NSTIs are life-threatening, invasive, soft-tissue infections with a necrotizing component involving any or all layers of the soft-tissue compartment, from the superficial dermis and subcutaneous tissue to the deeper fascia and muscle.
The vicious cycle of fulminant infection, toxin production, cytokine activation, micro thrombosis and ischemia, tissue dysfunction and death, and in turn, greater dissemination of infection is central to the rapidly progressive necrosis seen in NSTIs and differentiates it from that of the other SSTIs.
NSTIs have been described according to their anatomical locations (i.e., Fournier’s gangrene) and the depth of infections: dermal and subcutaneous components (necrotizing cellulitis), fascial component (necrotizing fasciitis), and muscular components (necrotizing myositis). However, resolution of these nomenclature issues requires a consensus among international infectious disease physicians, surgeons, and intensivists, and probably, these various methods of classification are not clinically useful.
Although many specific variations of NSTIs have been described, the initial approach to diagnosis, antibiotic treatment, and surgical intervention is similar for all forms. Identifying those infections needing immediate aggressive management is more important than determining the specific variant [8].
Diagnosis
Conditions associated with NSTIs include diabetes mellitus, renal insufficiency, arterial occlusive disease, intravenous drug abuse, body mass index (BMI) > 30 kg/m2, age < 65 years, liver disease, immunosuppression also in patients having tuberculosis and viral infections, recent surgery and traumatic wounds or incision of the skin, including minor lesions like insect bites and injections sites [45, 46].
Diabetic patients exhibit impaired wound healing and increased susceptibility to infection, which may affect the course of SSTIs. It is thus reasonable to speculate that this chronic, debilitating disease contributes to a more serious nature of NSTIs. Diabetes mellitus is the most common co-morbidity associated with NSTIs. Up to 44.5% of patients with this condition are diabetic [45, 46].
Patients with diabetes generally present with polymicrobial and have poorer outcomes.
Delay in diagnosis and delay in treatment of these infections increase the risk of mortality.
The initial differential diagnosis between cellulitis and NSTI that requires prompt operative intervention may be difficult. Most cases of NSTI are initially diagnosed as cellulitis. However, timely diagnosis is critical since time to operative debridement is an important determinant of outcome in NSTIs [47,48,49,50].
Patients with NSTI usually present with severe pain, which is out of proportion to the physical findings:
Local signs
The triad of swelling, erythema, and disproportionately severe pain should raise the suspicion of NSTI.
Systemic signs
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Fever
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Tachycardia
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Hypotension
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Shock
A rapidly progressive SSTI should be treated as an NSTI, from the beginning. The clinical picture may worsen very quickly, sometimes during a few hours. Clinical findings were reviewed by Goh et al. after a systematic literature search that identified swelling (present in 81% of NSTI cases), pain/tenderness (79%), erythema (71%), warmth (44%), bullae (26%), skin necrosis (24%), and crepitus (20%) as the most frequently encountered signs [45]. Fever was present in 40% of patients and hypotension in 21%, although the frequency of associated organ failures varies widely between studies.
Laboratory tests are not highly sensitive or specific for NSTIs. A rapidly progressive soft-tissue infection should be treated as a necrotizing infection from the beginning. The clinical picture may worsen very quickly, sometimes during a few hours.
To predict the presence of NSTI, the Laboratory Risk Indicator for Necrotizing infection (LRINEC) score was proposed (Table 1). LRINEC score assigns points for abnormalities in six independent variables: serum C-reactive protein level (> 150 mg/L), white blood cell (WBC) count (> 15,000/μL), hemoglobin level (< 13.5 g/dL), serum sodium level (< 135 mmol/L), serum creatinine level (> 1.6 mg/dL [142 mmol/l]), and serum glucose level (> 180 mg/dL [10 mmol/l]). With a score of 8 or higher, there is a 75% risk of an NSTI.
Subsequent evaluation of the LRINEC score has demonstrated conflicting results. Several studies have assessed the utility of LRINEC for the early diagnosis of necrotizing infections [51,52,53,54].
Recent evidence has demonstrated that it lacks the sensitivity to be a useful adjunct for diagnosing NSTIs [55]. The LRINEC score has poor diagnostic accuracy for NSTI, and a low score does not rule out the diagnosis.
Imaging
The diagnosis of NSTIs is primarily clinical. However, radiologic imaging may be able to provide useful information when the diagnosis is uncertain. A plain X-ray should not be used to rule out NSTI. However, it is important that if clinical suspicion of NSTI is high, radiologic imaging must neither delay nor deter surgery, because in this setting an early surgical debridement is essential to decrease mortality.
CT has a higher sensitivity than plain radiography in identifying early NSTIs. Findings consistent with necrotizing infections are fat stranding, fluid and gas collections that dissect along fascial planes, and gas in the involved soft tissues. Additionally, fascial thickening and non-enhancing fascia on contrast CT suggests fascial necrosis [56,57,58]
MRI has been considered the imaging modality of choice for necrotizing fasciitis [53]. However, MRI may be difficult to perform under emergency conditions and is not recommended as the first-choice imaging technique.
US has the advantage of being rapidly performed at the bedside and may help differentiate simple cellulitis from NSTIs [45], but again is not considered highly accurate nor definitive in most settings. Point-of-care US (POCUS) can improve diagnose accuracy for NSTI when used in combination with clinical evaluation as it is increasingly available, fast and can be performed at the bedside [59]. The main ultrasound findings are summarized in loss of the normal tissue architecture to a “cobblestone” appearance, with irregularity and thickening of the fascia, abnormal fluid collections along the fascia, seen as hypoechogenic zones, and, in more advanced cases, the presence subcutaneous air, defined by hyperechogenic foci with a posterior dirty acoustic shadowing.
Moreover, POCUS can show evidence of gas in the soft tissue, indicative of advanced disease and a marker of worse prognosis. The presence of a thickened fascia can make it difficult to differentiate the underlying structures. Yet, there is always the possibility of comparing with another similar unaffected structure, usually the other limb. Ultrasound can also be helpful to guide fluid drainage if a collection is present and rule out deep vein thrombosis.
A systematic review of the literature and meta-analysis including 23 studies was carried out to establish and compare the accuracy of physical examination, imaging, and LRINEC score in diagnosis of NSTIs [60]. Twenty-three studies were included in the analysis with a total of 5982 patients. Of physical examination signs, pooled sensitivity and specificity for fever was 46.0% and 77.0% respectively, for hemorrhagic bullae 25.2% and 95.8%, and for hypotension 21.0% and 97.7%. CT had sensitivity of 88.5% and specificity of 93.3%, while plain radiography had sensitivity of 48.9% and specificity of 94.0%. Finally, LRINEC ≥ 6 had sensitivity of 68.2% and specificity of 84.8%, while LRINEC ≥ 8 had sensitivity of 40.8% and specificity of 94.9%.
Invasive diagnosis
Fascial biopsy with frozen section has been suggested to achieve earlier diagnosis of NSTIs [61]. However, a frozen-section biopsy is not very practical and requires the availability and experience of pathologists, and the time taken to carry out and analyze the sample could be used for debridement [62]. The Finger test is another adjunct method described for diagnosing NSTIs. It is performed under local anesthesia. A 2-cm incision is made down to the deep fascia. Minimal tissue resistance to finger dissection (positive Finger test), the absence of bleeding, the presence of necrotic tissue, and/or murky and grayish (“dishwater”) fluid following incision all suggests the diagnosis of NSTI [63].
Treatment
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Surgical source control as soon as possible within 6 h after admission. Delay in early surgical increases mortality.
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Appropriate and effective debridement techniques. Skin-sparing debridement techniques focusing on tissue directly involved in necrosis.
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Re-explorations should be repeated until the time when very little or no debridement is required.
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Empiric antibiotic therapy optimizing Pharmacokinetics (PK) and Pharmacodynamics (PD) targets.
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Deep samples collected at the interface between healthy and necrotized tissues during initial debridement and blood cultures allow the identification of causative pathogens in most cases.
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De-escalation of antibiotic therapy be based on clinical improvement, cultured pathogens, and results of rapid diagnostic tests where available
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(Organ) supportive measures
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Hyperbaric oxygen therapy where it is available
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Intravenous immunoglobulin (IVIG) in patients with streptococcal NSTIs
Early source control, antibiotic therapy, and (organ) supportive measures are the cornerstone of treatment in patients with sepsis or septic shock caused by NSTIs.
Early surgical debridement with complete removal of necrotic tissue, including potential major amputation is essential to decrease mortality and other complications in patients with NSTIs.
While antibiotic therapy, resuscitation and critical care evaluation are necessary in the treatment of patients presenting with NSTIs, the mainstay of therapy remains surgical treatment. Once the diagnosis of NSTI is suspected, early consultation with a surgeon is always warranted. Delay in the identification or early surgical management of these infections clearly increases mortality [8]. Debridements should be always performed in operating room where the best exposure and examination of the wound in a pain-free environment can be performed. Typical intraoperative findings in progressive NSTI are coagulative necrosis of the tissues and the subcutaneous layer with muddy, dishwater-like fluid.
Deep samples collected at the interface between healthy and necrotized tissues during initial debridement and blood cultures are crucial, allowing for the identification of causative pathogens in most cases.
In order to review the literature concerning the timing of surgery in relation to mortality and amputation in patients with NSTIs a systematic search and meta-analysis was recently published. A total of 109 studies, with combined 6051 NSTI patients, were included [27]. Of these 6051 NSTI patients, 1277 patients died (21.1%). A total of 33 studies, with combined 2123 NSTI patients, were included for quantitative analysis. Mortality was significantly lower for patients with surgery within 6 h after presentation compared to when treatment was delayed more than 6 h. Surgical treatment within 6 h resulted in a 19% mortality rate compared to 32% when surgical treatment was delayed over 6 h. Average mortality rates reported remained constant (around 20%) over the past 20 years. Early surgical debridement lowers the mortality rate for NSTI with almost 50%. Thus, a sense of urgency is essential in the treatment of patients with NSTIs.
Early surgical debridement with complete removal of necrotic tissue is essential to decrease mortality and other complications in patients with NSTIs [64]. It is the most important determinant of outcome in patients with NSTIs and should be performed as soon as possible, but at least within the first 6 h after admission.
Skin grafting and extensive rehabilitation are necessary to mitigate disfigurement after invasive debridements, limited joint mobility, and chronic pain. When debridement focuses only on tissue directly involved in necrosis, viable skin and subcutaneous tissue can remain in place despite wide debridement of deeper tissue planes [28, 29].
Skin-sparing debridement techniques have been described in the literature. Relative to traditional debridement, skin-sparing debridement for source control of NSTI results in significantly more wounds closed completely by delayed primary suture of existing skin flaps and a significantly lower overall wound percentage closed by skin graft, while demonstrating equivalent efficacy of source control and a similar low mortality rate.
Scheduled re-explorations should be done at least every 12–24 h after the initial operation or sooner if clinical local or systemic signs of worsening infection become evident, as well as with worsening laboratory parameters (WBC count, C Reactive Protein and Procalcitonin). Re-explorations should be repeated until the time when very little or no debridement is required.
After debridement and once the wound is stable, the subsequent use of negative pressure therapy allows reduction of the wound surface, extraction of wound exudate and cell residues, as well as induction of granulation.
Microbiologically, NSTIs have been classified as either type 1 (polymicrobial) or type 2 (mono-microbial) or type 3 (gas gangrene). Occasionally in immunocompromised patients, NSTIs may be also caused by mycotic species.
Type I NSTIs is a polymicrobial infection involving aerobic and anaerobic organisms. It is associated with surgical procedures involving the bowel or penetrating abdominal trauma, with infections developed in damaged skin, such as decubitus ulcer or animal bites, with infections at the site of injection in injection drug users, or with a perianal, prostate or vulvovaginal abscess [6].
Type I infection may be often associated with gas in the tissue and thus is difficult to distinguish from gas gangrene.
Type II NSTI is a mono-microbial infection. In the monomicrobial form, the most common pathogens are anaerobic streptococci and S. aureus. Staphylococci and streptococci can occur simultaneously. Most infections are community-acquired and present in the limbs, with approximately two-thirds of cases in the lower extremities. Vibrio vulnificus and Aeromonas hydrophila are the most common Gram-negative bacteria causing type II NSTIs.
Gas gangrene (clostridial myonecrosis), or type III NSTI, is an acute infection by clostridium or bacillus of healthy living tissue that occurs spontaneously or as a result of traumatic injury.
Occasionally in immunocompromised patients, NSTIs may also be caused by mycotic species. Empiric coverage against fungi should be started in high-risk patients.
Since it is impossible to exclude with certainty a polymicrobial NSTI, an aggressive broad-spectrum empiric antimicrobial therapy should initially be selected to cover Gram-positive, Gram-negative, and anaerobic organisms until culture-specific results and sensitivities are available. An acceptable empiric antibiotic regimen should always include antibiotics, which cover MRSA with the additional benefit of inhibiting invasive hamolytic streptococci virulence proteins.
Selection of antibiotics that inhibit toxin production may be helpful, particularly in those patients who have evidence of toxic shock syndrome (TSS), potentially present in patients who have streptococcal and staphylococcal infections [65,66,67]. Protein cytotoxins, such as superantigens, play an important role in the pathogenesis of various staphylococcal and streptococcal infections, and toxin production should be considered when selecting an antimicrobial agent for Gram-positive pathogens. Linezolid and clindamycin play an important role because they may significantly inhibit exotoxin production from Gram-positive pathogens [8]. Culture-specific results and sensitivities can direct both broadening of antibiotic regimen if it is too narrow and a de-escalation if it is too broad particularly in critically ill patients where de-escalation strategy is one of the cornerstones of antimicrobial stewardship programs [8].
In the absence of definitive clinical trials, antibiotic therapy should be administered until further debridement is no longer necessary.
In patients with NSTIs the antibiotic dosing regimen should be established depending on host factors and properties of antibiotic agents [68]. The achievement of appropriate target site concentrations of antibiotics is essential to eradicate the pathogens. Suboptimal target site concentrations may have important clinical implications, and may explain therapeutic failures, in particular, for bacteria for which in vitro MICs are high. One major consequence of septic shock, affecting half of patients with NSTIs, is the intense vasodilation and extravasation of fluid into the interstitial space from endothelial damage and capillary leakage. This phenomenon is commonly described as ‘third spacing’. Moreover, to contrast hypotension, large volumes of resuscitation fluids are administered distributing into interstitial space, thereby significantly increasing interstitial volume [69].
The “dilution effect”, also called the ‘third spacing’ phenomenon, must be considered when administering hydrophilic agents such as β-lactams, aminoglycosides, and glycopeptides, which selectively distribute to the extracellular space [69]. Low plasma antibiotic levels can contribute to lower-than-expected antibiotic concentrations in soft tissue with potentially reducing antibiotic delivery to the target tissues. In addition, hypoalbuminaemia is a common condition in patients with NSTIs. With low albumin concentrations, an increase in the unbound fraction of antibiotics can occur. The unbound fraction of antibiotics is not only available for elimination, but also for distribution to the target tissue.
Knowledge of the pharmacokinetic and pharmacodynamic antibiotic properties may provide a more rational determination of optimal dosing regimens in terms of the dosing interval. Optimal use of the pharmacokinetic/pharmacodynamic relationship of antibiotics is important to obtain an optimal target site concentration. It is related to the concept of time-dependent versus concentration-dependent killing [69]. Beta-lactams exhibit time-dependent activity and exert optimal bactericidal activity when drug concentrations are maintained above the MIC. Therefore, it is important that the serum concentration of beta-lactam agents exceeds the MIC for appropriate duration of the dosing interval. Higher frequency dosing, prolonged infusions and continuous infusions have been utilized to achieve this effect.
Finally, tissue penetration is also an important aspect because high concentrations at the site of infection can optimize the effect of antibiotics. One recent study included 11 obese patients with severe SSTI, of whom 9 had NSTI, and evaluated the pharmacokinetics of linezolid. Although linezolid has an excellent soft tissue distribution, the probability of target attainment for this antibiotic was low using the standard dosing of 600 mg every 12 h [70].
Despite significant advancements in critical care management and improved knowledge regarding NSTIs, mortality remains elusively high. Adjunctive and less conventional treatment options have been explored to improve outcomes in this group of patients. Hyperbaric oxygen (HBO) is one of these modalities [71]. The role of HBO as an adjunctive treatment has been debated, and no prospective randomized clinical trials have been published nor valid research evidence produced regarding the effects of HBO therapy on wound healing.
HBO could be considered, if available, but it should not interfere with nor delay the standard treatment, including aggressive ICU support if required. Furthermore, the patient should not be transferred to carry out HBO therapy, thereby delaying critical care.
Intravenous immunoglobulin therapy has been postulated to improve outcomes in a selected population of patients with NSTIs. Most reported studies evaluated its use for invasive GAS infections, including GAS-related NSTIs with streptococcal toxic shock syndrome (STSS) [72] with variable results.
Finally, intensive care for hemodynamic and metabolic support should be performed as soon as possible. Disease severity, reflected by the severity of illness scores such as the APACHE II [73] or hypotension and/or vasopressor need [74], are risk factors for mortality.
Patients with NSTIs are very complex and may lose fluids, proteins, and electrolytes through a large surgical wound. In addition, hypotension is caused by vasodilation induced by the systemic inflammatory response syndrome to infection and cytotoxins [75]. Fluid resuscitation and analgesia are the mainstays of support for patients with advanced sepsis, usually combined with vasoactive amines associated with mechanical ventilation and other organ function support, if needed. No ideal fluid has been proven: however, resuscitation therapy must be prompt and immediate as in any type of shock.
Recently the new guidelines of Surviving Sepsis Campaign have been published [76]. Below a brief summary of what is pertinent to NSTIs is reported.
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As soon as possible after diagnosing sepsis (organ dysfunctions) associated with a NSTI, administer a 1-L bolus of a balanced crystalloid solution over 30 min. In hypotensive patients or those with an elevated serum lactate level additional fluid should be administered to achieve 30 ml/kg of initial volume resuscitation. This should be administered within 3 h.
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In patients who do not achieve a MAP ≥ 65 mmHg with initial volume resuscitation within one hour, start a norepinephrine infusion and titrate as needed. This can initially be administered through a peripheral IV while central venous access is being obtained.
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Simultaneously, administer within 1-h broad spectrum antimicrobial agent(s) to cover potential pathogens.
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If the norepinephrine infusion increases to ≥ 15 mg/min, add low dose vasopressin at infusion rate of 0.03 U/min. Do not increase this dose of vasopressin.
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Start low dose steroids (hydrocortisone 50 mg q 6 h) in patients requiring ongoing high doses of norepinephrine and vasopressin to achieve MAP ≥ 65 mmHg.
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Additional fluid resuscitation (beyond the initial 30 ml/kg) will likely be needed but should be based on the assessment that the patient will be fluid responsive.
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Patients with impaired cardiac function should inotropic agent started. Dobutamine is the preferred agent but will cause hypotension in hypovolemic patients.
New agents to treat NSTIs
Reltecimod (previously known as AB103 or p2TA), a peptide derived from the T-cell receptor CD28, modulates the host immune response by targeting the co-stimulatory pathway, which is essential for the induction of multiple pro-inflammatory cytokines. Consequently, reltecimod has demonstrated beneficial effects against different bacterial infections such as NSTIs.
A randomized, double-blind, placebo-controlled trial of single dose reltecimod (0.5 mg/kg) administered within 6 h of NSTI diagnosis was recently published [77]. Reltecimod was associated with improved resolution of organ dysfunction and hospital discharge status. Further studies are warranted to establish the real efficacy in clinical practice.
Wound management after source control
The rapidly spreading infection followed by aggressive surgical intervention and repeated debridements creates challenges for wound management.
Negative pressure wound therapy (NPWT) refers to wound dressing systems that continuously or intermittently apply sub-atmospheric pressure to the surface of a wound. NPWT has become a popular treatment modality for the management of many acute and chronic wounds [8]. In the setting of necrotizing infections once the necrosis is removed, NPWT can help wound healing physiologically. The negative pressure leads to an increased blood supply, increasing tissue perfusion, reducing edema, absorbing fluids and exudates, inhibiting infection, and finally drying the wound and thus the migration of inflammatory cells into the wound. Additionally, it promotes and accelerates the formation of granulation tissue by the removal of bacterial contamination and exudates. A modification of the original system added intermittent automated instillation of topical wound irrigation solutions to traditional NPWT. It, named NPWTi, has been shown to be effective in the treatment of a variety of complex wounds. NPWTi has been shown to reduce biofilms present in wounds helping heal clinically infected wounds.
As alternative the plastic surgical closure and reconstruction an optimal option. However, it needs a strict collaboration with the plastic surgeons. Although skin grafting may fulfill this role, techniques higher on the reconstructive ladder, including local, regional and free flaps, are sometimes undertaken [78].
Empiric antibiotic regimens. Normal renal function
The initial empirical antibiotic regimen should comprise broad-spectrum drugs, including anti-MRSA and anti-Gram-negative coverage. Antitoxin active antibiotics such as clindamycin or linezolid should be included in the empirical antibiotic regimen to treat NSTIs.
In stable patients
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One of the following antibiotics
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Amoxicillin/clavulanate 1.2/2.2 g every 8 h
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Ceftriaxone 2 g every 24 h + Metronidazole 500 mg every 8 h
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Cefotaxime 2 g every 8 h + Metronidazole 500 mg every 8 h
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+
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Clindamycin 600–900 mg every 8 h
In unstable patients
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One of the following antibiotics
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Piperacillin/tazobactam 4.5 g every 6 h
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Meropenem 1 g every 8 h
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Imipenem/Cilastatin 500 mg every 6 h
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+
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One of the following antibiotics
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Linezolid 600 mg every 12 h
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Tedizolid 200 mg every 24 h
or
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Another anti-MRSA-antibiotic as
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Vancomycin 25–30 mg/kg loading dose then 15–20 mg/kg/dose every 8 h
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Daptomycin 6–8 mg/kg every 24 h *
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Telavancin 10 mg/kg every 24 h
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+
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Clindamycin 600–900 mg every 8 h
*Approved at the dosage of 4–6 mg/kg/24 h, it is currently used at higher dosages.