: www.uptodate.com/contents/epidemiology-of-methicillin-resistant-staphylococcus-aureus-infection-in-adults. Accessed on June 28, 2011.

      CA-MRSA is linked to Sccmec type IV and type V and has been associated with the gene that encodes for Panton Valentin Leucocidin.
      • Tacconelli E.
      • De Angelis G.
      Pneumonia due to methicillin resistant Staphylococcus aureus: clinical features, diagnosis and management.
      Panton Valentin Leucocidin is a staphylococcal toxin known to be associated with tissue necrosis.
      • Hidran A.I.
      • Low C.E.
      • Honig E.G.
      • et al.
      Emergence of community-associated methicillin-resistant Staphylococcus aureus strain USA300 as a cause of necrotising community-onset pneumonia.
      In addition, most CA-MRSA are typified by a USA300 or USA400 pulse-field electrophoresis pattern.

      Boyce JM. Epidemiology of methicillin-resistant infection in adults, UpToDate Available at: www.uptodate.com/contents/epidemiology-of-methicillin-resistant-staphylococcus-aureus-infection-in-adults. Accessed on June 28, 2011.

      In many occasions, the diagnosis is made on the basis of epidemiology, which has changed in the past few years. CA-MRSA risk factors include a person’s residence in an area of low socioeconomic status, intravenous drug abuse and incarceration. Patients with CA-MRSA pneumonia are significantly younger than the typical patient and without significant health problems. CA-MRSA pneumonia is usually preceded by a viral prodrome, similar to influenza or influenza-like illness.
      • Shorr A.F.
      • Haque N.
      • Taneja C.
      • et al.
      The changing epidemiology of non-nosocomial Staphylococcus aureus pneumonia.
      In contrast, HA-MRSA risk factors include steroid use, chronic obstructive pulmonary disease, antimicrobial use in the preceding 90 days and high frequency of antibiotic resistance in the hospital or community.
      • Ganesan A.
      Methicillin-resistant Staphylococcus aureus bacteremia and pneumonia.
      Patients with HA-MRSA are frequently the elderly population and have significant underlying diseases.
      • Rubinstein E.
      • Kollef M.H.
      • Nathwani D.
      Pneumonia caused by methicillin-resistant Staphylococcus aureus.
      Effective antibiotics for the treatment CA-MRSA are usually not a part of the initial empiric antibiotic regimens for community-acquired pneumonia.
      • Moran G.J.
      • Talan D.A.
      MRSA community-acquired pneumonia: should we be worried?.
      Vancomycin remains the first-line antibiotic when CA-MRSA pneumonia is suspected.
      • Ganesan A.
      Methicillin-resistant Staphylococcus aureus bacteremia and pneumonia.
      • Moran G.J.
      • Talan D.A.
      MRSA community-acquired pneumonia: should we be worried?.
      However, the success of therapy is linked to high trough levels of 15 to 20 μg/mL, which could be toxic.
      • Jeffres M.N.
      • Isakow W.
      • Doherty P.S.
      • et al.
      Predictors of mortality for methicillin-resistant Staphylococcus aureus health-care-associated pneumonia.
      The current guidelines give both Vancomycin and Linezolid a A-II recommendation. (A, good evidence to support an evidence; II, evidence from greater than one well-designed clinical trials, without randomization, from cohort or case-control analytic studies [preferably from >1 center])
      • Lam A.P.
      • Wunderink R.G.
      The role of MRSA in healthcare-associated pneumonia.
      • Liu C.
      • Bayer A.
      • Cosgrove S.E.
      • et al.
      Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
      CA-MRSA isolates are also characteristically susceptible to a great number of non-β lactamic antibiotics such as clindamycin, macrolides, trimethoprim/sulfamethoxazole (TMP/SMX), tetracyclines, and fluoroquinolones, although this cannot be implied with the exception of clindamycin for MRSA pneumonia if the isolate is susceptible.
      • Kilbane B.J.
      • Reynolds S.L.
      Emergency department management of community-acquired methicillin-resistant Staphylococcus aureus.
      • Liu C.
      • Bayer A.
      • Cosgrove S.E.
      • et al.
      Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
      The epidemiology and sensitivity to antibiotics for MRSA pneumonia is changing extremely fast, potentiating it to become a “super bug.” In this study, we will describe the epidemiology and sensitivity of MRSA pneumonia at Christus Spohn Memorial Hospital Corpus Christi, Texas.

      METHODS

      Patients were identified by a database search generated in the laboratory at Christus Spohn Memorial Hospital in Corpus Christi, Texas, for positive MRSA sputum cultures from January 1, 2006, to December 31, 2008.
      For the purpose of this investigation, the distinction between colonization and infection, pneumonia was defined based on clinical, radiographic and microbiological criteria. Clinical criteria include a temperature greater than 38°C or 100.4°F with no other recognized cause, white blood cell count <4×103/mL or >103/mL with no other recognized case and exhibiting one or more of the following signs: new onset of purulent sputum, change in the character of the sputum, dyspnea, tachypnea, increased oxygen requirements and increased ventilation demand. Radiographic criteria include lung consolidation within the 72 hours of admission. Microbiologic criteria include sputum or bronchial washing culture positive for MRSA.
      Patients with positive MRSA sputum cultures were selected and further divided into 2 groups: HA-MRSA and CA-MRSA. As we are unable to distinguish HA-MRSA and CA-MRSA through their genetic differences due to limited resources for testing, an alternative method was used. To determine which category patients were placed, guidelines by the Center of Disease Control (CDC), American Thoracic Society and Infectious Diseases Society of America were used.
      In this study, CA-MRSA pneumonia was defined as any individual who had an MRSA infection and lacks the following factors: surgery, hospitalizations or residence in a long-term care facility within the year, presence of a percutaneous device or indwelling catheter, dialysis within the previous year, hospitalization greater than 48 hours before MRSA culture and previous MRSA infection or colonization.
      HA-MRSA pneumonia was defined as infection occurring 48 hours or more after admission, no incubation at the time of admission, any patient who was hospitalized in an acute care hospital for 2 or more days within 90 days of the infection, resident in a nursing home or long-term care facility, patients who received recent intravenous antibiotic therapy or chemotherapy, wound care within the past 30 days of the current infections and patients who have recently attended a hospital or are dialysis patients.
      After patients were identified by the database, we collected pertinent information necessary to distinguish HA-MRSA and CA-MRSA during their hospital admission. This information included their age, medical history, recent hospitalizations, MRSA resistance, and sensitivity to antibiotics and disposition.

      RESULTS

      Review of the charts from January 1, 2006, to December 31, 2008, revealed that 98 patients met the criteria. Of the 98 patients, 24 fulfilled the category of CA-MRSA, whereas 74 patients met the criteria for HA-MRSA. There was no difference in distribution between male and female among CA-MRSA or HA-MRSA. The distribution on the basis of age is presented in Table 1.
      Table 1Showing total number of cases and its distribution based on age and gender
      CA-MRSAHA-MRSA
      Total no.2474
      Male15 (62.5%)46 (62.16%)
      Female9 (37.5%)28 (37.84%)
      Age (yr)No. casesNo. cases
      10–2014
      21–3033
      31–4035
      41–50425
      51–60914
      61–70210
      71–8024
      81–9007
      91–10002
      MRSA, methicillin-resistant Staphylococcus aureus; CA, community acquired; HA, hospital acquired.
      Among the susceptibilities to clindamycin and TMP/SMX, TMP/SMX shows no resistance pattern for both CA-MRSA and HA-MRSA. On the contrary, the resistance patterns were seen for clindamycin between both CA-MRSA and HA-MRSA. The resistance for clindamycin was much higher for HA-MRSA, but almost 37.5% of CA-MRSA also showed resistance as presented in detail in Table 2.
      Table 2Illustrating sensitivity and resistant patterns for CA-MRSA and HA-MRSA
      Clindamycin RClindamycin SRifampin RRifampin STMP/SMX RTMP/SMX SVancomycin RVancomycin S
      CA MRSA9 (37.5%)15 (62.5%)0 (0%)24 (100%)0 (0%)24 (100%)0 (0%)24 (100%)
      HA-MRSA42 (56.75%)32 (43.25%)5 (6.75%)69 (93.25%)0 (0%)74 (100%)0 (0%)74 (100%)
      R, resistant; S, sensitivity; MRSA, methicillin-resistant Staphylococcus aureus; CA, community acquired; HA, hospital acquired; TMP, trimethoprim; SMX, sulfamethoxazole.

      DISCUSSION

      Based on the January 4, 2011, “Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections in Adults and Children,” empiric MRSA treatment should be considered for hospitalized patients with severe community-acquired pneumonia requiring intensive care unit admission, patients who have necrotizing or cavitary infiltrates or patients who have an empyema. This is particularly true in the context of a preceding or concurrent influenza-like illness.
      • Liu C.
      • Bayer A.
      • Cosgrove S.E.
      • et al.
      Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
      The guidelines recommend 3 agents for use: Vancomycin (AII), Linezolid (AII) or Clindamycin (B-III), (B, moderate evidence to support a recommendation; III, evidence from opinions of respected authorities, based on clinical experience, descriptive studies or reports of expert committees) if susceptible. The recommended duration of therapy is 7 to 14 days and depends on the extent and resolution of the infection.
      • Liu C.
      • Bayer A.
      • Cosgrove S.E.
      • et al.
      Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
      We believe that TMP/SMX could be a viable option in MRSA pneumonia, although additional studies will be needed to determine its role in this indication. The in vitro data for TMP/SMX against CA-MRSA shows a susceptibility of 95% to 100%
      • Fridkin S.K.
      • Hageman J.C.
      • Morrison M.
      • et al.
      Methicillin-resistant Staphylococcus aureus disease in three communities.
      • Naimi T.S.
      • LeDell K.H.
      • Como-Sabetti K.
      • et al.
      Comparison of community-and health care-associated methicillin-resistant Staphylococcus aureus infection.
      and has been an effective prophylactic for MRSA ventilator-associated pneumonia in burn patients.
      • Kimura A.
      • Mochizuki T.
      • Nishizawa K.
      • et al.
      Trimethoprim-sulfamethoxazole for the prevention of methicillin-resistant Staphylococcus aureus pneumonia in severely burned patients.
      Our data represent 100% susceptibility for both CA-MRSA and HA-MRSA strains. The activity of TMP/SMX can be explained by its rapid bactericidal effect resulting in a >2 log10 cfu/mL decrease at 8 hours and a >3 log10 cfu/mL decrease at 24 hours.
      • Diep B.A.
      • Gill S.R.
      • Chang R.F.
      • et al.
      Complete genome sequence of USA 300, an epidemic clone of community-acuired methicillin-resistant Staphylococcus aureus.
      Overall, TMP/SMX showed no difference in its in vitro activity against HA-MRSA and CA-MRSA.
      • Diep B.A.
      • Gill S.R.
      • Chang R.F.
      • et al.
      Complete genome sequence of USA 300, an epidemic clone of community-acuired methicillin-resistant Staphylococcus aureus.
      • Kaka A.S.
      • Rueda A.M.
      • Shelburne 3rd, S.A.
      • et al.
      Bactericidal activity of orally available agents against methicillin-resistant Staphylococcus aureus.
      TMP/SMX has been evaluated in other invasive pneumonias such as Stenotrophomonas maltophilia and Pneumocystis jiroveci pneumonia. One randomized control trial has indicated its potential efficacy in treating invasive staphylococcal infections, such as bacteremia and endocarditis.
      • Markowitz N.
      • Quinn E.L.
      • Saravolatz L.D.
      Trimethoprim-sulfamethoxazole compared with vancomycin for the treatment of Staphylococcus aureus infection.
      Other invasive infections such as MRSA pneumonia should be studied to evaluate its potential in vivo. Being a single-center retrospective study and looking only at the epidemiology and reactivity changes suggest the need for prospective study, where beside these factors looking at the outcome data on the basis of treatment received can provide more valuable information.

      CONCLUSION

      MRSA in the past has been primarily known as a nosocomial pathogen, affecting adult intensive care and neonatal care units. As the organism has evolved, many surveillance surveys have identified it in community settings outside the normal risk factors for acquisition. With the rise of MRSA infections in the community, several surveys and expert communities, including the CDC, have brought forth 2 different classifications: HA-MRSA and CA-MRSA. Differences are mainly in the gene subtypes, USA100 and 200 isolates being of a health care associated nature. USA300 and 400 are mainly community-acquired isolates. As this organism has evolved outside the boundaries of the healthcare silos, so has its virulence factor. We are plagued with a continuous battle with the organism and are faced with the fact that this despite newer and older agents will continue to evolve. We are seeing this evolution now and believe that it will become very difficult to differentiate the strain of MRSA due to its ability to transfer genes between the subtype isolates. The CDC has recently published MRSA guidelines for adult and pediatric patients, but there are still tremendous areas of unknown research, particularly in pneumonia.

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