3.
Abbreviations
BAL: Bronchoalveolar
Lavage
CINAHL: Cumulative
Index to Nursing & Allied Health Literature
COI: Conflict
of Interest
ICD-9: International
Classification of Diseases, Ninth Revision
ICU: Intensive
Care Unit
IV: Intravenous
MIC: Minimum
Inhibitory Concentration
MRSA: Methicillin-resistant
Staphylococcus aureus
MSOF: Multisystem
Organ Failures
PICOT: Patient,
Intervention, Comparison, Outcome, Time
PO: Per
Oral (Oral)
VAP: Ventilator-Associated
Pneumonia
VRE: Vancomycin-Resistant
Enterococci
4.
Introduction
In
patients diagnosed with MRSA pneumonia, which drug-linezolid or vancomycin-is
superior to the other in reducing mortality? In this PICOT-formatted question,
the “P” stands for the Patient Population; this includes
patients
diagnosed with MRSA pneumonia. The “I” stands for Intervention; this refers to
the antimicrobial
medications
in question. The “C” stands for Comparison; which represents the comparison
between linezolid and vancomycin. The “O” stands for the outcome; which is to
reduce mortality. The “T” stands for Time; the time it takes for the
intervention to achieve an outcome or how long the participants are observed.
In
January 2014, twenty studies were reviewed for relevance. Search engines
utilized included Google Scholar, PubMed, Medline, and CINAHL (Cumulative Index
to Nursing & Allied Health Literature). Keywords included “MRSA”, “MRSA
pneumonia”, “vancomycin”, “linezolid”, and “Zyvox”. Search phrases included
“MRSA and pneumonia”, “vancomycin versus linezolid and MRSA and pneumonia”,
“vancomycin and linezolid and MRSA and pneumonia”, “vancomycin and MRSA and
pneumonia”, and “linezolid and MRSA and pneumonia”. From the initial twenty
studies, the search was narrowed resulting in the selection of three articles
that were recent and relevant and included a comparison of linezolid and vancomycin
for MRSA pneumonia.
The
studies chosen had designs that observed the outcomes of linezolid and
vancomycin in subjects with proven MRSA infection by culture or inoculation of
a known pathogen, and were published five or fewer years ago.
Research
was excluded if the free full-text versions were not available. Papers were
omitted if they were
published
more than five years ago. (Note: The study by Wunderink et al.
(2008) [3]
was published in
December
2008; the initial search was done in early January 2014 which dates the
publication at precisely five years.) The research needed to include human
subjects. Investigations were excluded if they did not include
human
subjects or if linezolid or vancomycin were not statistically compared. Papers
were rejected if their
“limitations
of research” proved problematic or if any “Conflict of Interest” (COI)
statement seemed suspect in influencing the results; and in the case of one
dismissed article, the COI statement was absent from the
publication.
5.
Discussion
The
three peer-reviewed articles chosen are cited below for easy reference.
Caffrey AR, Quilliam BJ, LaPlante K L,
(2010) Comparative effectiveness of Linezolid and vancomycin among a cohort of
patients infected with methicillin-resistant Staphylococcus aureus. Antimicrobial Agents and Chemotherapy
54: 4394-4400 [4].
Wunderink
RG, Mendelson MH, Somero MS, Fabian TC, May AK, et al. (2008). Early
microbiological
response
to linezolid vs. vancomycin in ventilator-associated pneumonia due to
methicillin-resistant
Staphylococcus
aureus.
Chest 134: 1200-1207 [3].
Wunderink RG, Neiderman MS, Kollef MH,
Shorr A F, Kunkel M J, et al. (2012). Linezolid in
methicillin-resistant Staphylococcus aureus nosocomial
pneumonia: A randomized, controlled study. Clinical Infectious Disease 54:
621-629 [2].
The discussion that follows is formatted
into two sections: “Description and Findings” of each study and
“Critical Analysis and Comparison” for
each study; followed by a Summary and Conclusion.
The Caffrey, Quilliam,
and LaPlante (2010) [4] Study-Description and Findings.
The
Caffrey et al. (2010) [4] research examined
retrospectively the efficacy of linezolid versus vancomycin in 20,107 patients
with MRSA infections, with the exclusion of VRE and endocarditis [4]. Patients were
included based on medical records review and ICD-9 codes. The evaluation was
based on clinical outcomes with the two antibiotics and then compared
statistically. Parameters examined included length of time to discharge, time
to discontinuation of therapy, survival time, and 90-day readmission. The
results revealed linezolid was associated with less time to discharge than
vancomycin (6 days versus 9 days, p < 0.001), longer time to discontinuation
of therapy with linezolid than vancomycin (16 days versus 13 days, p <
0.001), and average survival time and
90-day
readmission were not significantly different between the two groups [4].
The
Wunderink et al. (2008) [3] Study-Description
and Findings.
The
Wunderink et al. (2008) [3] research evaluated
100 patients with culture-proven MRSA ventilator-associated pneumonia (VAP)
obtained from bronchoalveolar lavage (BAL) from November 2002 to January 2005 [3]. Patients
received vancomycin or linezolid (both optimally dosed based on trough levels).
If the culture from BAL confirmed MRSA, patients were analyzed and
compared in both groups. Patients who died were analyzed as a separate group.
The study found that, although the differences in the parameters were not
significant, linezolid was associated with increased microbiological cure
rates, clinical cure rates, survival rates, and time spent alive not on a
ventilator; and decreased mean duration of ventilation, hospitalization, and
days of ICU stay. A notable finding was none of
the patients treated with linezolid died, but five of the patients treated with
vancomycin died (p = 0.03). Although the difference in deaths was suggestive,
the researchers
determined at the time that non-inferiority between linezolid
and vancomycin could not be established because the power (N=10 for each group)
was inadequate [3].
The
Wunderink et al. (2012) [2] Study-Description
and Findings.
The
Wunderink et al. (2012) [2] research included
1,225 patients with culture-positive MRSA pneumonia and significant clinical signs
and symptoms; examined internationally from October 2004 to January 2010 [2].
Patients
were randomly assigned to receive optimally-dosed vancomycin or optimally-dosed
linezolid and were evaluated by researchers every 72 hours for clinical signs
and symptoms, chest x-ray findings, and sputum
culture
results. The two groups were analyzed and compared. Results showed that, by the
end of the study,
linezolid
was associated with a higher clinical cure rate than vancomycin (p = .042).
Vancomycin was linked to a higher incidence of nephrotoxicity than linezolid
(18.2% versus 8.4%). Mortality at 60 days was similar
between
the two groups (15.7% linezolid, 17% vancomycin) [2].
The Caffrey et al.
(2010)
[4] Study-Critical
Analysis and Comparison.
The
research by Caffrey et al. (2010) [4] included a
considerable number of human subjects (20,107) which is a strength of this
study. Moreover, no variables were manipulated; it was pure observation. For
these reasons, this study was chosen. However, a recognized weakness in the investigation was the use of ICD-9 codes for
inclusion criteria. ICD-9 codes, alone, do not prove that a subject had
MRSA as cultures may have been negative or not taken. Also,
although it was stated that VRE and endocarditis were excluded, it was not
reported what
percentage of the patients had MRSA pneumonia versus other MRSA
infections. In
contrast, the other two
studies
reported herein take into account culture-proven MRSA in patients with high
clinical suspicion.
The
results appear straightforward, except for certain findings. It makes sense
that time to discontinuation of therapy was longer with linezolid than with
vancomycin since linezolid had an oral (PO) formulation for MRSA infections
while vancomycin did not. Thus, linezolid subjects could continue with oral
linezolid as outpatients while intravenous (IV) vancomycin patients, when
discharged, had no non-extemporaneous PO vancomycin available to them, and
treatment would have ended. Linezolid having had a PO formulation and vancomycin
having none may have also contributed to the difference in discharge time as
patients receiving linezolid may have been discharged with a PO formulation but
those patients receiving vancomycin may have remained
admitted
with an IV formulation [4].
It
is abstruse, however, that in some matched groups examined with “infections not
specified”, the readmission rates for linezolid were higher. Had the
researchers been able to delineate which specific infections were
included
in this “infections not specified” group, this characterization may have
ascribed more meaning to this finding and provided more relevant information.
One consideration that this study did not account for was
vancomycin
trough levels [4].
In contrast, the other two studies monitored vancomycin trough levels, and
optimized
its dose. In MRSA infections, excluding VRE and endocarditis, it can be
inferred from this study that vancomycin (trough levels unknown) and linezolid
(trough levels not tested) were similar regarding mortality, given that
differences in survival were not statistically significant.
The
Wunderink et al. (2008) [3] Study-Critical
Analysis and Comparison.
The
research by Wunderink et al. (2008) [3] has several
strengths including its design. In contrast to the research done by Caffrey
et al. (2010) [4],
this study allowed its variables to be accounted for and manipulated. Due to
the strength of a clinical trial, this report and the Wonderink
et al. (2012) [2]
report were chosen. Another apparent strength of this study is that MRSA was
proven on cultures obtained by BAL. BAL-derived cultures tend to be more
accurate than standard sputum cultures since the specimen in BAL is obtained
directly from the
affected
lung tissue [3].
In
contrast, sputum cultures–such as those obtained in Wunderink
et al. (2012) [2]–tend
to be less accurate as they may be colonized with multiple organisms not
necessarily involved in the infectious process. On the other hand, BAL is
invasive and expensive and requires a trained clinician to perform the
procedure; the authors
attributed
these factors for why relatively few patients were included in the 2008 study [3]. The low number
of participants, a total of 100 (with 50 being culture-positive for MRSA), is a
weakness in this study; the authors of the study acknowledged this fact [3].
Nonetheless, linezolid outperformed
vancomycin on the parameters mentioned above even when vancomycin was
optimally-dosed based on trough levels. Interpretation of the results was
consistent with the study
population and findings, except for one
finding that the authors considered statistically significant rather than
suggestive–the number of deaths in each
group (as previously pointed out). The authors of the study described this as a
50% increased risk of death if the patient was treated with vancomycin. While
this description is
technically correct, from this small study
group it cannot be applied to the general population in the way the
authors proposed. Their assumption is also in doubt due to
conflicting results reported by other
researchers.
Furthermore, the authors attributed death
to microbiological response failure which infers that the MRSA was resistant to
vancomycin; this is still a rare occurrence [1]. While
this scenario is possible, it is unlikely that all five patients died due to
vancomycin resistance. Death in patients with MRSA pneumonia is more likely to
be caused by inflammation, such as myocardial infarction or multisystem organ
failure (MSOF).
The
Wunderink et al. (2012) [2] Study-Critical
Analysis and Comparison.
The research by Wunderink
et al. (2012) [2]
investigated non-ventilated patients with MRSA pneumonia rather than ventilated
patients with MRSA pneumonia as in the Wunderink et al. (2008) [3] research. The
methods were similar, with the difference that sputum cultures were obtained
rather than cultures by BAL. The sputum cultures were collected by a variety of
researchers which, theoretically, could have impacted the results of the
cultures. While this Wunderink et al. (2012) [2] study did not
include as many subjects as the study by Caffrey
et al. (2010) [4],
it did have a larger population than the Wunderink et al. (2008) [3] study and is,
therefore, stronger in that regard.
The results of the Wunderink
et al. (2012)
[2] study
are compatible with the other two studies. Linezolid tended to outperform
vancomycin regarding clinical cure rates. The mortality rates were slightly
different between the two groups, but not
statistically significant [2].
The results, interpreted by the authors, seem consistent with the findings. The authors went
on to state that the differences in the results may have been due to the
increasing MICs of vancomycin. While vancomycin may still prove useful, the
MICs for linezolid, at the time, were lower and resulted in enhanced clinical
and microbiological cure rates [2].
6.
Summary
of the Selected Studies
The
findings of the three selected studies contribute to answering the PICOT
question posed in the Introduction.
In
patients diagnosed with MRSA pneumonia, which drug–linezolid or vancomycin–is
superior to the other in reducing mortality? All three studies, although
factorially distinct, demonstrated consistency in their results. Neither
antibiotic was superior to the other regarding mortality in treating patients
with MRSA pneumonia (as non-inferiority between the two drugs could not be
established). However, trends showed that linezolid was
associated
with better rates of microbiological cure, among other parameters. It is
appreciable that none of the three studies showed vancomycin associated with a
higher microbiological cure rate than linezolid; linezolid outperformed
vancomycin in that regard.
Docobo-Perez et al. (2012) [1] concluded that
clinical differences in vancomycin and linezolid were due to the changing MICs
of vancomycin over time. This conclusion seems to explain the results of the
studies reviewed herein. Wunderink et al. (2012) [2] referred to a
similar conclusion. Also, as discussed above, vancomycin tends to be associated
with a higher incidence of renal failure than linezolid.
Among the three studies, the
beneficial findings regarding linezolid were
shorter hospital stay with p < 0.001 (Caffrey et al., 2010) [4], higher clinical cure rate
with p = 0.042 (Wunderink et al., 2012) [2], and no deaths
occurred with linezolid in
patients with VAP with p = 0.03 [3]. Despite these findings, again, there was no
mortality advantage noted
with linezolid versus vancomycin that was
statistically significant.
Linezolid performed better
than vancomycin in microbiological cure rates (56.5% vs. 47.4% p = 0.757),
clinical cure rates (66.7% vs. 52.9%), survival rates (86.7% vs. 70%), mean
duration of ventilation (10.4 vs. 14.3 days), hospitalization (18.8 vs. 20.1
days), days in ICU (12.2 vs. 16.2 days), and time spent alive while not
receiving ventilation (15.5 vs. 11.1 days) [3].
In
Wunderink et al. (2012) [2], linezolid was associated
with lower rates of nephrotoxicity (18.2% with
vancomycin
and 8.4% with linezolid) and lower mortality at 60 days (17% with vancomycin
and 15.7% with linezolid). Wunderink et al. (2012) [2] stated the clinical cure rate as significant (p =
0.042) while Wunderink et al. (2008) [3] reported it was not.
7.
Conclusion
If
MICs are increasing for vancomycin (and recent studies are suggesting such),
this antibiotic could be reserved for patients who are clinically stable. It
takes time to achieve effective trough levels, and patients, critically ill
with MRSA pneumonia, can decompensate quickly. Clinically stable patients show
fewer tendencies in
developing
renal failure; thus, vancomycin could be prescribed for this population. Vancomycin could be
considered for noncritical
cases with no renal compromise.
In
patients with overt renal failure, vancomycin should be avoided as the
incidence of renal failure is
dramatically
increased with vancomycin. If vancomycin is dosed all of the time
appropriately, it can be inferred that microbiological cure rates may stabilize
with vancomycin over time. However, concerning trough levels, vancomycin is
problematic to dose and requires thorough monitoring. These characteristics are
exacting and may result in the rejection of the usage of vancomycin in the
future.
Given
that mortality rates appear similar between the two drugs; linezolid is
indicated over vancomycin for
critically
ill patients with suspected MRSA. Linezolid levels do not require detailed
monitoring. More effective dosing will likely occur with linezolid than
vancomycin; this may add to better outcomes with linezolid.
Based on the evidence presented from the three selected
papers and a review of numerous external articles and studies, clinicians are
best advised that–although neither of the two antibiotics was superior to the
other regarding mortality–linezolid outperformed vancomycin even when the
latter drug wass optimally-dosed. Linezolid was associated with enhanced outcomes, such as fewer
side effects, easier dosing, higher clinical and
microbiological cure rates,
and shorter ICU stays.
Further
research is needed to more accurately access why mortality rates of linezolid
and vancomycin were
similar
while microbiological cure rates among other outcomes were superior with
linezolid. MIC trends should be studied and compared in these two
antibiotics for different strains of MRSA in different geographical
regions. Studies evaluating MICs of
linezolid and vancomycin in animal models have found that MICs tended to be
lower with linezolid due to heightened lung tissue perfusion. Nonetheless,
these results should be replicated in human subjects, preferably in clinical
trials, so that mortality can be assessed based on MICs; in addition to
clinical outcomes and microbiological cure rates.
This paper focuses on treatment
considerations between linezolid and vancomycin in the confirmed presence of
MRSA pneumonia. By design, it does not discuss the procedures or protocol to
diagnose MRSA pneumonia which is, deservedly, a distinct review. However, it
seems appurtenant to note that MRSA pneumonia can only be diagnosed in the
presence of pneumonia. Obtaining cultures when pneumonia is not likely may lead
to
ambiguous results. MRSA can colonize
multiple sites, including the upper airways, in normal, healthy patients
without disease. MRSA coverage remains a clinical decision that may take into
account multiple factors.
8. Acknowledgments
None.
9. Conflict of Interest Statement
The
authors declare that this paper was written in the absence of any commercial or
financial relationships that could be construed as a potential conflict of
interest.
perspective