what antibiotic is used to treat gram positive cocci?

Abstract

Gram-positive bacteria to include methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible Staphylococcus aureus (MSSA), and enterococci, to include vancomycin-resistant enterococci (VRE), display a remarkable assortment of resistance and virulence factors, which have contributed to their prominent role in infections of the critically ill. Over the last iii decades infections with these pathogens has increased as has their overall resistance to available antimicrobial agents. This has led to the development of a number of new antibiotics for the treatment of Gram-positive leaner. At present, it is important that clinicians recognize the changing resistance patterns and epidemiology of Gram-positive bacteria every bit these factors may affect patient outcomes. The increasing range of these pathogens, such equally the emergence of community-associated MRSA clones, emphasizes that all specialties of physicians treating infections should have a good understanding of the infections acquired by Gram-positive leaner in their area of practise. When initiating empiric antibiotics, it is of vital importance that this therapy be timely and advisable, equally delays in treatment are associated with agin outcomes. Although vancomycin has traditionally been considered a first-line therapy for serious MRSA infections, multiple concerns with this agent accept opened the door for culling agents demonstrating efficacy in this role. Similarly, the expansion of VRE equally a pathogen in the ICU setting has required the development of agents targeting this of import pathogen.

Scope of the problem

Sepsis represents a major heath intendance problem with half of the cases occurring in the critically ill and it is associated with a high bloodshed (l% for septic shock) for intensive care unit (ICU) patients [1, two]. The administration of early on appropriate antibiotics is recognized as one of the near of import interventions linked to improving patient outcomes in sepsis [3–5]. The microbiology in the ICU has changed in the concluding 2 to three decades so that Gram-positive cocci (GPC) now represent ane of the dominant species. A recent survey showed that GPC cause the majority of nosocomial infections with Staphylococcus aureus (xvi%, with more than 50% being methicillin-resistant [MRSA]) and Enterococcus species (xiv%, with vancomycin-resistant enterococci [VRE] accounting for approximately iii.5% of all infections) predominating [6]. New resistance patterns are also emerging to include vancomycin - intermediate Staphylococcus aureus (VISA), increases in the Staphylococcus aureus minimum inhibitory concentration (MIC) to vancomycin without breaching the resistance threshold (i.e., MIC pitter-patter), vancomycin-resistant Staphylococcus aureus (VRSA) due to acquisition of the vanA gene, every bit well as daptomycin and linezolid resistance. Given these newly described resistance patterns, testing for susceptibility and adequate antibiotic dosing are of paramount importance for proper management of critically sick infected patients.

For the purpose of this review we will focus on the contribution of GPC to infections in critically sick patients emphasizing the agents available for their treatment. In the ICU, respiratory tract infections especially pneumonia, stand for the about common infection and bear the highest bloodshed [2]. The microbiology of pneumonia varies considerably based on the presence of take chances factors for antibody resistance. While most community-acquired pneumonia (CAP) cases are caused past Streptococcus pneumoniae, health care associated pneumonias (HCAPs), particularly ventilator-associated pneumonia (VAP), are often acquired by MRSA. Community-acquired MRSA pneumonia tin also occur and accounts for 3% of bacterial pneumonia cases [7], commonly being associated with younger patients, mail service-influenza, and necrotizing pneumonia. The rates of penicillin and ceftriaxone resistant strains of Streptococcus pneumoniae are relatively depression in adults [8]. Yet, macrolide resistance can be seen in up to thirty% of strains. Run a risk factors for resistant pathogens appear to be identical for both CAP and HCAP and include: prior hospitalization and antibiotics, immunosuppression, not-ambulatory status, tube feeds and gastric acid suppressive agents [9].

With the advance of invasive devices (e.thousand. ventricular assisted devices, intravenous catheters) has come a rising in the incidence of bacteremia due to GPC. Forth with device removal and a meticulous search for metastatic foci of infection (discitis, osteomyelitis, epidural abscess), antibiotic treatment remains the cornerstone of therapy. As volition be discussed various choices are available for the treatment of bacteremia due to GPC. When Staphylococcus aureus is suspected, combination therapy with an anti-staphylocccal penicillin (nafcillin, oxacillin) and vancomycin should be considered until susceptibility results are known [10]. Daptomycin has emerged as a skilful alternative amanuensis for Staphylococcus aureus bacteremia and endocarditis [11]. It too offers the reward of proven efficacy in patients with MRSA bacteremia with vancomycin MIC >1 mg/L and for infections attributed to heteroresistant VISA, but non for VRSA [12, xiii]. Linezolid has also been shown to accept good activity as compared to vancomcyin in Staphylococcus aureus bacteremia [14].

Although less mutual than pneumonia and bacteremia, complicated skin and soft tissue infections (SSTIs) can exist grave enough to warrant ICU care. Also, postsurgical site infections tin can complicate ICU stays. The master pathogen isolated in these infections is MRSA which makes empirical coverage mandatory [fifteen]. In recent years, most new drugs targeting GPC (e.g. linezolid, ceftaroline, telavancin, daptomcyin, tigecycline) take come up to marketplace by gaining indication for treatment of SSTIs. Moreover, there are now recognized subpopulations of patients with SSTIs who are at increased risk of bacteremia necessitating more ambitious and prolonged therapy [16, 17].

Usually dominated by Gram - negative rods and anaerobes, health-care associated intra-abdominal infections in devitalized patients oftentimes crave empirical coverage for enterococci including VRE. The true pathogenicity of enterococci in these polymicrobial infections remains unclear, but isolation of enterococci from peritoneal fluid in severe infections was found to be an independent predictor of mortality [18]. So far, limited data are available to codify guideline recommendations for the coverage of GPC except for VRE coverage in sure loftier-gamble patient populations (liver transplant recipients, mail-surgical complications in patients with prior antibiotics, patients undergoing hepatobilliary surgery, patients with known VRE colonization) [19].

Advances in the direction of patients with neurologic disorders and injuries have too resulted in increasing occurrence of infections at these sites, particularly with MRSA [20]. Although microbiology varies depending on type of intervention and antibody prophylaxis, more than than 2 thirds of the cases are due to Staphylococcus species (approximately one-half of them Staphylococcus aureus), with this percentage increasing over the last two decades [21, 22]. As with bacteremias and intravascular infections, it is imperative to remove strange devices such every bit shunts and intraventricular catheters. Handling should include vancomycin and/or ceftriaxone at doses that will insure adequate penetration into the central nervous system (CNS). Linezolid has as well emerged as an culling agent peculiarly when vancomcyin is not an option due to unachievable trough levels or renal toxicity, due to excellent CNS penetration of linezolid fifty-fifty in the absenteeism of inflamed meninges. Ceftaroline also appears to be an adequate agent for Streptococcus pneumoniae meningitis based on fauna information, only man studies are defective. The following section will focus on the available agents to care for infections caused by GPC in critically ill patients.

Review

Linezolid

Linezolid is an oxazolidinone antibiotic that blocks assembly of the initiation complex required for protein synthesis providing broad activity confronting Gram-positive bacteria with footling to no Gram-negative activity [23]. Linezolid has high oral bioavailability (approximately 100%) with toxicity primarily being myelosuppression, peripheral and optic neuropathy, lactic acidosis, and serotonin syndrome [23]. Linezolid is indicated in the US for vancomycin-resistant Enterococcus faecium (VRE) infections, including bacteremia; nosocomial pneumonia acquired by Staphylococcus aureus (MSSA and MRSA), or Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP]); complicated and uncomplicated SSTIs; and CAP acquired by Streptococcus pneumoniae (including MDRSP) and MSSA.

The greatest utility of linezolid seems to be for the handling of Staphylococcus aureus infections, especially nosocomial pneumonia [24–26]. This is especially true for isolates with MICs > 1.0 mg/mL where linezolid appears to be a superior agent [26–28]. Linezolid is also indicated for the treatment of necrotizing pneumonia due to MSSA and MRSA strains secreting the Panton–Valentine leukocidin (PVL) virulence gene given its power to block toxin production [29] and has been extensively studied for SSTIs, outperforming vancomycin in terms of clinical cures [xxx–35]. Linezolid has successfully been used off label for the handling of secondary MRSA bacteremia [36, 37], endocarditis [38, 39], and fundamental nervous system infections [40–42]. The greater efficacy of linezolid over vancomycin observed in some of the in a higher place noted clinical studies may be due to the upward drifting MICs of MSSA ansd MRSA to vancomycin likewise every bit the presence of heteroresistance to vancomycin, although not all studies are consequent in demonstrating greater mortality with the presence of heteroresistance [43–fifty].

Similar all other antibiotics, resistance to linezolid has emerged and is a concern given the drug's potent activity for difficult to treat infections acquired by GPC [51]. However, several new oxazolidinone antibiotics are in development, including tedizolid in phase iii clinical trials, that offer advantages over linezolid to include coverage of linezolid-resistant isolates and in one case daily dosing [52, 53].

Daptomycin

Daptomycin is a bactericidal concentration-dependent lipopeptide that promotes the efflux of potassium out of bacterial cells, leading to cell expiry. Information technology is indicated for the treatment of SSTIs (6 mg/kg) and Staphylococcus aureus bloodstream infections (eight mg/kg) including right-sided infective endocarditis, and information technology has been used off label for the treatment of difficult central nervous system infections caused by Gram-positive leaner [52]. Daptomycin should not be used for patients with pneumonia due to the inability to establish non-inferiority to ceftriaxone in a clinical trial, in large office due to the inhibition of daptomycin by surfactant [54, 55]. The main toxicities of daptomycin include eosinophilic pneumonia and skeletal musculus injury.

Guidelines from the Infectious Diseases Order of America (IDSA) for the treatment of MRSA recommend consideration of high-dose (x mg/kg) daptomycin in patients with persistent MRSA bacteremia associated with vancomycin failure and possibly endocarditis [56]. These recommendations are grounded on the concentration-dependent pharmacokinetic (PK)–pharmacodynamic (PD) contour of daptomycin [57]. Suboptimal daptomycin area under the concentration-fourth dimension bend (AUC) values indexed to the minimum inhibitory concentration (MIC), or AUC/MIC, have been linked to clinical failure, whereas trough (C_min) concentrations are correlated with skeletal muscle toxicity [57, 58]. Recently, investigators observed high daptomycin clearance amidst critically ill patients and significantly lower drug exposures with the use of standard doses [59]. These investigators propose that daptomycin doses of 750 mg/day may be more effective then the 6 to 8 mg/kg dosing, particularly early on when creatinine clearance and volume of distribution may be augmented, especially in septic patients [59].

Several large multicenter observational case series have documented the rubber of high-dose daptomycin, to include the handling of VRE bacteremia which is also an off label indication for its use [60–63]. Moreover, combination with a beta-lactam, trimethoprim/sulfamethoxazole, rifampin or gentamicin have been recommended along with higher dose daptomycin to avoid the emergence of resistance when used as save therapy for vancomycin treatment failures [52]. Clinicians should besides be enlightened that recurrent or quantum bacteremia following prolonged treatment of Staphylococcus aureus or enterococcal infection, to include endocarditis, may signal the emergence of daptomycin resistance, necessitating a change in therapy [11, 64].

Vancomycin

Vancomycin is a glycopeptides antibiotic with a number of labeled indications for use in the Us confronting GPC, primarily MRSA, to include catheter-related infections, Clostridium difficile-associated diarrhea (oral), complicated infections in seriously ill patients, enterocolitis due to Staphylococcus aureus (oral), Grouping B streptococcus (neonatal prophylaxis), meningitis (with 3rd-generation cephalosporin for penicillin-resistant Streptococcus pneumonia), pneumonia, prophylaxis confronting infective endocarditis, and susceptible (MIC ≤1 mcg/mL) Gram-positive infections. There are also many off-label indications where vancomycin is often used as commencement line therapy to include bacteremia, fundamental nervous system infections due to MRSA (brain abscess, subdural empyema, spinal epidural abscess), endocarditis (native valve or prosthetic valve due to Enterococcus with vancomycin MIC ≤4 mg/50, streptococci with penicillin MIC >0.5 mg/L or patient intolerance to penicillin, or MRSA), endophthalmitis, SSTIs, prosthetic articulation infections, and surgical prophylaxis. The main toxicities of vancomycin for concern in critically ill patients include hypersensitivity reactions, renal toxicity and cytopenias.

The major current problem associated with increasing vancomycin usage over the last several decades is the increasing occurrence of treatment failures due to drug resistance. Rising MICs to vancomycin appears to be the main mechanism associated with these treatment failures [65]. Although uncommon, horizontal transfer of the vanA operon from VRE has led to VRSA, while repeated exposure to vancomycin has allowed staphylococci to adapt under selective force per unit area leading to the emergence of both VISA and heterogeneous-resistant VISA (hVISA) [66, 67]. Surveillance studies have reported the prevalence of hVISA among clinical MRSA isolates to be between zero and 74% [68–73]. The true prevalence of hVISA is hard to determine since many institutions do not routinely screen for information technology and there are no standardized methods for rapid detection of hVISA as the 'gold standard' population analysis is labor intensive to perform.

Given the emerging resistance of GPC, especially MRSA, to vancomycin, the IDSA has recommended that vancomycin be administered according to torso weight (xv–20 mg/kg/dose, actual body weight) every 8–12 hours, non to exceed ii thou per dose, in patients with normal renal function (56). Yet, in seriously ill patients (eg, those with sepsis, meningitis, pneumonia, or infective endocarditis) with suspected MRSA infection, a loading dose of 25–30 mg/kg (actual body weight) may be considered. Vancomycin trough concentrations should be monitored in such patients and maintained between xv–20 μg/mL. Unfortunately, clinical studies do not support an clan between greater vancomycin trough levels and improved clinical outcomes supporting the use of culling agents when suspected or proven infection with loftier MIC isolates is encountered [26, 33, 74, 75]. Moreover, the MIC test method has a significant impact on vancomycin AUC/MIC interpretation [76]. Clinicians should exist enlightened that the current target AUC/MIC of ≥400 for vancomycin was derived using the reference broth microdilution method and does non apply to the utilize of other automated methods [76].

Ceftaroline

Ceftaroline is an anti-MRSA cephalosporin that was approved by the FDA in 2010 for the treatment of customs-acquired bacterial pneumonia (CABP) and acute bacterial pare and soft structure infections (ABSSSI). Ceftaroline works by binding to penicillin-bounden proteins (PBPs) inhibiting their ability to function as transpeptidases in cell wall synthesis. Nonetheless, information technology is unique for its analogousness for PBP2a and PBP2x providing action against MRSA and MDRSP including ceftriaxone resistant strains [77]. The approved indications for ceftaroline include SSTIs and CAP at a dose of 600 mg every 12 hours. However, it is of import to note that the CAP trials only enrolled patients who were not critically ill [77, 78]. It is non articulate whether the approved dose of ceftaroline is adequate for critically ill patients with augmented creatinine clearance and volumes of distribution. In critically ill patients with normal or augmented renal function 600 mg every 8 hours should be considered until more data become bachelor in this population.

Despite ceftaroline having activity confronting MRSA, little information is available for its use in severe infections caused by Gram-positive leaner such every bit infective endocarditis or osteomyelitis. However, a number of case series accept recently appeared suggesting that ceftaroline solitary, or in combination with another agent, tin can be used to care for such infections attributed to MRSA or Enterococcus faecalis[79–83]. Though limited clinical data supporting ceftaroline for hVISA, VISA or daptomycin non-susceptible Staphylococcus aureus infections is currently bachelor, positive in vitro data exists to support such off characterization apply [84–86].

Tigecycline

Tigecycline is a glycylcycline, an analog of tetracyclines with an extended spectrum of activity to include resistant Gram-positive organisms such equally MRSA, specific resistant Gram-negative bacteria, to include the extended-spectrum β-lactamase producing Enterobacteriaceae, and as relieve therapy for susceptible strains of Acinetobacter and other multi-drug resistant (MDR) pathogens. Tigecycline is approved for utilise past the FDA and European Medicines Bureau (EMA) for adults with complicated intra-abdominal infections (cIAIs) and SSTIs also every bit for CAP [87–89]. Tigecycline has also been used off label for hospital-acquired pneumonia (HAP) and VAP, diabetic foot infections, urinary tract infections (UTIs), and refractory Clostridium difficile infection [ninety].

A major business concern with the use of tigecycline in critically sick patients has to do with the current dosing which is half of the originally planned dosing. This modify was made due to perceived unacceptable nausea and emesis at the college dose. Peradventure equally a result of this dosing issue several meta-analyses have institute the incidence of death to be greater for tigecycline compared to the comparator antibiotics, this was nearly axiomatic in the nosocomial pneumonia studies [91–93]. However, this bloodshed excess seems to be driven past infections with Gram-negative bacteria, possible considering standard tigecycline doses provide serum concentrations that are beneath the MICs of virtually Gram-negative pathogens. Moreover, Ambrose et al. take proposed a tigecycline breakpoint of 0.25 mg/Fifty for Staphylococcus aureus and streptococci classifying more than isolates as resistant [94]. The utilise of tigecycline in critically sick patients should be carefully considered in light of the available clinical outcomes data regarding its use.

Telavancin

Telavancin is a once-daily, intravenous, lipoglycopeptide antibody canonical in the Us for the treatment of acute bacterial skin and skin construction infections due to Gram-positive pathogens and has recently received approval for the treatment of HAP acquired by these pathogens. Different other glycopeptides, telavancin maintains its antimicrobial action against pathogens with decreased susceptibility to glycopeptides, including VISA and hVISA strains, and exhibits more rapid concentration-dependent bactericidal activity confronting susceptible organisms [95].

In two clinical trials of HAP due to Gram-positive pathogens, especially MRSA, treatment with telavancin achieved higher cure rates in patients with monomicrobial Staphylococcus aureus infection and cure rates comparable to vancomycin in patients with MRSA infection [96]. In patients with mixed Gram-positive/Gram-negative infections, cure rates were higher in the vancomycin group. Incidence and types of adverse events were comparable between the treatment groups. Mortality rates for telavancin-treated versus vancomycin-treated patients were 21.5% versus xvi.half-dozen% and 18.5% versus 20.6% for the two trials. Increases in serum creatinine level were more common in the telavancin group (sixteen% vs x%) [96].

Due to updated FDA guidance [97] for time to come antibiotic clinical trials of bacterial nosocomial pneumonia that recommend using diagnostic criteria from the American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines [98], and using a primary end point of 28-twenty-four hour period all-cause mortality, a mail-hoc reanalysis of the ii HAP studies was undertaken [99]. Clinical cure rates at final follow-up were adamant in the refined all-treated (AT) and clinically-evaluable (CE) groups (ATS/IDSA-AT and ATS/IDSA-CE, respectively) and the exploratory finish point of 28-day survival was evaluated in the ATS/IDSA-AT group. Non-inferiority of telavancin versus vancomycin was demonstrated, with like cure rates in the ATS/IDSA-AT (59% versus 59%, respectively) and ATS/IDSA-CE groups (83% versus 80%, respectively). Cure rates favored telavancin in ATS/IDSA-CE patients where Staphylococcus aureus was the sole pathogen (86% versus 75%). Overall, 28-twenty-four hours survival was similar in the telavancin (76%) and vancomycin (77%) groups, but lower in telavancin-treated patients with pre-existing moderate-to-severe renal impairment (CL_CR <50 ml/min). The FDA approval indicates that telavancin should merely exist administered to patients with moderate-to-severe renal impairment if treatment do good outweighs risk, or if no suitable alternatives are available.

Conclusions

The rise in infections attributed to GPC in critically sick patient mandates that clinicians treating these individuals exist familiar with the pathogen types, virulence factors, and susceptibilities of GPC in their local practice areas. Moreover, the availability of MICs, especially for vancomycin and daptomycin in MRSA, should assistance direct the use of these agents, as well equally the new antimicrobials targeting GPC. This is specially of import in potentially life-threatening infections or infections associated with foreign bodies. Moreover, there is a need for the development of not-traditional agents such as vaccines and monoclonal antibodies directed against GPC such as MRSA in club to help forbid these infections and better their outcomes [100].

Authors' data

MHK holds the Virginia Eastward. and Sam J. Golman Chair in Respiratory Intensive Intendance Medicine and is full professor At Washington University.

Abbreviations

ABSSSI:

Acute bacterial skin and soft construction infections

AT:

All-treated

ATSD:

American Thoracic Society

AUC:

Area under the curve

CABP:

Community-acquired bacterial pneumonia

CAP:

Customs-acquired pneumonia

CE:

Clinically-evaluable

cIAI:

Complicated intra-abdominal infection

CLCR:

Creatinine clearance

Cmin:

Concentration minimum

CNS:

Central nervous organization

GPC:

Gram-positive cocci

HAP:

Hospital-associated pneumonia

HCAP:

Healthcare-associated pneumonia

hVISA:

Heteroresistant vancomycin-intermediate Staphylococcus aureus

ICU:

Intensive care unit

IDSA:

Communicable diseases Society of America

MDRSP:

Multidrug-resistant Streptococcus pneumoniae

MIC:

Minimum inhibitory concentration

MSSA:

Meticillin-susceptible Staphylococcus aureus

MRSA:

Methicillin-resistant Staphylococcus aureus

PBP:

Penicillin binding protein

PD:

Pharmacodynamic

PK:

Pharmacokinetic

PVL:

Panton–Valentine leukocidin

SSTI:

Skin and soft tissue infections

UTI:

Urinary tract infection

VAP:

Ventilator-associated pneumonia

VISA:

Vancomycin intermediate Staphylococcus aureus

VRSA:

Vancomycin-resistant Staphylococcus aureus

VRE:

Vancomycin-resistant enterococci.

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Acknowledgements

The authors thank Rebecca Calorie-free for her assistance in preparing this manuscript.

Dr. Kollef's try was supported by the Barnes-Jewish Hospital Foundation.

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Affiliations

1. Division of Infectious Diseases, University of New Mexico, Albuquerque, United mexican states

   Cristina Vazquez-Guillamet

2. Division of Pulmonary and Disquisitional Care Medicine, Washington University School of Medicine, St. Louis, Missouri

   Marin H Kollef

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Correspondence to Marin H Kollef.

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Competing interests

MHK served as an advisory lath member for Cubist and received honoraria for lectures from Cubist. Dr. Kollef's effort was supported by the Barnes-Jewish Hospital Foundation.

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All authors agreed on the focus and structure of the paper. MHK and CVG conducted the literature search, drafted the offset version of the manuscript, and contributed substantially to the final version.

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Vazquez-Guillamet, C., Kollef, Thou.H. Treatment of gram - positive infections in critically ill patients. BMC Infect Dis 14, 92 (2014). https://doi.org/x.1186/1471-2334-14-92

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• Received: 17 Jan 2014

• Accepted: 03 February 2014

• Published: 28 November 2014

• DOI : https://doi.org/ten.1186/1471-2334-14-92

Keywords

• Gram-positive cocci
• Antibiotics
• Staphylococcus aureus
• Enterococci
• Resistance

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