Staphylococcus aureus bacteraemia

S.aureus infection tends to progress rapidly, cause a more severe infection than other staphylococci,  affect relatively healthy people, stimulate a vigorous SIRS response, and occasionally produce a toxic-shock-like superantigen-driven syndrome. Question 1 from the second paper of 2021 asked for "assessment and specific management related to the staphylococcal bacteremia". This specific line of questioning had not been seen before; however coagulase-negative staphylococci and MRSA did have some attention from the examiners. For a free narrative review, Thwaites et al (2011) is an excellent resource, or Tong et al (2015). It would also be harmless to read the UpToDate article on the clinical management of S.aureus bacteraemia, especially if one has some sort of free institutional access. The IDSA guideline for the management of S.aureus bacteraemia is "in development" at the time of writing in late 2021, but perhaps some lucky reader will one day stumble across this page and finally find a real guideline at the end of that link. 

Microbiology of Staphylococcus aureus

These cocci are:

• Gram-positive
• Catalase-positive
• Coagulase-positive

The presence of coagulase effect is usually used to distinguish S.aureus from the other (coagulase-negative) staphylococci. Coagulase creates a defensive fibrin film over the cocci, protecting them from phagocytosis antibodies and complement. The coagulase-negative staphylococci are therefore grouped into a large low-virulence group which is discussed elsewhere. The finding of these bugs in the blood culture is therefore viewed with some scepticism, as they are rather defenceless against normal immune system mechanisms, and are therefore unlikely to cause a genuine bacteremia (giving rise to the suspicion that the blood culture was contaminated with skin organisms).

Not so for S.aureus. Its repertoire of immune evasion mechanisms is vast, extending well beyond the simple act of hiding in a fibrin coat. A short list compiled from DeLeo et al (2005) is presented here, but is probably not necessary, as it would probably not attract any additional exam marks:

• Exopolymer capsule (positively charged; protects from neutrophil phagocytosis)
• Chemotaxis inhibitory proteins (block receptor-mediated recognition by phagocytes)
• Complement-blocking surface proteins (prevent opsonisation)
• Complement-inhibiting surface enzymes (eg. the C3 convertase blocker SCIN; prevent the normal mechanisms of the complement cascade)
• Reactive oxygen species scavengers to ameliorate the damage from neutrophil granule content (eg. staphyloxanthin, the yellow pigment responsible for the golden appearance of S.aureus colonies)
• Nonspecific proteases, which digest various antimicrobial peptides (eg. those produced by neutrophils, as well as by other competing microorganisms)
• Leukocidins, which - as the name suggests - kill leukocytes. They do this by forming membrane pores, something similar to the membrane attack complex of complement. Of these, the most interesting and memorable is Panton-Valentine leukocidin, found in community-acquired MRSA and associated with a more severe infection.
• α-hemolysin and β-hemolysin, also pore-forming cytotoxins, but ones which target erythrocytes. Why would S.aureus want to destroy your red cells? Probably to get at the delicious iron inside them. More broadly, all sorts of these water-soluble pore-forming membrane drills are common among bacteria. 

In short, there is reason enough to be concerned, if S.aureus is cultured from the blood. Could it still be a skin contaminant? Sure. Strictly speaking, it does not really belong on the skin surface, as human nares are the main reservoir of S.aureus (though owing to our close association with them, there's a substantial cross-colonisation of farm animals with human strains of S.aureus, which theoretically means that you could get MRSA from handling a pig). Why the nose? Difficult to say. Of the large and diverse team of staphylococci currently swarming all over your body, most have a clear preference for one or two anatomical sites. S.epidermitis and S.hominis prefer the skin, S.capitis the scalp, S.oralis the mouth, etc. Perhaps one half of all adults carry it, which means that half don't (i.e. some of your patients will not have S.aureus anywhere on their body), and some of us are more likely to be colonised than others (eg. healthcare workers, regular needle users like diabetics, frequently hospitalised people). When one becomes the host for this organism, the relationship with it is not exactly symbiotic, but at least it generally does no harm, and the uneasy truce between you and this parasite can be described as "healthy carriage" at a stretch (Williams, 1963).

If the nares are colonised, usually so are the hands (guess why), and from there the skin, where it could theoretically survive for months. There, one could theoretically pick it up on the end of the needle, contaminating one's blood culture and creating an unnecessary course of antibiotics. However, this is sufficiently rare (and true bacteremia is sufficiently devastating) that most authors list S.aureus along with E.coli and Candida as organisms which, when cultured from the blood, should always be assumed to represent a true bacteremia (Hall & Lyman, 2006). 

Possible sources of S.aureus bacteraemia

Where is it coming from? Could be anywhere; but there seems to be a pattern. For example, Tong et al (2015) list the following possibilities on the basis of the sources identified in large observational studies of patients with MSSA or MRSA bacteraemia:

• Hospital-acquired pneumonia
• Intravascular devices
• Skin and soft tissue infections (eg. various scratched pimples or skin abrasions, diabetic feet, pressure areas, cellulitis, basically any broken skin could act as a portal of entry)
• Infective endocarditis
• Osteomyelitis
• Discitis or septic arthritis
• Epidural abscess or brain abscess
• Infected prosthetic devices and implants (eg. pacemaker leads)

The Tong article is especially awesome by its content of locally sourced infective focus data. Many countries are listed in that table, but the author will selfishly reproduce only the rows relevant to his own practice:

Location	Infective endocarditis	Osteo- articular	Skin etc	Lung	CLAB	Unknown
Central Australia	7.2%	16%	34%	8.8%	7.2%	24%
Australia in general	6%	13%	20%	7.2%	19%	15%
Sydney, NSW	3.8%	9%	20%	13%	35%	10%

In short, skin and line-related sepsis is by far the most common source of S.aureus bacteremia.

"Complicated" vs "uncomplicated": One occasionally comes across this classification in various antibiotic guidelines, usually where the dosing and duration of therapy is discussed. For example, the Sanford guide recommends 2 weeks of antibiotics for uncomplicated bacteremia, and 4-6 weeks if it's complicated. The definition for what "complicated" means mainly comes from Fowler et al (2003), though there are a few alternative versions. For exam purposes, it would not be necessary to deep-dive into those controversies. The following definition of a complicated S.aureus bacteremia will suffice:

• CNS involvement: meningitis, brain or epidural abscess, mycotic aneurysm
• Septic emboli (pulmonary, liver, spleen, etc)
• "Metastatic" sites of infection (i.e. multiple infected regions simultaneously, eg. infective endocarditis and an epidural abscess)
• Recurrent infection within the same 12 week period

With any one of these features, a longer course of therapy is called for, mainly because the infection is more difficult to eradicate. The morbidity and mortality is also higher in these patients. In short, there is some non-administrative purpose in labelling their bacteraemia as "complicated" 

Do you really need to know where it is coming from? Yes, the answer is always yes. Thwaites et al (2011) quote data from numerous studies that demonstrate that the risk of relapse or treatment failure is much greater if you fail to identify and remove the infected thing. Still, apparently in up to 40% of cases the identity of the infected thing will not be revealed until autopsy (and in those cases vertebral osteomyelitis or infective endocarditis are often found, according to a case series by Fowler et al, 2003). In short, even when you are convinced it's not the disks or valves, it's probably still the disks or valves.

Knowing the primary source of infection also helps you predict mortality. From Tong et al (2015):

Source	Mortality
Unknown	22-48%
Infective endocarditis	25-60%
Lung	39-67%
CLAB	7-21%
Skin and soft tissue	15-17%

Those are scary numbers, if one takes into account the fact that mortality from sepsis in developed countries is decreasing and is now down to something like 15% in Australia. S.aureus in the bloodstream is clearly a much more dangerous foe than a urinary E.coli. 

Is the bacteraemia still going? Let's say that you have commenced the patient on some sort of empirical therapy. Having done this, you should feel motivated to make sure that this therapy is working. The failure of the bacteremia to resolve is a major negative prognostic marker. For example, when Chong et al (2013) had looked at patients who had remained bacteraemic for 7 days or longer, the mortality was 9.2%, versus 2.4% for patients whose cultures turned clean after the first three days.

Assessment and investigations for S.aureus bacteraemia

Following from the discussion of sources and possible complications, the following series of investigations present themselves:

• Clinical assessment:
  • A skin check, looking for:
    • Cellulitis and broken skin (ulcers, etc)
    • Signs of disseminated disease, eg. the peripheral stigmata of IE
  • Intravascular device assessment, focusing on:
    • the condition of the insertion site
    • the age of the line
    • the need for the line
  • Cardiovascular/respiratory examination, looking for:
    • New murmurs
    • New heart failure
    • Features of pneumonia
  • Neurological examination, looking for:
    • New focal neuro deficit (embolic CNS disease)
    • Peripheral neuro deficit suggestive of epidural abscess
  • Musculoskeletal examination, looking for:
    • Joint effusions
    • Myositis/fasciitis
    • Osteomyelitis/discitis
• Bloods and biochemistry:
  • LFTs, to (also, to assess the effect the flucloxacillin is having on the liver)
  • EUC/CMP to establish baseline renal function and to detect any glomerulonephritis
• Imaging studies:
  • Echocardiography, looking for IE
  • CT chest/abdomen/pelvis/brain with IV contrast, looking for metastatic foci of infection and septic emboli
  • MRI spine, looking for discitis osteomyelitis and epidural abscess
• Microbiology investigations:
  • Repeat sets of blood cultures (ideally, repeated daily or second-daily until the bacteremia is cleared)
  • Specific site sampling, including potentially:
    • Wound swabs
    • Line tip cultures
    • Abscess aspirates
    • Joint aspirates
    • Tissue cultures (eg. from valves)
• Infectious diseases referral

A specialist Infectious Diseases physician consultation is listed alongside TTE and repeat blood cultures as a potentially lifesaving or management-changing option, which might sound weird - but in fact this referral is strongly associated with increased survival. There is something strongly protective about having a specialist take charge of this specific aspect of their care, even in the closed ICU model where the intensivist is in overall control of the management. In fact, the ID physician has to come and physically see the patient, as a telephone consultation does not seem to have the same beneficial effect. It is almost as if the ID specialist radiates some sort of antimicrobial AoE debuff. A less stupid explanation would focus on the enhancement of various quality of care metrics, such as making sure that repeat blood cultures happen, correct duration of antibiotics is prescribed, follow-up imaging is organised, and so forth.  

Trans-oesophageal echo looking for endocarditis is de rigueur for staphylococcal bacteremia, though if vegetation can be identified on a transthoracic echo, this is usually viewed as sufficient. Practically speaking, this means that most patients will be expected to have at least a TTE, and /or a TOE. There are several risk factors which make the finding of endocarditis more likely, including:

• Persistent bacteraemia
• Prosthetics (eg. heart valves, orthopaedic metal, etc)
• Existing valve disease
• High risk populations (IV drug users, patients with chronic renal failure, or the immunocompromised)

Specific management for S.aureus bacteraemia

The typical S.aureus bacterium will, in this 21st century, be almost always resistant to plain benzylpenicillin. it is still possible to find a wild specimen which is still somehow antibiotic-naive, but these are so rare that it is almost a pity to kill them. 

• Antibiotic options:
  • When sensitivity data is not available:
    • Empirical combination therapy: vancomycin plus flucloxacillin
    • The vancomycin is for patients who are at risk of MRSA infection, eg. those who have enjoyed a prolonged hospital stay, those with chronic renal failure, or institutionalised populations such as prison inmates or nursing home residents. The empirical flucloxacillin would be enough for patients who are at low risk of MRSA colonisation. 
    • Empirical clindamycin or moxifloxacin are alternatives for patients who are intolerant of vancomycin or penicillins
  • Sensitivity-guided management of MSSA:
    • ETG recommend flucloxacillin or cephazolin
    • For patients who are allergic to β-lactams,  desensitization therapy should be attempted, because the β-lactams are a clearly superior choice, and should be used wherever possible (instead of just resorting to vancomycin).  Vancomycin is a terrible antibiotic and we really only use it if we absolutely have to. Without going into too much unnecessary detail, the treatment failure rates and relapse rates with vancomycin are about four times higher than with a comparable β-lactam.
• Source control:
  • If at all possible, the source of the bacteremia needs to be removed. 
  • This may require:
    • Removal of suspected intravascular devices
    • Washout of infected joints
    • Explantation of infected prostheses
    • Valve replacement
• Control potential sources:
  • ​​​​​​​It may actually be worthwhile removing all long-term intravascular devices (eg. PICC lines), waiting until the bacteraemia has resolved, and then resiting them after 2-3  blood cultures have returned negative results. 
  • This is a common enough practice, but not entirely supported by the data. For example, Stewart & Runnegar (2018) retrospectively audited PICC lines inserted within 48 hours of the first bacteremia and did not find any increased risk of line colonisation treatment failure or relapse. Having said that, one can be reasonably sure that the examiners would want the CICM Part II candidates to demonstrate their maturity by treating the findings of a single-centre retrospective audit with some scepticism, especially when making decisions about patients who cannot afford to have treatment failure (eg. the elderly, immunocompromised, or for whom valve surgery is not an option). In those cases, one could make the argument that line placement delayed until negative cultures might be somehow safer. The counterargument to this line of reasoning would be that the patient will still require IV antibiotics, which will be administered via multiple peripheral cannulas, requiring multiple skin punctures and therefore amplifying the risk of a new bacteraemia.