Invasive Staphylococcus aureus infections in diabetes

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Invasive Staphylococcus aureus infections in diabetes mellitus Lukman Hakeem, Robert BS Laing, Ivan Tonna, John G Douglas and Alexander R Mackenzie British Journal of Diabetes & Vascular Disease 2013 13: 164 DOI: 10.1177/1474651413500830 The online version of this article can be found at: http://dvd.sagepub.com/content/13/4/164

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DVD13410.1177/1474651413500830The British Journal of Diabetes & Vascular DiseaseHakeem et al.

Review

Invasive Staphylococcus aureus infections in diabetes mellitus

The British Journal of Diabetes & Vascular Disease 13(4) 164­–177 © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1474651413500830 dvd.sagepub.com

Lukman Hakeem, Robert BS Laing, Ivan Tonna, John G Douglas and Alexander R Mackenzie

Abstract Staphylococcus aureus, the most virulent of the many staphylococcal species, has remained a major cause of morbidity and mortality despite the availability of numerous effective anti-staphylococcal antibiotics. S. aureus causes disease through both toxin-mediated and non-toxin-mediated mechanisms. This organism is responsible for both healthcare associated and community-based infections ranging from relatively minor skin and soft tissue infections to severe life threatening systemic infections. Patients with diabetes mellitus are at increased risk of invasive S. aureus infections.This article focuses on the spectrum of invasive S. aureus infections and discusses the clinical features, investigations and management of these infections in patients with diabetes mellitus. Keywords antibiotics; bacteraemia; diabetes mellitus; invasive infections; S. aureus

Introduction Staphylococci are Gram-positive cocci that form grapelike clusters on Gram stain. They are capable of prolonged survival on environmental surfaces in varying conditions. Staphylococcus aureus is a part of the normal human flora. About 25–50% of healthy persons may be persistently or transiently colonised.1,2 The rate of colonisation is higher among patients with insulin-dependent diabetes, HIV infection, patients undergoing haemodialysis, and individuals with skin damage. The anterior nares are the most frequent site of human colonisation, although the skin (especially when damaged), vagina, axilla, perineum, and oropharynx may also be colonised. These colonisation sites serve as a reservoir of strains for future infections, and persons colonised with S. aureus are at greater risk of subsequent infection than uncolonised individuals. S. aureus has an environment-resistant peptidoglycan cell wall surrounded by a microcapsule that determines the serotype.1 Of the 13 capsular types, type 5 and 8 account for 85% of clinical isolates.3–6 The bacterium produces a battery of surface proteins involved in host colonisation, several enzymes engaged in tissue invasion, and a multitude of toxins.1 These include cytolytic toxins, exfoliative toxins, enterotoxins and TSST-1. The cytotoxins can lyse neutrophils, resulting in the release of the lysosomal enzymes that subsequently damage

surrounding tissues. Staphylococcal scalded skin syndrome, characterised by exfoliative dermatitis, is mediated by exfoliative toxins. Staphylococcal enterotoxins are mostly associated with food poisoning and pseudomembranous enterocolitis. TSST-1 is responsible for menstruation-associated and nearly half of non-menstruation-associated staphylococcal toxic shock syndrome.7 Increased virulence shown by some of the community acquired S. aureus strains has been attributed to genes (lukS-PV and lukF-PV) that encode the subunits of PVL, a cytolytic toxin.8 PVL has been associated with both superficial and severe skin and soft-tissue infections and necrotising pneumonia among CA-MSSA isolates and later among CA-MRSA organisms.9–11 The escalation in morbidity and mortality associated with PVL-MRSA has caused public health concern worldwide. To date most PVL-S. aureus strains in the UK have been MSSA, but a major problem has emerged with CA-MRSA in North America, most of which produce PVL.12 In the UK the genes encoding for PVL are carried by 2 mg/L, daptomycin MIC ≤1 mg/L)

PJI following resection 4–6 weeks arthroplasty with or without planned staged reimplantation as above

Highly bioavailable oral regime could be used to complete course of antibiotics.45

Flucloxacillin 2 g 4–6 h iv 4 weeks Vancomycin iv aiming for 4 weeks trough levels of 15–20 mg/L and rifampicin 300–600 mg 12 h po Daptomycin 6 mg/kg 24 4 weeks h iv and rifampicin 300–600 mg 12 h po OR gentamicin 1 mg/kg iv 12 h

Use 4-h regimen if weight >85 kg Use for vancomycin, rifampicin-susceptible S. aureus strains or when known penicillin allergy. Use lower dose of rifampicin if creatinine clearance 2 mg/L, daptomycin MIC ≤1 mg/L)

Daptomycin 6 mg/kg 6 weeks 24 h iv and rifampicin 300–600 mg 12 h po and gentamicin 1 mg/kg iv 12h

Monitor CPK weekly and adjust daptomycin dose according to renal function.

Pneumonia MSSA

Flucloxacillin 1–2 g 6 h iv 10–14 days

Exclude complicating issues (e.g. abscess, empyema)

MRSA

PVL S.aureus (necrotising pneumonia )

Vancomycin iv aiming for trough levels of 15–20 mg/L OR linezolid 600 mg 12 h iv/po Linezolid 600 mg 12 h and clindamycin 1.2 g 6h iv and if severe disease e.g. TSS add rifampicin 600 mg bd ± IVIG 2 g/kg.

Refer to text for surgical interventions

Suspect PVL-S. aureus pneumonia when patient presents with haemoptysis, hypotension leucopenia, raised CK level and CXR showing multilobular infiltrates, usually accompanied by effusions and later cavitation.12

(Continued)

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Table 1. (Continued) Types of infection Antibiotics used Complicated urinary tract infections MSSA MRSA

Duration

Other comments

Flucloxacillin 1–2 g 6 h iv 14 days for pyelonephritis.

Catheter change should be undertaken for patients with long-term urinary catheters.

Vancomycin iv aiming for Abscesses may require trough levels of 15–20 mg/L a longer course.

Patients with peri-nephric or intra-renal abscesses may require radiology guided or surgical drainage.

Daptomycin could be considered54 Eye and CNS infections MSSA MRSA

Flucloxacillin 2 g 6 h iv Vancomycin iv aiming for trough levels of 15–20 mg/L Consider adding rifampicin 300–450 mg 12 h orally to vancomycin62

There is insufficient evidence to make specific recommendations in deep eye and CNS infection.54 The limited data suggest that linezolid may be considered for the treatment of patients with meningeal or cerebral infections.54,90 Intrathecal vancomycin could be considered for CNS infections. Acute endophthalmitis is a vision threatening medical emergency. Patients should be referred to the ophthalmologists for intravitreal antibiotics and to be considered for vitrectomy.62

Key: bd: twice daily; CK: creatinine kinase; CNS: central nervous system; CXR: chest X-ray; iv: intravenous; IVIG: intravenous immunoglobulin; MRSA: methicillin resistant S.aureus; MSSA: methicillin sensitive S.aureus; OPAT: out-patient parenteral antibiotic therapy; MIC: minimum inhibitory concentration; NV: native valve; po: orally; PVL: Panton-Valentine leukocidin; THA: total hip arthroplasty; TKA: total knee arthroplasty; TSS: toxic shock syndrome.

fewer adverse events.66 Teicoplanin has an advantage in terms of its single daily dosing and could also be used three times weekly after appropriate loading for patients suitable for OPAT. Linezolid is a bacteriostatic, synthetic oxazolidinone, that inhibits initiation of protein synthesis at the 50S ribosome.30 Linezolid has good penetration into bone and excellent oral bioavailability, characteristics that are desirable in the treatment of bone infections.67 Based on a number of clinical trails there is evidence suggesting that linezolid is comparable to standard antibiotic therapy in the treatment of S. aureus infections.30,68,69 Reversible myelosuppression is a potential serious adverse event associated with linezolid therapy, especially with long term use. Other reported adverse events include lactic acidosis, ocular toxicity and peripheral neuropathy and a serotonin-like syndrome when co-administered with serotonergic agents.62,70 Daptomycin is a cyclic lipopeptide with rapid bactericidal activity against S. aureus.30 Daptomycin was non-inferior to standard therapy in studies, in the treatment of S. aureus bacteraemia, IE, and complicated skin and soft tissue infections due to MRSA infection.62,1 Promising data on daptomycin use in bone infections were reported in a recent systematic review of uncontrolled case series.72 Patients receiving daptomycin should be evaluated regularly for

clinical evidence of peripheral neuropathy and myopathy. Serum CK should be monitored at least weekly. It has also been associated with eosinophilic pneumonia.62,73 Generally daptomycin is a well tolerated antibiotic that has the advantage of once daily dosing which also make it suitable for OPAT.74 It should not be used for cases of pneumonia because it is inactivated by pulmonary surfactant.75 Of concern however is treatment-emergent resistance.75 Tigecycline is a glycylcycline antibiotic with a bacteriostatic effect on Gram-positive bacteria including S. aureus. It can be used for complicated skin, soft tissue and intra-abdominal infections. It is effective against MRSA and extended spectrum beta lactamase producing enterobacteriaeceae. Due to concerns regarding achieving adequate tigecycline serum drug concentrations, caution should be used with tigecycline for the treatment of patients with bacteraemia. Tigecycline has not been associated with any organ toxicity or severe adverse events.30,76 Most PVL-S. aureus strains in the UK are susceptible to flucloxacillin, erythromycin and clindamycin. For severe infections, where PVL-S. aureus (MSSA or MRSA) is suspected with features of toxic shock, necrotising fasciitis, necrotising pneumonia or purpura fulminans there may be a theoretical case for using two or three agents. HPA guidance recommends linezolid combined with clindamycin and rifampicin. This is based on in-

Figure 7.  Guidance on management of proven suspected Staphylococcus aureus bacteraemia in adults. Reproduced with the permission of the Scottish Antimicrobial Prescribing Group.88

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vitro synergy and the ability of linezolid and clindamycin to switch off toxin production.12,77 Intravenous flucloxacillin is not recommended for necrotising pneumonia, even in combinations with agents such as rifampicin or clindamycin. Although bactericidal, there are concerns that at concentrations just above the MIC (likely with poor penetration into necrotic tissue) flucloxacillin may increase PVL production as it does in vitro.78 IVIG should be considered in addition to intensive care support and high dose antimicrobial therapy because of its action in neutralizing exotoxins and superantigens, particularly enterotoxins A, B and C and TSST-1. The dosage of 2 g/ kg of IVIG recommended for streptococcal toxic shock syndrome12,79 may be applicable for PVL- S. aureus infection, and may be repeated after 48 hours if there is still evidence of sepsis, or failure to respond. It is very important to undertake early surgical debridement.12 Imaging modalities may help identify the source of S. aureus bacteraemia and the extent of the infection with any metastatic spread. Surgical input may be needed for source clearance.

Surgical management S. aureus is the predominant pathogen in diabetic foot infections. Clinicians should seek urgent surgical consultation for patients presenting with evidence of a life or limb-threatening infection, necrotising fasciitis or if the involved limb has critical ischaemia.80 Surgical input is also required for evidence of a deep-space infection or abscess (Figure 4). The most common site for a severe foot infection is the plantar surface. A plantar wound accompanied by dorsal erythema or fluctuance suggests that the infection has passed through fascial compartments, likely to require surgical drainage. Prompt and adequate surgical debridement, including limited resection or amputation, may decrease the likelihood that a more extensive amputation is needed.81, 82 Development of an abscess within the foot, especially in the presence of ischaemia, can rapidly lead to irreparable tissue damage. Prolonged duration of antibiotic therapy is required for osteomyelitis. This may be in part due to the observation in experimental models that S. aureus can persist following digestion by osteoblasts.83 In addition, antibiotic penetration into bone may be unreliable in some patients, particularly in those with vasculopathy as in patients with diabetes. Cardiac surgery is indicated for patients with IE when they develop uncontrolled heart failure, uncontrolled infection or when they are at risk of embolic events. Patients with aortic or mitral valve IE who develop severe acute regurgitation or valve obstruction causing refractory pulmonary oedema, and patients who develop a fistula into a cardiac chamber or pericardium causing refractory pulmonary oedema should be considered for

The British Journal of Diabetes & Vascular Disease 13(4)

emergency cardiac surgery. Patients with locally uncontrolled infection (including abscess, false aneurysm, enlarging vegetation), persisting fever and positive blood cultures for 10 or more days after commencing appropriate antimicrobial therapy and infections caused by multiresistant organisms should also be considered for cardiac surgery. Large aortic and mitral valve vegetations (>10 mm) with one or more embolic episodes despite antibiotic therapy and isolated very large vegetations (>15 mm) are also indications for cardiac surgery.40,47 The management of PJI almost always necessitates the need for surgical intervention and prolonged courses of intravenous or oral antimicrobial therapy as shown in Table 1. Patients diagnosed with a PJI who have a wellfixed prosthesis without a sinus tract and are within approximately 30 days of prosthesis implantation or less than 3 weeks of onset of infectious symptoms should be considered for a debridement and retention of the prosthesis. A one-stage or direct exchange strategy or more commonly a two-stage exchange strategy is considered in other patients who are medically able to undergo multiple surgery. 45 In cases of spondylodiscitis indications for surgical intervention include compression of neural elements, spinal instability due to extensive bony destruction, severe kyphosis, or failure of conservative management.34,84 Anterior decompression and inter-body fusion with posterior stabilisation has become the mainstay of surgical management.49 Epidural abscesses are usually managed by surgical or percutaneous drainage, especially in thoracic and cervical spine where the canal is narrow increasing the risk of rapid neurological compromise.46 Spinal cord compression is a surgical emergency.

S. aureus carriage Carriers of S. aureus who undergo medical procedures are at risk of developing bacteremia.2 There are reports showing that about 11% of patients who were colonised with MRSA at hospital admission developed nosocomial MRSA infection.85,86 Although it was initially believed that the highest risk of bacteraemia occurred during the period immediately after colonisation, more recent studies have suggested that the risk of infection and mortality may be higher during the first year after colonisation (33%) then gradually falling in subsequent years. The risk of infection and mortality may however be completely unrelated to the duration of MRSA colonisation. 24,86,87 These data support the use of methods for decolonisation in MRSA nasal carriers who are admitted to the hospital or who are scheduled to undergo inpatient procedures.86 However, the long-term effects of MRSA decolonisation on the incidence of infection remain unclear.

Hakeem et al.

Conclusion Patients with diabetes mellitus are a high-risk group for developing invasive S. aureus infection and associated complications. Detection of S. aureus in blood culture should trigger a chain of events beginning with assessment of the patient to determine signs of sepsis and to identify a potential deep-seated source, or metastatic complications. The level of risk of a patient having MRSA infection must be assessed. This assessment should not delay urgent treatment with appropriate antibiotic therapy in a patient with signs of sepsis and early surgical intervention. A recently published algorithm developed by the Scottish Antimicrobial Prescribing Group may assist clinicians on the management of proven or suspected S. aureus BSI in adults (Figure 7).88 Treatment should be guided by local antibiotic policy alongside advice from microbiology and/or infectious diseases consultants. Declaration of conflicting interests The author declares that there is no conflict of interest.

Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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