New Insights on Therapy for Resistant S aureus

[Guest guest]

Finally Some Good News: New Insights on Therapy for Resistant S aureus

Stratton, MD Disclosures

San Diego, Sunday, September 29, 2002 -- The third day of ICAAC finally

brought some good news for the practicing clinician. In a well-attended

symposium on Staphylococcus aureus convened by Gordon L. Archer, MD, and

Henry F. Chambers, MD, the final speaker, P. Levine, MD,

discussed vancomycin treatment failure.[1] This discussion, as well as

others in this symposium[2-5] and during the past several days, provides

some new and valuable insights into the therapy of serious S aureus

infections caused by both resistant and susceptible strains. As S aureus

infections are among the most commonly encountered infections in both

community and hospital settings,[6] these insights will be appreciated

by all practicing clinicians. These insights will be presented in

context with a brief overview of the diagnosis and therapy of

staphylococcal infections.

S aureus, then simply called a " micrococcus, " was first described by Sir

Ogston, a ish physician, in 1882.[3] In the past 120

years, medicine has learned a great deal about this pathogen. It is a

common and innocuous colonizer of nares in 30% to 50% of healthy adults

and of skin in 12% to 25%. Colonization is increased in diabetics,

dialysis patients, intravenous-drug users, and HIV-infected persons.

This microorganism may be spread to the hands by nosepicking[7] and from

there to cuts on the skin. S aureus can be spread to others by sneezing

during a common cold.[8

The Truth Is Rarely Pure, and Never Simple Human infection can occur

when S aureus is able to enter tissues because of a breach in mucosal or

cutaneous barriers. Once S aureus has gained entrance to tissues and/or

the bloodstream, it has the potential to become a lethal pathogen due to

a diverse armamentarium of virulence factors.[3] Initial replication

during the exponential-growth phase results in expression of surface

proteins that mediate staphylococcal attachment to selected host

surfaces via tissue matrix molecules. When a large density of

microorganisms is achieved, microbial quorum sensors detect this

phsiologic state, which results in activation of accessory gene

regulators (agr). These regulators activate the synthesis of toxins such

as enterotoxin B, TSST-1 and alpha-toxin. Toxin-mediated staphylococcal

disease is becoming increasingly recognized. A number of these toxins

function as superantigens and produce a sepsis syndrome. Neutralization

of these superantigens by antibodies has been shown to be beneficial in

streptococcal toxic shock-like syndrome[9] and may prove beneficial in

staphylococcal toxic shock syndrome.[10] Clinical trials will be needed

to demonstrate any efficacy of intravenous gamma globulin as adjunct

therapy for staphylococcal toxic shock syndrome. Needless to say, such

therapy would need to be initiated as early as possible.

Once infection in tissues occurs, local immune defenses may prevail, or

the infection may persist and/or spread. S aureus is able to persist in

abscesses or in avascular tissues in a biofilm milieu[11,12] that avoids

phagocytosis. Persistence also may be related to the ability of small

colony variants of S aureus[13] to invade and survive within

epithelial/endothelial cells.[14] The primary component of the host

response is the polymorphonuclear cell. However, phagocytosis of S

aureus by polymorphonuclear cells may actually serve to spread this

organism to other sites.[3] Should S aureus enter the bloodstream,

infectious endocarditis may occur. Platelets have been thought to play a

role in the initiation of staphylococcal endocarditis on a normal heart

valve, but recent evidence suggest that platelets may also have

microbicidal proteins that would protect against staphylococcal

infection.[15

As already mentioned, infections caused by S aureus are facilitated by a

large number of virulence factors produced by this microorganism, some

of which have only recently been delineated due to the complete

sequencing of staphylococcal genomes for both S aureus and S

epidermidis.[4,16] Among these virulence factors are serine proteases,

leucocidins, and lipoproteins as well as earlier-described enterotoxins

and exotoxins. Of note is the observation that some of these virulence

genes are arranged in mobile pathogenicity islands and thus can be

transferred from isolate to isolate. Some of these virulence genes such

as those for leucocidin are carried on staphylococcal bacteriophages.

Finally, genomic comparisons reveal that S aureus has many more

attachment factors and virulence factors than does S epidermidis.

Moreover, these attachment and virulence factors for the most part are

unique to each species.

A Complicated Story

S aureus infections are often serious and complicated by bacteremia and

metastatic abscesses. Relapse may occur after therapy due either to

persistence in abscesses or to antimicrobial failure. Complications of S

aureus bacteremia are common, but are often difficult to identify in the

clinical setting.[5,17] The mortality rate has been found to be

significantly higher for patients with complicated S aureus bacteremia

vs those with uncomplicated bacteremia.[17] Serious complications of S

aureus bacteremia include vertebral osteomyelitis,[18] spinal epidural

abscess,[19] and infective endocarditis.[20] Detection of such

complications requires heightened awareness and appropriate diagnostic

measures. Vance G. Fowler, MD,[5] discussed several clinical and

diagnostic characteristics that are useful as indicators of complicated

S aureus infection. The first of these is community-acquired S aureus

bacteremia. Endocarditis should be suspected if no obvious source of

infection is found. Also useful if present are physical manifestations

of embolic events. These should be sought frequently over the course of

therapy. Splinter hemorrhages, Roth spots, and Janeway's lesions are

indicative of infectious endocarditis.[20] Persistent fever at 72 hours

after the initiation of appropriate antimicrobial therapy suggests a

complicated S aureus bacteremia as does positive blood cultures drawn on

days 2-4 after therapy.[21,22]

Blood cultures should always be repeated within 2-4 days after

appropriate antimicrobial therapy has been initiated; positive blood

cultures at this time predict a complicated course. The presence of S

aureus bacteremia in a patient with a prosthetic device almost always

equals trouble. Similarly, S aureus bacteremia following a mediastinal

incision means mediastinal infection until proven otherwise. If

infectious endocarditis is suspected in a patient with S aureus

bacteremia, transesophageal echocardiography (TEE) provides the optimal

diagnostic approach.[23]The TEE, if positive, provides an estimation of

the size of the vegetation. Vegetation size greater than 2 cm has been

associated with increased mortality.[24] In bacteremic patients with

native valves, a negative TEE virtually excludes endocarditis; this

approach is useful in patients with catheter-associated S aureus

bacteremia.

Resisting Arrest

The antimicrobial therapy of S aureus has long been complicated by the

ability of this pathogen to become resistant to commonly used

antibiotics.[25] Indeed, few microorganisms can equal the ability of

this pathogen to acquire resistance. Among the mobile pathogenicity

islands described by Dr. Archer are those that carry multiple resistance

genes.[4]

When Dr. Levine discussed vancomycin treatment failure, he quickly

pointed out that true treatment failure is hard to define.[1] There are,

however, a number of reasons that vancomycin treatment may fail. These

most recently include vancomycin-resistant strains of S aureus (VRSA),

which has been reported at this ICAAC. In addition,

vancomycin/glycopeptide-intermediate strains (VISA/GISA), tolerant

strains, and heteroresistant strains may result in failure.[26] Finally,

poor intrinsic activity of vancomycin and glycopeptides in general as

well as poor penetration of these agents into tissues such as lung[27]

or CNS and into abscesses[28] and/or vegetations[29] are other factors

that may result in failure.

It is clear that initial antimicrobial therapy in patients with S aureus

bacteremia should include an antistaphylococcal beta-lactam agent such

as nafcillin or ampicillin/sulbactam. If methicillin-resistant S aureus

(MRSA) is suspected, vancomycin should be added, not substituted, for

the antistaphylococcal beta-lactam agent.[29] Should the isolate prove

to be VISA/GISA, the beta-lactam agent and vancomycin should be

continued. If the isolate proves to be MRSA, many would continue both

agents as well. If vancomycin is used alone, a high

area-under-the-inhibitory-cure predicts an improved clinical outcome.

Basically, this means that if the MIC is < 1 mcg/mL, standard dosing of

1 g every 12 hours may be used. If the MIC is > 1, a higher dose of 1.5

g every 12 hours may be needed.

Addition of gentamicin in an in vitro infection model suggest that 2 g

of vancomycin per 24 hours plus gentamicin ( once a day or every 12

hours) provides the most rapid rate of kill.[30] Clinical studies are

needed to confirm this. Addition of other agents such as cefepime has

been studied in the same in vitro infection model and has proven more

effective than vancomycin alone, but this also needs to be validated by

clinical studies.[31] Finally, this in vitro infection model has been

used to evaluate several antimicrobial agents on VRSA.[32] Of currently

available agents, quinupristin-dalfopristin was the most active and was

more active than linezolid. Hopefully, our future clinical experience

with VRSA will be limited.

Becki

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