C L I N I C A L F E AT U R E S
Staphylococcus aureus Bacteremia: Targeting the Source
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DOI: 10.3810/pgm.2014.09.2811
Sharon Rainy Rongpharpi, MD 1 Shalini Duggal, MD 2 Hitesh Kalita, MD 3 Ashish Kumar Duggal, MD 4 Senior Resident, Department of Microbiology, Dr. Baba Saheb Ambedkar Hospital, New Delhi, India; 2Specialist, Department of Microbiology, Dr. Baba Saheb Ambedkar Hospital, New Delhi, India; 3Senior Resident, Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India; 4Senior Resident, Department of Neurology, Gobind Ballabh Pant Hospital, Delhi, India 1
Abstract: Bacteremia due to Staphylococcus aureus is one of the major causes of morbidity and mortality in India, but studies targeting the source of Staphylococcus aureus bacteremia are lacking. S. aureus has a vivid armamentarium consisting of toxins, adhesins, and other virulence factors by virtue of which it can cause varied types of infections, sometimes of a serious nature. This review highlights the possible causes of S. aureus bacteremia, and discusses the necessity of tracing its source and eliminating it with proper antibiotic therapy to avoid recurrences or relapses. Keywords: Staphylococcus aureus; bacteremia; cause; complications
Introduction
Bacteremia is defined as the presence of viable bacteria in blood, and it is not necessarily associated with clinical manifestations of disease. Staphylococcus aureus bacteremia (SAB) is defined as the presence of $ 1 positive blood culture for S. aureus. It is considered clinically significant if, in addition, the patient has signs and symptoms consistent with bacteremia.1 Staphylococcus aureus is one of the most common pathogens in all age groups, accounting for 19% to 25% of all bloodstream infections worldwide. Staphylococcus aureus bacteremia carries a significant mortality of 20% to 35%, which has been consistent for the past few decades.2 In the preantibiotic era, mortality was close to 80%.3 Staphylococcus aureus bacteremia is community acquired if S. aureus is isolated within 48 hours after hospital admission, or the patient has symptoms or signs suggestive of infection at admission and if the patient has not been transferred from another hospital. In general, community-onset staphylococcal infections occur in younger patients with unknown infective foci. Hospital-onset SAB presents in older patients with usually known sources.4 Isolation of S. aureus from blood, therefore, should prompt source tracing and follow-up so that it can be adequately treated.
Microbiology
Correspondence: Shalini Duggal, MD, Department of Microbiology, Dr. Baba Saheb Ambedkar Hospital, New Delhi, India 110085. Tel: +91-11-9968679771 E-mail: [email protected]
Staphylococci are gram-positive cocci of the family Micrococcaceae. These organisms are catalase-positive, nonmotile aerobes or facultative anaerobes. More than 30 staphylococcal species are pathogenic including S. aureus, which can be distinguished from other staphylococcal species by its production of coagulase, fermentation of mannitol, and the presence of protein A and DNAse.5 Approximately 25% to 50% of healthy persons may be persistently or transiently colonized with S. aureus. Anterior nares are the most frequent site; skin, vagina, axilla, perineum, and oropharynx may also be colonized. Staphylococci aureus nasal carriage has been found to vary from 13% to 28% among health care workers.6–8 Colonization is higher among patients with insulin-
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dependent diabetes, HIV infection, and skin damage, and in patients undergoing hemodialysis. These colonization sites serve as a reservoir of strains for future infections.
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Immunology
The innate immune system forms the first line of defense against invasive infectious agents. This includes anatomical barriers, complement, and immune effector cells. The most common acquired defect of the innate immune system is secondary to chemotherapy-induced neutropenia, especially for the treatment of hematological malignancies.9 Chronic granulomatous disease is the most commonly occurring deficiency. This heterogeneous condition is characterized by the inability of cells to phagocytose catalase-positive microorganisms, resulting in an increased risk of recurrent infections, especially SAB.9 Staphylococcus aureus produces considerable immune response in the infected, and deleterious effects in the host have been related to immunopathological mechanisms. It not only induces a proinflammatory response, but also may modulate the host immune system. Specific molecules embedded in the peptidoglycan layer of the staphylococcal cell wall bind to the toll-like receptor TLR2 on the antigen-presenting cells of the host. This induces a strong interleukin-10 (IL-10) response that downregulates the adaptive T-cell response.10 Mortality in patients with SAB has been linked to elevated IL-10 concentrations.11 The lack of IL-1β response has been seen in patients with prolonged SAB.
Causes of SAB
The initial focus for SAB and infection is most often a skin or soft tissue infection-like wound or furuncle.12 The bacterium spreads superficially and a bloodstream infection follows, but any organ can be infected by S. aureus. Nolan and Beaty12 proposed that infective foci in SAB can be divided into 2 groups, and criteria were established for designation of lesions in various body sites as primary (ie, portal of entry) or secondary foci (ie, metastatic infection). Any site in the body may be considered as the primary focus for SAB if the signs and symptoms of infection are typically associated with the bacterial culture results from that site13; in three-fourths of hemodialysis cases, prosthetic devices are the portal of entry.14 Unless any evidence of direct inoculation by surgery or trauma is present, conditions such as endocarditis, meningitis, septic arthritis, and osteomyelitis are considered secondary to SAB, resulting from metastatic seeding.4 Local complications at the fistula sites are common. Thrombosis, 168
hemorrhage, impending rupture, and persistent bacteremia can cause loss of the fistula. Pneumonia can be secondary to SAB when caused by embolization of infected thrombotic material from tricuspid vegetations or vice versa. Usually urinary isolation of S. aureus is also considered secondary to SAB.15 The Infectious Diseases Society of America recommends echocardiography in all adults presenting with SAB, with transesophageal echocardiograms preferable over transthoracic echocardiograms. Also, additional blood cultures should be done 2 to 4 days after the initial positive culture to document clearance of the bacteremia.16 It has been estimated that in up to 30% cases seeding may occur due to SAB, most commonly in the bones, joints, heart, kidneys, and lungs,17 and SAB has been found as a cause of endocarditis in 25% to 35% cases where mortality may range from 20% to 40%.17 Factors predisposing to SAB include previous hospitalization, alcohol abuse, malignancy, corticosteroids, diabetes mellitus, chronic renal failure, cytostatic and immunosuppressive therapy, cirrhosis of the liver, cardiomyopathy, intravenous drug abuse, and congenital heart disease. Primary foci usually considered to cause SAB are depicted in Figure 1. Studies that attempted source tracing of SAB are listed in Table 1.18–25
Pathogenesis and Virulence Factors
The key factor in enabling S. aureus to persist in the bloodstream, to seed deep tissues, and to form secondary foci of infection is the organism’s ability to upregulate its virulence factors in stressful conditions. Staphylococcus aureus strains are able to adhere to and colonize the skin and mucosa of nares, invade the bloodstream, form protective biofilms, and develop resistance to several antibiotics. The virulence of S. aureus is generally considered multifactorial and due to combined action of several virulence determinants, as discussed in the following subsections.
Adhesion and Colonization
A major class comprises proteins covalently anchored to cell peptidoglycans (via the threonine residue in the sorting signal motif at their C-terminus), which specifically attach to the plasma or extracellular matrix components and collectively termed the microbial surface component recognizing adhesive matrix molecules. These molecules recognize the most prominent components of the extracellular matrix or blood plasma, including fibrinogen, fibronectin, and collagens. Members of the microbial surface component recognizing adhesive matrix molecules family are staphylococcal
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Staphylococcus aureus Bacteremia
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Figure 1. Primary foci usually considered to cause Staphylococcus aureus bacteremia.
Abbreviations: CRP, C-reactive protein; CT, computed tomography; ESR, erythrocyte sedimentation rate; MRI, magnetic resonance imaging; SSSS, staphylococcal scalded skin syndrome; TEE, transesophageal echocardiogram; TLC, total lymphocyte count; TSS, toxic shock syndrome; TTE, transthoracic echocardiogram; USG, ultrasonography.
protein A, fibronectin-binding proteins A and B, collagenbinding protein, and clumping factor A and B proteins.26 These members can adhere to skin, implants, or prostheses, leading to bacteremia.
Invasion
Nearly all strains of S. aureus produce exoproteins such as exotoxins and enzymes, including nucleases, proteases, lipases, hyaluronidase, and collagenase. Cytolytic toxins include α-hemolysin, β-hemolysin, γ-hemolysin, leukocidin, and Panton-Valentine leukocidin.5 Panton-Valentine leukocidin is a bi-component cytolysin that inserts itself into the host’s plasma membrane, especially leukocytes, and hetero-oligomerize to form a pore.27 Staphylococcus aureus produces enterotoxins (SEA, SEB, SEC, SED, SEE, SEG, SEH, and SEI), toxic shock syndrome toxin-1, and the exfoliative toxins A and B. They belong to the group of toxins known as pyrogenic toxin superantigens (eg, enterotoxins and toxic shock syndrome toxin-1),28 which subvert the normal immune response by inducing strong, polyclonal stimulation and expansion of T-cell receptor Vβ (variable β)– specific T cells, followed by the deletion or suppression of these T cells to an anergic state.29 Superantigenicity of toxic shock syndrome toxin-1 and the staphylococcal enterotoxins refers to their ability to directly stimulate proliferation of T-lymphocytes. Staphylococcus aureus can disrupt the skin barrier by secreting these exfoliative toxins.5 Invasion may be triggered when the immune system is compromised, when
there is a break in the physical integument, or when localized inflammation occurs.30
Evasion of the Immune System
Staphylococcus aureus evades the host immune response by secreting anti-opsonizing proteins. Chemotaxis inhibitory protein of S. aureus prevents phagocytosis by neutrophils. Other proteins are the staphylococcal complement inhibitor, chemotaxis inhibitory protein of staphylokinase, extracellular fibrinogen binding protein, extracellular adherence protein, and formyl peptide receptor-like-1 inhibitory protein. Staphylococcal complement inhibitor is a C3-convertase inhibitor that inhibits human neutrophils from phagocytosing S. aureus.31 Chemotaxis inhibitory protein of S. aureus formyl peptide receptor-like-1 inhibitory protein blocks neutrophil receptors for chemoattractants,32 extracellular adherence protein blocks migration of neutrophils from blood vessels into the tissue,33 chemotaxis inhibitory protein of staphylokinase binds to α-defensins,34 and extracellular fibrinogen binding protein inhibits both classic and alternative pathways of complement activation.35 Protein A, located on the surface of S. aureus cells, also has antiphagocytic properties.
Biofilms
Staphylococcus aureus quorum sensing may regulate gene expression to form slimy biofilms on damaged skin, fitted medical devices, and healthy or damaged heart valves. The depletion of nutrients and oxygen causes bacteria to enter a
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Table 1. Studies in Which Source Tracing of SAB was Attempted S. No. First Author, Year
No. of Age Group Cases
1
Prasad, 200718
4
2
Karande, 201219
1
3
Sood, 201220
126
4
Ladhani, 200421
97
5
Chamis, 200122
33
6
Engemann, 200523
210
7
Muder, 200613
13
8
Czachor, 200124
1
9
Van Mierlo, 200225 1
Source
Treatment Given
6 months–5.5 years Deep vein thrombosis Cefotaxime, gentamicin, cloxacillin 7 years Native aortic valve Ceftriaxone, endocarditis gentamicin, vancomycin 1 day–16 years Pneumonia in 42, Not mentioned empyema in 14, pneumatoceles in 4, superficial abscess in 36,URTI in 23 _ Superficial abscess, Cloxacillin cellulitis, septic benzyl penicillin, arthritis, SSSS gentamicin _ 15 cardiac device Vancomycin, infections nafcillin Vascular access – (hemodialysis) in 185 Average 75 years Genitourinary – infections following instrumentation 47 years TSS with multiple Oxacillin abscess 48 years Intra-abdominal Flucloxacillin abscess
Resistance Outcome Pattern
Geographic Area
–
1 expired
Varanasi, India
–
Expired
Mumbai, India
11% MRSA
24 expired
Himachal Pradesh, India
_
_
Kenya
_
2 died, 1 relapse Durham
–
–
North Carolina
10 MRSA
–
Pittsburgh, PA
–
Recovered
Ohio
–
Recovered
Netherlands
Abbreviations: MRSA, methicillin-resistant S. aureus; URTI, upper respiratory tract infection; TSS, toxic shock syndrome; SAB, Staphylococcus aureus bacteremia; SSSS, staphylococcal scalded skin syndrome.
nongrowing state in which they are less susceptible to some antibiotics. In particular, small-colony variants of S. aureus, when adherent and in the stationary phase, demonstrate almost complete resistance to antimicrobial agents.36 The biofilm matrix provides protection against immune cells and may restrict the penetration of some antibiotics.37
Antibiotic Resistance
Strains of S. aureus have developed resistance to antibiotics, including penicillin, cephalosporins, methicillin, vancomycin, and linezolid. Staphylococcus aureus abrogates the effects of penicillin by producing β-lactamase. More than 90% of staphylococcal isolates produce penicillinase.38 Staphylococcus aureus that is oxacillin and methicillin resistant, historically termed methicillin-resistant S. aureus (MRSA), is resistant to all β-lactam agents, including cephalosporins and carbapenems. Since 1996, MRSA strains with decreased susceptibility to vancomycin (minimum inhibitory concentration [MIC], 8 to 16 µg/mL) and strains fully resistant to vancomycin (MIC $ 32 µg/mL) have been reported. Methicillin resistance by S. aureus strains occurs by virtue of acquired penicillin binding protein PBP2a, encoded by 170
the mecA gene. Structurally, PBP2a possesses both transglycosylase and transpeptidase, and confers resistance to all β-lactam antibiotics and is regulated by the mecI or BlaI gene. The mecI and blaI repressors are controlled by the mecRI and blaRI transducers. Other genetic loci, the fem (factors essential for methicillin resistance) and aux (auxiliary) genes, also regulate resistance in S. aureus. Many fem and aux factors have now been identified that are involved in formation of the staphylococcal cell wall. The fem gene confers resistance to methicillin, penicillinase-resistant penicillins, and cephalosporins.39 The mecA gene is located within a larger region of chromosome known as the staphylococcal cassette chromosome mec (SCCmec) region (21–67 kilobase [kb]). The basic elements of SCCmec are the mecRI-mecI-pbp2a region and ccrA. Nosocomial isolates have a larger SCCmec, owing to the accumulation over time of integrated plasmids or transposons that contribute to multidrug resistance. There are currently 5 described SCCmec types (I, II, III, IV, and V; type IV is divided into IVa and IVb). Types I, II, and III are found predominantly in health care–associated MRSA, whereas type IV is commonly found in the more susceptible community-associated MRSA, though
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Staphylococcus aureus Bacteremia
overlapping of these types may occur in both settings. Type IV SCCmec element is small and transferable by transduction. Types I to III SCCmec elements are large and hence do not transfer by bacteriophage. They are predominantly transferred by person-to-person spread of MRSA in the hospital rather than the spread of the resistant determinant from strain to strain. The spread of MRSA within institutions, therefore, is largely due to the transmission of resistant organisms from patient to patient, probably on the hands of transiently colonized health care workers.40,41 True vancomycin resistance in S. aureus appears to rely on acquisition of the vanA gene, whereas reduced vancomycin susceptibility in vancomycin-intermediate S. aureus and hetero-resistant vancomycin-intermediate S. aureus have been linked to mutations in structural or regulatory genes associated with the accessory gene regulator pathway.42 The phenomenon of “MIC creep,” best recognized with respect to the glycopeptide class of antibiotics, refers to insidious, small increases in MICs over time that reflect a clinically significant reduction in susceptibility.43 Vancomycin resistance has been noted in rare cases.44,45 Linezolid resistance is conferred by a mutation in S. aureus ribosomal RNA.46 Empiric therapy of SAB, therefore, should include vancomycin and an antistaphylococcal penicillin, followed by de-escalation after antibiotic susceptibility results.47
Material and Methods
Diagnosis of SAB is made by blood culture. About 10 mL of blood is collected in 2 sets of blood culture bottles (1 aerobic and 1 anaerobic). A direct Gram stain smear from a positive blood culture should be done to make a preliminary diagnosis of bacteremia, which will aid in the initiation of therapy. Correlation between the S. aureus isolated from blood culture and from a primary focus is required to ascertain the casual relationship. For this purpose, culture of all suspected sites or radiological methods should be used to establish a causal relationship. Typing methods such as biotyping, phage typing, and antibiogram typing have been used in the past. Now newer methods of molecular typing such as ribotyping, pulse-field gel electrophoresis analysis, plasmid profiling, multilocus enzyme electrophoresis, and multilocus sequence typing are being used. Multilocus typing using variable numbers of tandem repeats has recently been used for MRSA typing, and pulse-field gel electrophoresis is the commonest staphylococcal typing method used worldwide.5 Antibiotic susceptibility tests are done to determine methicillin resistance and classify the strains as MRSA or methicillin-sensitive S. aureus.
Treatment
The duration of therapy for SAB depends on whether or not the infection is complicated or uncomplicated.48 Categorization and treatment guide is depicted in Table 2.2,49
Recurrences in SAB
Recurrence of SAB should be considered if there is reappearance of S. aureus with the same susceptibility pattern after 2 weeks of documented negative blood culture but within 1 year of the initial treatment of SAB.50–52 Persistent bacteremia has been defined as bacteremia that lasts for $ 7 days.52 Persistence of bacteremia enables the establishment of occult foci and subsequent relapses. Persistence of MRSA bacteremia and relapses have been associated with vancomycin treatment,53 with isolates having higher vancomycin MIC values. Recurrence can be subclassified as reinfection (different pulsed-field gel electrophoresis patterns) or relapse (same pulsed-field gel electrophoresis pattern).50 Another study has described relapse as identical typing results of sequential isolates, defined as 95% similarity and no band differences.52 Recurrences in SAB range from 9% to 17%.50–52 Risk factors include valvular heart disease, cirrhosis of the liver, deep-seated infection (including endocarditis), indwelling devices, prolonged vancomycin therapy, diabetes, HIV infection, MRSA infections, and inadequate antibiotic treatment.
Role of Vaccines
There is currently no vaccine licensed for prevention against staphylococcal bacteremia in humans, but research is ongoing for identification of potential vaccine targets. Staphylococcus aureus generates significant humoral response, and immunogenicity of different antigens has been tested by various researchers; 56 antigens have been tested so far.54 Though a number of virulence factors operate in SAB, the most immunogenic marker should be identified, which can effectively generate a protective immune response. One such marker is the putative iron-regulated ABC transporter SA0688, which is immunogenic and is ubiquitously expressed by genetically distinct isolates under different culture conditions.55 Another vaccine candidate is Staphylococcus aureus alpha-hemolysin (HIa). It is a poreforming toxin expressed by most S. aureus strains, and it plays a key role in the pathogenesis of staphylococcal skin infections and pneumonia. The HIa recombinant subunit vaccine, designated as AT-62aa, along with a glucopyranosyl lipid adjuvant stable emulsion is currently undergoing clini-
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Table 2. SAB Categorization and Treatment Options
Indicated in SAB associated with complicated skin and soft tissue infections or with known or suspected right-sided infective endocarditis. Trough vancomycin monitoring recommended for patients who are morbidly obese, have renal dysfunction, or have fluctuating volume of distribution. Serum trough concentration should be obtained at steady-state condition prior to the fourth or fifth dose. Trough concentration of 15–20 µm/mL is recommended.49 c In cases where vancomycin cannot be given, these antibiotics may be considered as therapeutic options. Abbreviations: MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus aureus; SAB, Staphylococcus aureus bacteremia. a
b
cal trials, and has so far been reported to produce significant reduction in bacterial burden in internal organs. The primary mechanism has been considered to be antibody-mediated neutralization.56 It is not clear if an episode of staphylococcal infection provides any immunity to subsequent such infections, though strain-specific preimmunization has been demonstrated in some studies, especially in immunocompetent individuals.57
172
Recent Advances in SAB Diagnosis
Laboratory diagnosis of SAB should be as quick and specific as possible, so that antibiotic therapy can begin and target organs can be treated. An ideal laboratory test should essentially identify the organism directly from blood, and ascertain its virulence determinants and antibiotic resistance profile. The test should be fast and reliable with high sensitivity and specificity. The gold standard of bloodstream microbial detection and identification is by culture staining and phenotypic and biochemical identification. However, attempts
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Staphylococcus aureus Bacteremia
have been made to shorten the time for diagnosis by culture and identification by direct inoculation of positive cultures in automated identification panel systems.58 Molecular methods for diagnosis are rapid, and can target specific genes by use of peptide or nucleic acid probes, polymerase chain reaction (PCR), and other nucleic acid amplification techniques from flagged blood cultures. Amplification of multiple target sites within 16S ribosomal DNA has been widely used for microbial identification. Staphylococcus aureus peptide nucleic acid fluorescence in-situ hybridization is commercially available, which uses peptide nucleic acid probes targeting S. aureus 16S recombinant RNA for direct identification from positive blood culture bottles.59 The StaphPlex-50 system (Qiagen, Redwood City, CA) is a target-enriched multiplex PCR method for identification of S. aureus, and detection of Panton–Valentine leukocidin and several antimicrobial-resistance determinants such as the mecA, aacA, ermA, ermC, tetM, and tetK genes, which confer resistance to methicillin, aminoglycosides, macrolides, lincosamides, streptogramins, and tetracycline, respectively. The amplified products are further characterized by using a Luminex suspension array (Luminex Corp., Austin, TX). The whole process can be performed within 5 hours. In matrix-assisted laser desorption/ionization time of flight mass spectrometry (MS; Bruker Daltonics, Bremen, Germany),60 colonies from a solid or liquid culture of any organism are mixed with matrix-assisted laser desorption/ ionization and rapidly analyzed by MS. It works by comparison of the mass spectral signals obtained from postculture specimens with a database of spectra from reference standard spectra. SeptiFast (Roche Diagnostics, Mannheim, Germany) uses real-time PCR in a nonquantitative mode, which helps by identifying nonculturable pathogens rapidly (, 6 hours). This lightcycler is not available for use in the United States. Polymerase chain reaction amplification to electrospray ionization/MS is a further advancement, as it not only identifies the organisms but also provides information about its strain type, virulence factors, and resistance genes.61 A major strength of the PCR electrospray ionization/MS method is that the mass spectrometer is capable of analyzing multiple amplification products in a fast and automated fashion. These advances, particularly for the diagnosis of SAB, further emphasize its burden, its grave effects, and the importance of timely treatment.
Conclusion
Isolation of S. aureus is common in blood cultures. However, whether it was a skin colonizer and came as a contaminant
during specimen collection or an actual case of bacteremia is difficult to ascertain. Considering the vast potential of this organism to harbor virulence proteins and cause infections, every attempt must be made to treat this infection effectively and completely. Root-to-cause analysis of this infection starting from source tracing through to follow-up, which includes a detailed clinical examination of the patient, echocardiography, chest X-ray, and an abdominal ultrasonography must be done so that reservoirs of this bacterium are eliminated from relevant sites by using an antibiotic dose and duration relevant to that organ system or area of the body.
Conflict of Interest Statement
Sharon Rainy Rongpharpi, MD, Shalini Duggal, MD, Hitesh Kalita, MD, and Ashish Kumar Duggal, MD, have no conflicts of interest to declare.
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Rongpharpi et al 14. Kessler M, Hoen B, Mayeux D, Hestin D, Fontenaille C. Bacteremia in patients on chronic hemodialysis. A multicenter prospective study. Nephron. 1993;64:95–100. 15. Lee BK, Crossley K, Gerding DN. The association between Staphylococcus aureus bacteremia and bacteriuria. Am J Med. 1978;65:303–306. 16. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillinresistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1–38. 17. Lowy FD. Staphylococcal infections. In: Kasper DL, Fauci AS, Longo DL, Braunwald E, Hauser SL, Jameson JL, eds. Harrison’s Principles of Internal Medicine, 18th ed. New York: McGraw-Hill; 2012:902–1003. 18. Prasad R, Mishra OP, Pant P. Deep Vein Thrombosis with Staphylococcus aureus septicemia. Indian Paedtr. 2007;44:43–44. 19. Karande S, Muranjan M. Native aortic valve endocarditis secondary to Staphylococcus aureus Bacteremia. Indian Pediatr. 2012;49:764–768. 20. Sood M, Sharma S, Grover N Staphylococcus aureus infection: Clinical profile and outcome among children admitted to a tertiary care hospital in developing economy. Pediatr Infect Dis J. 2012;4(3):101–106. 21. Ladhani S, Konana OS, Mwarumba S, English MC. Bacteremia due to Staphylococcus aureus. Arch Dis Child. 2004;89:568–571. 22. Chamis AL, Peterson GL, Cabell CH, et al. Staphylococcus aureus bacteremia in patients with permanent pacemakers or implantable cardioverter-defibrillators. Circulation. 2001;104:1029–1033. 23. Engemann JJ, Friedman JY, Reed SD, et al. Clinical outcomes and costs due to Staphylococcus aureus bacteremia among patients receiving long-term hemodialysis. Infect Control Hosp Epidemiol. 2005;26(6):534–539. 24. Czachor JS, Herchline TE. Bacteremic non-menstrual staphylococcal toxic shock syndrome associated with enterotoxins A and C. Clin Infect Dis. 2001;32(3):53–56. 25. Van Mierlo PJ, De Boer SY, Van Dissel JT, Arend SM. Recurrent staphylococcal bacteremia and subhepatic abscess associated with gallstones spilled during laparoscopic cholecystectomy two years earlier. Neth J Med. 2002;60(4):177–180. 26. Kreis T, Vale R. Guidebook to the Extracellular Matrix, Anchor, and Adhesion Proteins. Oxford, UK: Oxford University Press; 1999. 27. Kaneko J, Kamio Y. Bacterial two-component and hetero-heptameric poreforming cytolytic toxins: structures pore-forming mechanism organization of the genes. Biosci Biotechnol Biochem. 2004;68:981–1003. 28. McCormick JK, Yarwood JM, Schlievert PM. Toxic shock syndrome and bacterial superantigens: an update. Annu Rev Microbiol. 2001;55:77–104. 29. Wang ZQ, Orlikowsky T, Dudhane A, et al. Staphylococcal enterotoxin B-induced T-cell anergy is mediated by regulatory T cells. Immunology. 1998;94(3):331–339. 30. Otto M. Quorum-sensing control in staphylococci—a target for antimicrobial drug therapy? FEMS Microbiol Lett. 2004;241(2):135–141. 31. Rooijakkers SH, Ruyken M, Roos A, Daha MR, Presanis JS, Sim RB. Immune evasion by a staphylococcal complement inhibitor that acts on C3 convertases. Nat Immunol. 2005;6(9):920–927. 32. Haas PJ, de Haas CJ, Kleibeuker W, Poppelier MJ, van Kessel KP, Kruijtzer JA. N-terminal residues of the chemotaxis inhibitory protein of Staphylococcus aureus are essential for blocking formulated peptide receptor but not C5a receptor. J Immunol. 2004;173:5704–5711. 33. Chavakis T, Hussain M, Kanse SM, et al. Staphylococcus aureus extracellular adherence protein serves as anti-inflammatory factor by inhibiting the recruitment of host leukocytes. Nat Med. 2002;8(7):687–693. 34. Bokarewa MI, Jin T, Tarkowski A. Staphylococcus aureus: staphylokinase. Int J Biochem Cell Biol. 2006;38(4):504–509. 35. Lee LY, Liang X, Hook M, Brown EL. Identification and characterization of the C3 binding domain of the Staphylococcus aureus extracellular fibrinogen-binding protein (Efb). J Biol Chem. 2004;279(49):50710–50716.
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36. Proctor RA, Kahl B, von Eiff C, Vaudaux PE, Lew DP, Peters G. Staphylococcal small colony variants have novel mechanisms for antibiotic resistance. Clin Infect Dis. 1998;27(Suppl 1):S68–S74. 37. Patel R. Biofilms and antimicrobial resistancexxx. Clin Orthop Relat Res. 2005;41–47. 38. Lowy FD. Antimicrobial resistance: the example of Staphylococcus aureus. J Clin Invest. 2003;111(9):1265–1273. 39. Jansen WT, Beitsma MM, Koeman CJ, Van Wamel WJ, Verhoef J, Fluit AC. Novel mobile variants of staphylococcal cassette chromosome mec in Staphylococcus aureus. Antimicrob Agents Chemother. 2006;50:2072–2078. 40. Loomba PS, Taneja J, Mishra B. Methicillin and vancomycin resistant S. aureus in hospitalized patients. J Global Infect Dis. 2010;2: 275–283. 41. Duggal S, Kaur N, Hans C. Outbreak of MRSA in burns ward. J Clin Diagn Res. 2011;5(3):476–479. 42. Tenover FC, Moellering RC Jr. The rationale for revising the Clinical and Laboratory Standards Institute vancomycin minimal inhibitory concentration interpretive criteria for Staphylococcus aureus. Clin Infect Dis. 2007;44:1208–1215. 43. Gould IM. The problem with glycopeptides. Int J Antimicrob Agents. 2007;30:1–3. 44. Saravolatz LD, Pawlak J, Johnson LB. In vitro susceptibilities and molecular analysis of vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus isolates. Clin Infect Dis. 2012;55:582–586. 45. Melo-Cristino J, Resina C, Manuel V, Lito L, Ramirez M. First case of infection with vancomycin-resistant Staphylococcus aureus in Europe. Lancet. 2013;382(9888):205. 46. Peeters MJ, Sarria JC. Clinical characteristics of linezolid-resistant Staphylococcus aureus infections. Am J Med Sci. 2005;330:102–104. 47. McConeghy KW, Bleasdale SC, Rodvold KA. The empirical therapy of vancomycin and a β-lactam for Staphylococcal bacteremia. Clin Infect Dis. 2013;57(12):1760–1765. 48. Mitchell DH, Howden BP. Diagnosis and management of Staphylococcus aureus bacteraemia. Intern Med J. 2005;35(Suppl 2):S17–S24. 49. Rybak MJ, Lomestro BM, Rotschafer JC, et al. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the Infectious Disease Society of America, the American Society of Health System Pharmacist, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis. 2009;49:325–327. 50. Chang FY, Peacock JE Jr, Musher DM, et al. Staphylococcus aureus bacteremia: recurrence and the impact of antibiotic treatment in a prospective multicenter study. Medicine (Baltimore). 2003;82(5):333–339. 51. Kreisel K, Boyd K, Langenberg P, Roghmann MC. Risk factors for recurrence in patients with Staphylococcus aureus infections complicated by bacteremia. Diagn Microbiol Infect Dis. 2006;55(3):179–184. 52. Welsh KJ, Skrobarcek KA, Abbott AN, et al. Predictors of relapse of methicillin resistant Staphylococcus aureus bacteremia after treatment with vancomycin. J Clin Microbiol. 2011;49:3669–3672. 53. Neuner EA, Casabar E, Reichley R, McKinnon PS. Clinical, microbiologic, and genetic determinants of persistent methicillin-resistant Staphylococcus aureus bacteremia. Diagn Microbiol Infect Dis. 2010;67:228–233. 54. den Reijer PM, Lemmens-den Toom N, Kant S, et al. Characterization of the humoral immune response during Staphylococcus aureus bacteremia and global gene expression by Staphylococcus aureus in human blood. PLoS One. 2013;8(1):e53391. 55. Adhikari RP, Karauzum H, Sarwar J, et al. Novel structurally designed vaccine for S. aureus α-hemolysin: protection against bacteremia and pneumonia. PLoS One. 2012;7(6):e38567. 56. Kolata J, Bode LG, Holtfreter S, et al. Distinctive patterns in the human antibody response to Staphylococcus aureus bacteremia in carriers and non-carriers. Proteomics. 2011;11(19):3914–3927. 57. Duggal S, Jesaiwal SK, Tandon N, Chugh TD. Direct inoculation on Phoenix panels for identification and antimicrobial susceptibility from positive BACTEC cultures: First study from India. Indian J Med Microbiol. 2011;29:283–287.
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Staphylococcus aureus Bacteremia 60. La Scola B, Raoult D. Direct identification of bacteria in positive blood culture bottles by matrix-assisted laser desorption ionisation time-offlight mass spectrometry. PLoS One. 2009;4(11):e8041. 61. Wolk DM, Blyn LB, Hall TA, et al. Pathogen profiling: rapid molecular characterization of Staphylococcus aureus by PCR/ ESI-MS and correlation with phenotype. J Clin Microbiol. 2009; 47(10):3129–3137.
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58. Oliveira K, Procop GW, Wilson D, Coull J, Stender H. Rapid identification of Staphylococcus aureus directly from blood cultures by fluorescence in situ hybridization with peptide nucleic acid probes. J Clin Microbiol. 2002;40(1):247–251. 59. Tang YW, Kilic A, Yang Q, et al. StaphPlex system for rapid and simultaneous identification of antibiotic resistance determinants and Panton–Valentine leukocidin detection of staphylococci from positive blood cultures. J Clin Microbiol. 2007;45(6):1867–1873.
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Staphylococcus aureus Bacteremia: Targeting the Source
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DOI: 10.3810/pgm.2014.09.2811
Sharon Rainy Rongpharpi, MD 1 Shalini Duggal, MD 2 Hitesh Kalita, MD 3 Ashish Kumar Duggal, MD 4 Senior Resident, Department of Microbiology, Dr. Baba Saheb Ambedkar Hospital, New Delhi, India; 2Specialist, Department of Microbiology, Dr. Baba Saheb Ambedkar Hospital, New Delhi, India; 3Senior Resident, Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India; 4Senior Resident, Department of Neurology, Gobind Ballabh Pant Hospital, Delhi, India 1
Abstract: Bacteremia due to Staphylococcus aureus is one of the major causes of morbidity and mortality in India, but studies targeting the source of Staphylococcus aureus bacteremia are lacking. S. aureus has a vivid armamentarium consisting of toxins, adhesins, and other virulence factors by virtue of which it can cause varied types of infections, sometimes of a serious nature. This review highlights the possible causes of S. aureus bacteremia, and discusses the necessity of tracing its source and eliminating it with proper antibiotic therapy to avoid recurrences or relapses. Keywords: Staphylococcus aureus; bacteremia; cause; complications
Introduction
Bacteremia is defined as the presence of viable bacteria in blood, and it is not necessarily associated with clinical manifestations of disease. Staphylococcus aureus bacteremia (SAB) is defined as the presence of $ 1 positive blood culture for S. aureus. It is considered clinically significant if, in addition, the patient has signs and symptoms consistent with bacteremia.1 Staphylococcus aureus is one of the most common pathogens in all age groups, accounting for 19% to 25% of all bloodstream infections worldwide. Staphylococcus aureus bacteremia carries a significant mortality of 20% to 35%, which has been consistent for the past few decades.2 In the preantibiotic era, mortality was close to 80%.3 Staphylococcus aureus bacteremia is community acquired if S. aureus is isolated within 48 hours after hospital admission, or the patient has symptoms or signs suggestive of infection at admission and if the patient has not been transferred from another hospital. In general, community-onset staphylococcal infections occur in younger patients with unknown infective foci. Hospital-onset SAB presents in older patients with usually known sources.4 Isolation of S. aureus from blood, therefore, should prompt source tracing and follow-up so that it can be adequately treated.
Microbiology
Correspondence: Shalini Duggal, MD, Department of Microbiology, Dr. Baba Saheb Ambedkar Hospital, New Delhi, India 110085. Tel: +91-11-9968679771 E-mail: [email protected]
Staphylococci are gram-positive cocci of the family Micrococcaceae. These organisms are catalase-positive, nonmotile aerobes or facultative anaerobes. More than 30 staphylococcal species are pathogenic including S. aureus, which can be distinguished from other staphylococcal species by its production of coagulase, fermentation of mannitol, and the presence of protein A and DNAse.5 Approximately 25% to 50% of healthy persons may be persistently or transiently colonized with S. aureus. Anterior nares are the most frequent site; skin, vagina, axilla, perineum, and oropharynx may also be colonized. Staphylococci aureus nasal carriage has been found to vary from 13% to 28% among health care workers.6–8 Colonization is higher among patients with insulin-
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Rongpharpi et al
dependent diabetes, HIV infection, and skin damage, and in patients undergoing hemodialysis. These colonization sites serve as a reservoir of strains for future infections.
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Immunology
The innate immune system forms the first line of defense against invasive infectious agents. This includes anatomical barriers, complement, and immune effector cells. The most common acquired defect of the innate immune system is secondary to chemotherapy-induced neutropenia, especially for the treatment of hematological malignancies.9 Chronic granulomatous disease is the most commonly occurring deficiency. This heterogeneous condition is characterized by the inability of cells to phagocytose catalase-positive microorganisms, resulting in an increased risk of recurrent infections, especially SAB.9 Staphylococcus aureus produces considerable immune response in the infected, and deleterious effects in the host have been related to immunopathological mechanisms. It not only induces a proinflammatory response, but also may modulate the host immune system. Specific molecules embedded in the peptidoglycan layer of the staphylococcal cell wall bind to the toll-like receptor TLR2 on the antigen-presenting cells of the host. This induces a strong interleukin-10 (IL-10) response that downregulates the adaptive T-cell response.10 Mortality in patients with SAB has been linked to elevated IL-10 concentrations.11 The lack of IL-1β response has been seen in patients with prolonged SAB.
Causes of SAB
The initial focus for SAB and infection is most often a skin or soft tissue infection-like wound or furuncle.12 The bacterium spreads superficially and a bloodstream infection follows, but any organ can be infected by S. aureus. Nolan and Beaty12 proposed that infective foci in SAB can be divided into 2 groups, and criteria were established for designation of lesions in various body sites as primary (ie, portal of entry) or secondary foci (ie, metastatic infection). Any site in the body may be considered as the primary focus for SAB if the signs and symptoms of infection are typically associated with the bacterial culture results from that site13; in three-fourths of hemodialysis cases, prosthetic devices are the portal of entry.14 Unless any evidence of direct inoculation by surgery or trauma is present, conditions such as endocarditis, meningitis, septic arthritis, and osteomyelitis are considered secondary to SAB, resulting from metastatic seeding.4 Local complications at the fistula sites are common. Thrombosis, 168
hemorrhage, impending rupture, and persistent bacteremia can cause loss of the fistula. Pneumonia can be secondary to SAB when caused by embolization of infected thrombotic material from tricuspid vegetations or vice versa. Usually urinary isolation of S. aureus is also considered secondary to SAB.15 The Infectious Diseases Society of America recommends echocardiography in all adults presenting with SAB, with transesophageal echocardiograms preferable over transthoracic echocardiograms. Also, additional blood cultures should be done 2 to 4 days after the initial positive culture to document clearance of the bacteremia.16 It has been estimated that in up to 30% cases seeding may occur due to SAB, most commonly in the bones, joints, heart, kidneys, and lungs,17 and SAB has been found as a cause of endocarditis in 25% to 35% cases where mortality may range from 20% to 40%.17 Factors predisposing to SAB include previous hospitalization, alcohol abuse, malignancy, corticosteroids, diabetes mellitus, chronic renal failure, cytostatic and immunosuppressive therapy, cirrhosis of the liver, cardiomyopathy, intravenous drug abuse, and congenital heart disease. Primary foci usually considered to cause SAB are depicted in Figure 1. Studies that attempted source tracing of SAB are listed in Table 1.18–25
Pathogenesis and Virulence Factors
The key factor in enabling S. aureus to persist in the bloodstream, to seed deep tissues, and to form secondary foci of infection is the organism’s ability to upregulate its virulence factors in stressful conditions. Staphylococcus aureus strains are able to adhere to and colonize the skin and mucosa of nares, invade the bloodstream, form protective biofilms, and develop resistance to several antibiotics. The virulence of S. aureus is generally considered multifactorial and due to combined action of several virulence determinants, as discussed in the following subsections.
Adhesion and Colonization
A major class comprises proteins covalently anchored to cell peptidoglycans (via the threonine residue in the sorting signal motif at their C-terminus), which specifically attach to the plasma or extracellular matrix components and collectively termed the microbial surface component recognizing adhesive matrix molecules. These molecules recognize the most prominent components of the extracellular matrix or blood plasma, including fibrinogen, fibronectin, and collagens. Members of the microbial surface component recognizing adhesive matrix molecules family are staphylococcal
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Staphylococcus aureus Bacteremia
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Figure 1. Primary foci usually considered to cause Staphylococcus aureus bacteremia.
Abbreviations: CRP, C-reactive protein; CT, computed tomography; ESR, erythrocyte sedimentation rate; MRI, magnetic resonance imaging; SSSS, staphylococcal scalded skin syndrome; TEE, transesophageal echocardiogram; TLC, total lymphocyte count; TSS, toxic shock syndrome; TTE, transthoracic echocardiogram; USG, ultrasonography.
protein A, fibronectin-binding proteins A and B, collagenbinding protein, and clumping factor A and B proteins.26 These members can adhere to skin, implants, or prostheses, leading to bacteremia.
Invasion
Nearly all strains of S. aureus produce exoproteins such as exotoxins and enzymes, including nucleases, proteases, lipases, hyaluronidase, and collagenase. Cytolytic toxins include α-hemolysin, β-hemolysin, γ-hemolysin, leukocidin, and Panton-Valentine leukocidin.5 Panton-Valentine leukocidin is a bi-component cytolysin that inserts itself into the host’s plasma membrane, especially leukocytes, and hetero-oligomerize to form a pore.27 Staphylococcus aureus produces enterotoxins (SEA, SEB, SEC, SED, SEE, SEG, SEH, and SEI), toxic shock syndrome toxin-1, and the exfoliative toxins A and B. They belong to the group of toxins known as pyrogenic toxin superantigens (eg, enterotoxins and toxic shock syndrome toxin-1),28 which subvert the normal immune response by inducing strong, polyclonal stimulation and expansion of T-cell receptor Vβ (variable β)– specific T cells, followed by the deletion or suppression of these T cells to an anergic state.29 Superantigenicity of toxic shock syndrome toxin-1 and the staphylococcal enterotoxins refers to their ability to directly stimulate proliferation of T-lymphocytes. Staphylococcus aureus can disrupt the skin barrier by secreting these exfoliative toxins.5 Invasion may be triggered when the immune system is compromised, when
there is a break in the physical integument, or when localized inflammation occurs.30
Evasion of the Immune System
Staphylococcus aureus evades the host immune response by secreting anti-opsonizing proteins. Chemotaxis inhibitory protein of S. aureus prevents phagocytosis by neutrophils. Other proteins are the staphylococcal complement inhibitor, chemotaxis inhibitory protein of staphylokinase, extracellular fibrinogen binding protein, extracellular adherence protein, and formyl peptide receptor-like-1 inhibitory protein. Staphylococcal complement inhibitor is a C3-convertase inhibitor that inhibits human neutrophils from phagocytosing S. aureus.31 Chemotaxis inhibitory protein of S. aureus formyl peptide receptor-like-1 inhibitory protein blocks neutrophil receptors for chemoattractants,32 extracellular adherence protein blocks migration of neutrophils from blood vessels into the tissue,33 chemotaxis inhibitory protein of staphylokinase binds to α-defensins,34 and extracellular fibrinogen binding protein inhibits both classic and alternative pathways of complement activation.35 Protein A, located on the surface of S. aureus cells, also has antiphagocytic properties.
Biofilms
Staphylococcus aureus quorum sensing may regulate gene expression to form slimy biofilms on damaged skin, fitted medical devices, and healthy or damaged heart valves. The depletion of nutrients and oxygen causes bacteria to enter a
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Table 1. Studies in Which Source Tracing of SAB was Attempted S. No. First Author, Year
No. of Age Group Cases
1
Prasad, 200718
4
2
Karande, 201219
1
3
Sood, 201220
126
4
Ladhani, 200421
97
5
Chamis, 200122
33
6
Engemann, 200523
210
7
Muder, 200613
13
8
Czachor, 200124
1
9
Van Mierlo, 200225 1
Source
Treatment Given
6 months–5.5 years Deep vein thrombosis Cefotaxime, gentamicin, cloxacillin 7 years Native aortic valve Ceftriaxone, endocarditis gentamicin, vancomycin 1 day–16 years Pneumonia in 42, Not mentioned empyema in 14, pneumatoceles in 4, superficial abscess in 36,URTI in 23 _ Superficial abscess, Cloxacillin cellulitis, septic benzyl penicillin, arthritis, SSSS gentamicin _ 15 cardiac device Vancomycin, infections nafcillin Vascular access – (hemodialysis) in 185 Average 75 years Genitourinary – infections following instrumentation 47 years TSS with multiple Oxacillin abscess 48 years Intra-abdominal Flucloxacillin abscess
Resistance Outcome Pattern
Geographic Area
–
1 expired
Varanasi, India
–
Expired
Mumbai, India
11% MRSA
24 expired
Himachal Pradesh, India
_
_
Kenya
_
2 died, 1 relapse Durham
–
–
North Carolina
10 MRSA
–
Pittsburgh, PA
–
Recovered
Ohio
–
Recovered
Netherlands
Abbreviations: MRSA, methicillin-resistant S. aureus; URTI, upper respiratory tract infection; TSS, toxic shock syndrome; SAB, Staphylococcus aureus bacteremia; SSSS, staphylococcal scalded skin syndrome.
nongrowing state in which they are less susceptible to some antibiotics. In particular, small-colony variants of S. aureus, when adherent and in the stationary phase, demonstrate almost complete resistance to antimicrobial agents.36 The biofilm matrix provides protection against immune cells and may restrict the penetration of some antibiotics.37
Antibiotic Resistance
Strains of S. aureus have developed resistance to antibiotics, including penicillin, cephalosporins, methicillin, vancomycin, and linezolid. Staphylococcus aureus abrogates the effects of penicillin by producing β-lactamase. More than 90% of staphylococcal isolates produce penicillinase.38 Staphylococcus aureus that is oxacillin and methicillin resistant, historically termed methicillin-resistant S. aureus (MRSA), is resistant to all β-lactam agents, including cephalosporins and carbapenems. Since 1996, MRSA strains with decreased susceptibility to vancomycin (minimum inhibitory concentration [MIC], 8 to 16 µg/mL) and strains fully resistant to vancomycin (MIC $ 32 µg/mL) have been reported. Methicillin resistance by S. aureus strains occurs by virtue of acquired penicillin binding protein PBP2a, encoded by 170
the mecA gene. Structurally, PBP2a possesses both transglycosylase and transpeptidase, and confers resistance to all β-lactam antibiotics and is regulated by the mecI or BlaI gene. The mecI and blaI repressors are controlled by the mecRI and blaRI transducers. Other genetic loci, the fem (factors essential for methicillin resistance) and aux (auxiliary) genes, also regulate resistance in S. aureus. Many fem and aux factors have now been identified that are involved in formation of the staphylococcal cell wall. The fem gene confers resistance to methicillin, penicillinase-resistant penicillins, and cephalosporins.39 The mecA gene is located within a larger region of chromosome known as the staphylococcal cassette chromosome mec (SCCmec) region (21–67 kilobase [kb]). The basic elements of SCCmec are the mecRI-mecI-pbp2a region and ccrA. Nosocomial isolates have a larger SCCmec, owing to the accumulation over time of integrated plasmids or transposons that contribute to multidrug resistance. There are currently 5 described SCCmec types (I, II, III, IV, and V; type IV is divided into IVa and IVb). Types I, II, and III are found predominantly in health care–associated MRSA, whereas type IV is commonly found in the more susceptible community-associated MRSA, though
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Staphylococcus aureus Bacteremia
overlapping of these types may occur in both settings. Type IV SCCmec element is small and transferable by transduction. Types I to III SCCmec elements are large and hence do not transfer by bacteriophage. They are predominantly transferred by person-to-person spread of MRSA in the hospital rather than the spread of the resistant determinant from strain to strain. The spread of MRSA within institutions, therefore, is largely due to the transmission of resistant organisms from patient to patient, probably on the hands of transiently colonized health care workers.40,41 True vancomycin resistance in S. aureus appears to rely on acquisition of the vanA gene, whereas reduced vancomycin susceptibility in vancomycin-intermediate S. aureus and hetero-resistant vancomycin-intermediate S. aureus have been linked to mutations in structural or regulatory genes associated with the accessory gene regulator pathway.42 The phenomenon of “MIC creep,” best recognized with respect to the glycopeptide class of antibiotics, refers to insidious, small increases in MICs over time that reflect a clinically significant reduction in susceptibility.43 Vancomycin resistance has been noted in rare cases.44,45 Linezolid resistance is conferred by a mutation in S. aureus ribosomal RNA.46 Empiric therapy of SAB, therefore, should include vancomycin and an antistaphylococcal penicillin, followed by de-escalation after antibiotic susceptibility results.47
Material and Methods
Diagnosis of SAB is made by blood culture. About 10 mL of blood is collected in 2 sets of blood culture bottles (1 aerobic and 1 anaerobic). A direct Gram stain smear from a positive blood culture should be done to make a preliminary diagnosis of bacteremia, which will aid in the initiation of therapy. Correlation between the S. aureus isolated from blood culture and from a primary focus is required to ascertain the casual relationship. For this purpose, culture of all suspected sites or radiological methods should be used to establish a causal relationship. Typing methods such as biotyping, phage typing, and antibiogram typing have been used in the past. Now newer methods of molecular typing such as ribotyping, pulse-field gel electrophoresis analysis, plasmid profiling, multilocus enzyme electrophoresis, and multilocus sequence typing are being used. Multilocus typing using variable numbers of tandem repeats has recently been used for MRSA typing, and pulse-field gel electrophoresis is the commonest staphylococcal typing method used worldwide.5 Antibiotic susceptibility tests are done to determine methicillin resistance and classify the strains as MRSA or methicillin-sensitive S. aureus.
Treatment
The duration of therapy for SAB depends on whether or not the infection is complicated or uncomplicated.48 Categorization and treatment guide is depicted in Table 2.2,49
Recurrences in SAB
Recurrence of SAB should be considered if there is reappearance of S. aureus with the same susceptibility pattern after 2 weeks of documented negative blood culture but within 1 year of the initial treatment of SAB.50–52 Persistent bacteremia has been defined as bacteremia that lasts for $ 7 days.52 Persistence of bacteremia enables the establishment of occult foci and subsequent relapses. Persistence of MRSA bacteremia and relapses have been associated with vancomycin treatment,53 with isolates having higher vancomycin MIC values. Recurrence can be subclassified as reinfection (different pulsed-field gel electrophoresis patterns) or relapse (same pulsed-field gel electrophoresis pattern).50 Another study has described relapse as identical typing results of sequential isolates, defined as 95% similarity and no band differences.52 Recurrences in SAB range from 9% to 17%.50–52 Risk factors include valvular heart disease, cirrhosis of the liver, deep-seated infection (including endocarditis), indwelling devices, prolonged vancomycin therapy, diabetes, HIV infection, MRSA infections, and inadequate antibiotic treatment.
Role of Vaccines
There is currently no vaccine licensed for prevention against staphylococcal bacteremia in humans, but research is ongoing for identification of potential vaccine targets. Staphylococcus aureus generates significant humoral response, and immunogenicity of different antigens has been tested by various researchers; 56 antigens have been tested so far.54 Though a number of virulence factors operate in SAB, the most immunogenic marker should be identified, which can effectively generate a protective immune response. One such marker is the putative iron-regulated ABC transporter SA0688, which is immunogenic and is ubiquitously expressed by genetically distinct isolates under different culture conditions.55 Another vaccine candidate is Staphylococcus aureus alpha-hemolysin (HIa). It is a poreforming toxin expressed by most S. aureus strains, and it plays a key role in the pathogenesis of staphylococcal skin infections and pneumonia. The HIa recombinant subunit vaccine, designated as AT-62aa, along with a glucopyranosyl lipid adjuvant stable emulsion is currently undergoing clini-
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Table 2. SAB Categorization and Treatment Options
Indicated in SAB associated with complicated skin and soft tissue infections or with known or suspected right-sided infective endocarditis. Trough vancomycin monitoring recommended for patients who are morbidly obese, have renal dysfunction, or have fluctuating volume of distribution. Serum trough concentration should be obtained at steady-state condition prior to the fourth or fifth dose. Trough concentration of 15–20 µm/mL is recommended.49 c In cases where vancomycin cannot be given, these antibiotics may be considered as therapeutic options. Abbreviations: MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus aureus; SAB, Staphylococcus aureus bacteremia. a
b
cal trials, and has so far been reported to produce significant reduction in bacterial burden in internal organs. The primary mechanism has been considered to be antibody-mediated neutralization.56 It is not clear if an episode of staphylococcal infection provides any immunity to subsequent such infections, though strain-specific preimmunization has been demonstrated in some studies, especially in immunocompetent individuals.57
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Recent Advances in SAB Diagnosis
Laboratory diagnosis of SAB should be as quick and specific as possible, so that antibiotic therapy can begin and target organs can be treated. An ideal laboratory test should essentially identify the organism directly from blood, and ascertain its virulence determinants and antibiotic resistance profile. The test should be fast and reliable with high sensitivity and specificity. The gold standard of bloodstream microbial detection and identification is by culture staining and phenotypic and biochemical identification. However, attempts
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Staphylococcus aureus Bacteremia
have been made to shorten the time for diagnosis by culture and identification by direct inoculation of positive cultures in automated identification panel systems.58 Molecular methods for diagnosis are rapid, and can target specific genes by use of peptide or nucleic acid probes, polymerase chain reaction (PCR), and other nucleic acid amplification techniques from flagged blood cultures. Amplification of multiple target sites within 16S ribosomal DNA has been widely used for microbial identification. Staphylococcus aureus peptide nucleic acid fluorescence in-situ hybridization is commercially available, which uses peptide nucleic acid probes targeting S. aureus 16S recombinant RNA for direct identification from positive blood culture bottles.59 The StaphPlex-50 system (Qiagen, Redwood City, CA) is a target-enriched multiplex PCR method for identification of S. aureus, and detection of Panton–Valentine leukocidin and several antimicrobial-resistance determinants such as the mecA, aacA, ermA, ermC, tetM, and tetK genes, which confer resistance to methicillin, aminoglycosides, macrolides, lincosamides, streptogramins, and tetracycline, respectively. The amplified products are further characterized by using a Luminex suspension array (Luminex Corp., Austin, TX). The whole process can be performed within 5 hours. In matrix-assisted laser desorption/ionization time of flight mass spectrometry (MS; Bruker Daltonics, Bremen, Germany),60 colonies from a solid or liquid culture of any organism are mixed with matrix-assisted laser desorption/ ionization and rapidly analyzed by MS. It works by comparison of the mass spectral signals obtained from postculture specimens with a database of spectra from reference standard spectra. SeptiFast (Roche Diagnostics, Mannheim, Germany) uses real-time PCR in a nonquantitative mode, which helps by identifying nonculturable pathogens rapidly (, 6 hours). This lightcycler is not available for use in the United States. Polymerase chain reaction amplification to electrospray ionization/MS is a further advancement, as it not only identifies the organisms but also provides information about its strain type, virulence factors, and resistance genes.61 A major strength of the PCR electrospray ionization/MS method is that the mass spectrometer is capable of analyzing multiple amplification products in a fast and automated fashion. These advances, particularly for the diagnosis of SAB, further emphasize its burden, its grave effects, and the importance of timely treatment.
Conclusion
Isolation of S. aureus is common in blood cultures. However, whether it was a skin colonizer and came as a contaminant
during specimen collection or an actual case of bacteremia is difficult to ascertain. Considering the vast potential of this organism to harbor virulence proteins and cause infections, every attempt must be made to treat this infection effectively and completely. Root-to-cause analysis of this infection starting from source tracing through to follow-up, which includes a detailed clinical examination of the patient, echocardiography, chest X-ray, and an abdominal ultrasonography must be done so that reservoirs of this bacterium are eliminated from relevant sites by using an antibiotic dose and duration relevant to that organ system or area of the body.
Conflict of Interest Statement
Sharon Rainy Rongpharpi, MD, Shalini Duggal, MD, Hitesh Kalita, MD, and Ashish Kumar Duggal, MD, have no conflicts of interest to declare.
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