Recent advances in Staphylococcus aureus bacteremia

Translated by Wang Bo, No.
903 Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army

objective

Review of recently published evidence
associated with Staphylococcus aureus bacteremia (SAB).

Recent discoveries

Staphylococcus aureus is the most common pathogen
that causes co-infection and superinfection in patients with new coronary pneumonia.
During the pandemic, the rate of bacteremia resistant to Staphylococcus aureus (MRSA) increased
dramatically.
The mortality rate of SAB is 18% at 1 month and 27% at 3 months, but has gradually decreased
over the past 30 years.
Relapse and reinfection are common (9%)
.
Standardized items to define complex SABs have been proposed, as well as new boundaries
for defining persistent bacteremia after 2 days of positive blood cultures.
Several antibiotic combinations, including vancomycin or daptomycin versus β-lactams, fosfomycin, or clindamycin, have been tested with no significant results
.
In recently published guidelines, vancomycin remains the first-line treatment
for methicillin-resistant Staphylococcus aureus bacteremia.
For the treatment of methicillin-sensitive Staphylococcus aureus, cefazolin-induced acute kidney injury is less frequent than flucloxacillin, and when sensitivity is demonstrated, it is recommended to downgrade penicillin G
.

summary

Our review confirms that Staphylococcus aureus represents a particular cause
of all causes of bloodstream infections.
The unique epidemiology and determinants of platforms and large trials are pending, requiring careful integration of clinical variables and the best available evidence to optimize patient outcomes
.

keyword

Bacteremia, MRSA, MSSA, Staphylococcus aureus

introduction

Staphylococcus aureus bacteremia (SAB) is a major cause of sepsis and septic shock and is associated with
significant morbidity and mortality.
While the past two years have been dominated by the COVID-19 pandemic, important publications related to the epidemiology and management of SAB have emerged, including new guidelines
on methicillin-resistant Staphylococcus aureus (MRSA).
With this update on SAB, we review and discuss scientific articles
published over the past 18 months that are important for clinicians to manage patients with SAB.

Recent epidemiology and data

The COVID-19 pandemic has put significant pressure on
healthcare systems worldwide.
This is associated with
hospital-acquired infections and increased antimicrobial resistance.
Weiner-Lastinger et al.
analyzed the National Health Safety Network (NHSN) database, which collects data
on hospital-acquired infections (HAIs) from most hospitals in the United States.
The NHSN publishes the Standardised Infection Rate (SIR), which is the observation-to-forecast ratio
used to assess HAI prevention programmes.
Prior to the pandemic, methicillin-resistant Staphylococcus aureus SAB (MR-SAB) SIR decreased
significantly year on year.
In the last two quarters of 2020, the national MR-SAB SIR was 23% and 34%
higher than last year, respectively.
Some states reported a 99% increase during the period, highlighting the pandemic's dramatic impact
on infection prevention and control.

Risk stratification of bacterial co-infection in patients with COVID-19 pneumonia admitted to the intensive care unit (ICU) is a major challenge
for clinicians.
Langford et al.
included 171 systematic review studies that used meta-regression analysis to assess microbiological characteristics and predictors
of respiratory and bloodstream infections (BSIs) in patients with COVID-19.
They found co-infection rates of 5% (95% confidence interval, CI 4-7%) and secondary infections of 13% (95%, CI 10-17%), and a global BSI prevalence of 9% (95%, CI 7-11%)
.
Staphylococcus aureus is the most common organism
in co-infections (25%) and secondary infections (16%).

Bai et al.
have published a series of articles supporting a systematic review and meta-analysis
of SAB mortality.
They included 536791 patients
from 341 studies published between 1991 and 2021.
They found that mortality was estimated at 18 per cent at one month, 27 per cent at three months and 30 per
cent at one year.
Mortality decreased over time compared to before 2001, with an adjusted odds ratio (aOR) of 0.
88 (95%, CI 0.
75 to 1.
03) from 2001 to 2010 and 0.
82 (95%, CI 0.
69 to 0.
97)
after 2011.
MR-SAB mortality was high, with aOR 1.
04 (95%, CI 1.
02 to 1.
06)
for every 10% increase in MRSA ratio.
Secondary analyses showed that the proportion of deaths due to SAB decreased over time, with optimal follow-up of 1 to 3 months
.
To investigate the external validity of randomised controlled trials (RCTs) for populations commonly encountered in clinical practice, they matched
each of the seven RCTs to four observational studies for the same decade, geographic region, population, and mortality time point.
Mortality was similar across all RCTs (8% at one month and 15% at three months), much lower than in observational studies (18% at one month and 26% at three months).

These differences may be due to exclusion of dying patients and strict eligibility criteria
in RCTs.
These findings are important for clinicians because, when considering RCT data, patients they see in clinical practice may have lower outcomes and possibly worse
outcomes.

Staphylococcus aureus bacteremia in patients with malignant neoplasms

Malignancy is commonly reported as a risk factor
for SAB.
In a meta-analysis investigating MR-SAB studies in cancer patients, Li et al.
reported that the prevalence of MRSA in all BSI patients was 3% and in patients with SAB was 44%, with high heterogeneity and wide geographic variability
.
The most associated risk factor for MR-SAB is hospital-acquisition
.
Mortality data were obtained from single-center cohorts only, 12% at 2 months and 43%
at 6 months.
In a matched bicenter SAB patient cohort comparing solid organ transplant (SOT) recipients and non-SOT recipients, Eichenberger et al.
reported lower but statistically similar mortality rates for SOT recipients [18% versus 29%; aOR 0.
74；95%CI（0.
44,1.
25）]
。 Grillo et al.
compared patients with and without cancer in a dual-center cohort of 978 SABs, 21% of whom were MRSA
.
They found that cancer patients had a similar 30-day mortality rate (25 percent versus 24 percent), but significantly lower
rates of infective endocarditis (3 percent versus 11 percent) and osteoarticular infections (2 percent versus 14 percent).
22% of patients with active cancer were younger (mean 59 versus 66 years), had lower rates of heart disease (9% versus 22%) and valvular disease (9% versus 19%), and had higher rates of catheter-related infections (41% versus 25%)
.
These intrinsic differences explain the difference
in prognosis between patients with and without cancer.

Persistent, recurrent, uncomplicated staphylococcus aureus bacteremia

An accurate classification of SABs is important
to guide treatment selection.
Currently, persistent SAB is broadly defined as a positive blood culture
of 2-7 days.
Kuehl et al.
report a secondary analysis of a multicenter cohort, including 987 cases of SAB and their subsequent culture
.
The second day of positive culture is the cut-off for higher mortality (22% at 1 day, 39% at 2-4 days, and 43% at 5-7 days).

Patients with positive blood cultures also had a significantly increased risk of septic metastasis, from 6% after 1 day to 13%
after 2 days.
Similarly, in a recent retrospective cohort study of 884 SAB Minejima et al.
, it was found that the relative risk of death increased by 1.
16 (95%, CI 1.
1-1.
22) for each additional day of bacteremia, with a significant increase
at 3 days.
Overall, it is recommended to redefine persistent SAB as positive blood cultures for 2 days or more, and despite aggressive antibiotic therapy, this may be a clinically relevant approach that can provide consistency
on this issue.

To investigate the true recurrence rate of SAB, Choi et al.
analyzed a single-center cohort
of 756 SABs.
A total of 69 (9%) patients developed new SAB at least 14 days after the last SAB-positive
blood culture.
Comparing isolates by pulsed field gel electrophoresis, they determined that 43 percent of relapses and 57 percent of new infections were due to different isolates (41 percent), or because at least 150 days (16 percent)
had passed since the SAB index.
In their multivariate analysis, risk factors for recurrence were higher severity scores and dialysis dependence, with black patients being more severe
than white patients.
The alarming proportion of new infections in this population reminds us of the important role of
secondary prevention in this high-risk population.

Hagel and 33 international infectious disease experts conducted two rounds of Delphi analysis (Delphi) to identify complex SABs
.
They believe that the presence of prosthetic valves (biological or mechanical), cardiovascular implanted electronic devices, or aortic stent grafting is highly relevant
.
They considered the presence of prosthetic joints, subsequent positive blood cultures, or unknown source of SAB to be moderately correlated
.
There is no consensus on chronic hemodialysis or immunosuppression regardless of age
.
These newly proposed cut-off points and definitions are expected to standardize research more and ultimately provide clear recommendations
in clinical practice guidelines.

Choice of antibiotics

There have been interesting developments
in management.
Comprehensive guidelines for the management of methicillin-resistant Staphylococcus aureus have been published in the United Kingdom (Table 1).

In the context of the 2007–2018 literature review, they identified only 30 eligible studies, four of which were related
to MR-SAB.
This is a welcome update, 13 years after its last version, and 10 years after
the publication of the Infectious Diseases Society of America (IDSA) MRSA guidelines.
The most interesting difference is front-line guidance
.
IDSA also recommends daptomycin or vancomycin
.
While the 2008 edition of the UK guidelines considered daptomycin as a possible alternative to glycopeptide, the current update only recommends daptomycin in third place when the first line is banned
.
This clearly indicates that there is a lack of sufficient high-quality evidence
in this area.
To complement these guidelines, we highly recommend the following two review articles
.
Davis et al.
guided us in the selection of empirical and targeted therapies
for MR-SAB through case discussions.
Through a discussion of the literature, Rose et al.
provide some interesting insights
into the rationale for methicillin-resistant Staphylococcus aureus (MRSA) combination therapy, especially daptomycin + β-lactam, and the important role of ceftaline in this indication.

Recently published SAB studies have focused specifically on combination therapies (Table 2).

Johnson et al.
compared the prognosis
of 30 patients with MR-SAB- who continued vancomycin in 2011-13 with 30 patients treated with DAP + CPT in 2013-20 when they studied the effects of daptomycin + ceftaline (DAP+CPT).
The primary prognosis for death and recurrence at 60 days of DAP+CPT was low, but there was no significant difference (43% vs.
20%, P1/40.
052), largely due to lower recurrence rates (30% vs.
0%, P<0.
01).

There was no significant increase in 90-day mortality in the DAP+CPT group (23% vs.
27%, P1/40.
77).

Given the small size of the cohort studies of patients over time periods and the significant risk of bias, these results require that this combination be investigated
in a sufficiently robust RCT.

In an open-label RCT that included 167 patients in 18 Spanish hospitals, the combination of daptomycin + fosfomycin for MR-SAB was compared
with daptomycin alone.
Pujol et al.
reported no significant difference in treatment success at 6 weeks of combination therapy, but was 12% higher (54% versus 42%; RR 1.
29[95%CI[0.
93-1.
8]，P¼0.
135）
。 Although the addition of fosfomycin reduces microbial or clinical treatment failure (0% versus 15%, P<0.
001) and accelerates the clearance of bacteremia, it also leads to an increased incidence of adverse events requiring treatment interruption (18% versus 5%, P1/40.
012).

Another important clue is the addition of antistaphylococcal β-lactam drugs (flucloxacillin, cloxacillin, or cefazolin)
as part of methicillin-resistant combination therapy.
The CAMERA-2 randomized controlled trial included 352 MR-SAB patients
from 27 hospitals in four countries.
Patients were randomized to 7 days of combination antistaphylococcal β-lactam therapy with standardized care (SOC) (99% vancomycin).

The primary combined results of 90-day mortality, persistent bacteraemia at day 5, relapse, or microbial failure were similar between groups (35% combined vs 39% SOC, absolute difference, -4.
2%; 95%CI，-14.
3–6.
0%）
。 Although mortality was similar at all time points in both groups, the incidence of persistent bacteremia on day 5 was lower and acute kidney injury (AKI)
was more common with combination therapy.
Importantly, in the combination group, 65% of patients were treated with flucloxacillin or cloxacillin, 27% of them developed AKI, 16% received cefazolin alone, and 4% (1/27) of them developed AKI
.
This suggests that AKI is secondary to flucloxacillin or cloxacillin rather than β-lactam therapy
.
Overall, we still lacked data to recommend any combination therapy as the final treatment
for MRSA-SAB.

In terms of susceptibility to SAB, Cheng et al.
randomized 115 MS-SAB patients to receive daptomycin or placebo in combination with cefazolin or cloxacillin for 5 days
, respectively.
The results did not support this combination treatment, as the duration of bacteremia was similar in the primary outcome in both groups (2.
04 days in the daptomycin group and 1.
65 days in the placebo group, P1/40.
4).

There was no statistically significant difference for any secondary outcome including 90-day mortality (19% vs.
18% P1/41.
0).

Together, these results support antibiotic downgrading
once the antibiotic atlas is available.

There is increasing evidence
for the use of cefazolin in MS-SAB.
In a cost-benefit analysis, Pliakos et al.
concluded that cefazolin saved $
97,157 per death averted compared with anti-staphylococcal penicillin for MS-SAB.
In a post-hoc analysis of a multicenter cohort of methicillin-sensitive Staphylococcus aureus (MSSA) infective endocarditis, Lecomte et al.
found similar mortality (24% vs.
29%), but cefazolin was discontinued for adverse events (most commonly AKI) less frequently (0% versus 8%)
compared with antistaphylococcal penicillin.
These results are consistent with previous data, such as a 2018 meta-analysis by Bidell et al.
, which showed lower mortality and better
tolerability of cefazolin.

The antitoxin properties of clindamycin may play an important role
in this indication.
The CASSETTE pilot trial randomized 34 patients into two groups, with 59% receiving SAB treatment, i.
e.
clindamycin + SOC or SOC
alone.
The primary endpoint was days of survival without SIRS on day 14, which was similar between groups (3 days vs.
4 days).

At 90 days, there were no deaths in the clindamycin group (0%) and three deaths in the SOC group (18%)
.
Although all-cause diarrhea was higher in the clindamycin group (47% vs.
35%), the SOC group had the only case of Clostridium difficile-associated diarrhea
.
These data do not inform practice, but they are the context of the
clindamycin field of the Staphylococcus aureus Network Adaptive Platform Trial.
Such platform trials have been extremely successful
due to their flexible and adaptable design, which provides strong and reliable evidence during the coronavirus pandemic.
We believe that the coming years will see interesting developments, with the platform trial providing high-quality evidence
that we are missing in the management of infectious diseases in intensive care units.

Whether ceftriaxone can be used for MS-SAB remains controversial
.
Previous cohort studies of patients with MS-SAB have shown that ceftriaxone is less
effective than cefazolin and/or cloxacillin.
Two meta-analyses have recently been reported, which have yielded similar mortality results
when comparing ceftriaxone with SOC for MS-SAB or MSSA infection.
All included studies were retrospective observational studies and were at high risk of
bias due to indications and residual confounders.
These will be reflected in any meta-analysis of its results, which can only be considered hypothesis generation and should not inform practice
.
Pharmacodynamic studies have attracted further attention
.
Heffernan et al.
investigated the bactericidal effect
of increasing doses of ceftriaxone on bacteria in a hollow fiber MSSA infection model.
A 2 g Q12h ceftriaxone regimen is required to achieve bacterial killing and sustained inhibition of bacterial growth
.
This is twice the usual dose used for sepsis or BSI and does not support maintenance of ceftriaxone as the final treatment
of MS-SAB.
For this indication, we recommend flucloxacillin or cefazolin
.

Optimistically, in Sweden's Scania region, the prevalence of penicillin-sensitive Staphylococcus aureus (PSSA) has increased by 30%.

Aldman et al.
conducted a retrospective cohort study
of 618 adult patients with PSSA-SAB.
Cloxacillin and penicillin had similar 90-day mortality (19% vs.
13%, P1/40.
24).

The complication rate of cloxacillin was significantly higher (odds ratio, OR 2.
38, 95% CI 1.
28–4.
44; P1/40.
006).

In addition, patient-centered outcomes of 90-day survival without complications supported penicillin (71% vs.
55%, P1/40.
02).

These results support the use of antibiotics to penicillin in patients with PSSA-SAB rather than continuing usual care
.

Duration of treatment

Unlike gram-negative BSI, there were no RCT data recommending the optimal duration of antibiotics for SAB, which was recommended as 14 days for uncomplicated SAB and 28 days
for complication.
Two recently published cohort studies provide some insights
.
In a single-center cohort study of 530 patients with SAB (58% complex SAB and 18% MRSA), Abbas et al.
found that durations longer than 14 days were only associated with higher 90-day survival in patients with complex SAB and not with
90-day survival in uncomplicated SAB.
There was no association
between duration and recurrence.
Thorlacius Ussing et al.
studied this question and included 2205 patients with uncomplicated MS-SAB from 3 cohorts in the Copenhagen area from 1995 to 2018
.
They used a multivariate model fitted to the inverse probability of treatment weights to address risk of
bias.
Importantly, they assessed mortality and recurrence rates up to 90 days after the end of antibiotic treatment, addressing the risk
of immortal time bias inherent in the issue of delay or duration of antibiotic treatment.
The median duration was 8 days in the short-course group (IQR, 7-10) and in the long-course group was 14 days (IQR 13-15).

In each individual cohort or pooled analysis, duration did not affect 90-day mortality
.
These data are encouraging because they open up discussions, but they are not enough to change our practice, because we cannot exclude residual bias
through indicators, even with the best statistical adjustment methods.
Doctors may treat patients they believe are at higher risk and need to last longer, leading to similar results
.
Importantly, this cohort is the preface to the same ongoing SAB7 randomized controlled trial comparing 284 patients with uncomplicated SAB for 7 to 14 days, which is expected to provide the means to
provide evidence-based practice guidelines.

Conclusion

In summary, we present and review contemporary research in SAB on topics that are not limited to epidemiology, clinical features, multiple positive blood cultures, antibiotic selection, and duration
。 SAB is complex and many important aspects cannot be further explored at this time, including eosinophilia studies with daptomycin, oral reduction therapy with clindamycin, fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) to improve diagnosis, source control such as removal of cardiac implantable electronic devices associated with reduced mortality, the importance of serial negative blood cultures, and the significance of
Staphylococcus aureus bacteriuria in SAB patients 。 In addition, optimizing the use of clinical scoring systems for stratified patient treatment or utilizing echocardiographic resources is a major area of research worth
reviewing.

conclusion

Our review confirms that Staphylococcus aureus represents a particular cause
of all causes of bloodstream infections.
In fact, Staphylococcus aureus is the most common microorganism responsible for HAI in COVID-19 hospitalized patients, and MR-SAB rates have risen
dramatically during the pandemic.
SAB carries a significant risk of persistent bacteremia and recurrence, and classification as complex or uncomplicated remains challenging
.
Given their high mortality rate, multiple combination regimens have been studied, but no significant results
have been found.
Before evidence from large and platform trials becomes available, clinical variables and the best available evidence must be carefully integrated to optimize patient outcomes
.