さまよう薬剤師のブログ

学位を持っても、センスのない、感染制御専門薬剤師のブログ.  I have Ph.D. but less sense ID pharmacist.

抗MRSA薬の種類は?

当院は、VCM99%とLZD1%です。

尊敬する先生の大学病院はVCMのみと聞きました。

我が国にない薬剤も多いですが、NEJMやJAMAに報告された試験も多く要確認が必要です。

そこで、抗MRSA薬を簡単に復習してみたいと思います。

UpToDate より引用

Vancomycin 

Vancomycin is a glycopeptide that inhibits cell wall synthesis. It remains an important antibiotic for the treatment of invasive methicillin-resistant S. aureus (MRSA) infections, despite increasing concern about "minimum inhibitory concentration (MIC) creep" (ie, a reported overall decrease in susceptibility of S. aureus isolates to vancomycin in different geographic regions). Vancomycin has a relatively good safety profile and favorable pharmacokinetics that facilitate convenient administration. In addition, vancomycin is the agent for which there is the greatest cumulative clinical experience for the treatment of a variety of invasive clinical syndromes, including bacteremia, endocarditis, pneumonia, and osteomyelitis. 

Vancomycin kills staphylococci more slowly than do beta-lactam antibiotics in vitro and is clearly inferior to beta-lactams for treatment of methicillin-susceptible S. aureus (MSSA) bacteremia and infective endocarditis. Tissue penetration is highly variable and depends upon the degree of inflammation. In particular, penetration is limited for bone, lung epithelial lining fluid, and cerebrospinal fluid .

Vancomycin minimum inhibitory concentration breakpoints for Staphylococcus aureus are defined as follows

●Susceptible: MIC ≤2 mcg/mL
●Intermediate: MIC 4 to 8 mcg/mL
●Resistant: MIC ≥16 mcg/mL

Alternatives to vancomycin should be considered in the setting of adverse effects due to vancomycin or infection with a pathogen with inadequate susceptibility to vancomycin coupled with a poor clinical response.

Daptomycin 

Daptomycin is a cyclic lipopeptide bactericidal antibiotic that causes depolarization of the bacterial cell membrane.The strongest data for use of daptomycin are in the setting of complicated skin and skin structure infections (cSSSI) and bacteremia with or without endocarditis due to MRSA and other selected gram-positive pathogens.Daptomycin should not be used for treatment of MRSA pneumonia since its activity is inhibited by pulmonary surfactant.

The efficacy of daptomycin for treatment of cSSSI (patients with simple abscesses, impetigo, and uncomplicated cellulitis were excluded) was demonstrated in a randomized trial that included 45 patients with cSSSI due to MRSA; among these patients, the clinical success rate of daptomycin was similar to that of vancomycin (84 percent).

The noninferiority of daptomycin to vancomycin plus low-dose gentamicin for S. aureus bacteremia was demonstrated in a trial of 246 patients with S. aureus bacteremia with or without right-sided endocarditis (99 with MRSA) . Successful outcomes were observed in 44 and 42 percent, respectively. In a post-hoc analysis of this study, the authors concluded that daptomycin may be considered as an alternative to standard therapy in the treatment of patients with S. aureus bacteremia and osteoarticular infections.

Linezolid 

Linezolid is a bacteriostatic, synthetic oxazolidinone antibiotic that inhibits initiation of protein synthesis at the 50S ribosome.It does not exhibit cross resistance with other protein synthesis inhibitors. Its mechanism of action may lead to enhanced efficacy against strains producing toxins such as Panton-Valentine leukocidin, alpha-hemolysin, and toxic-shock syndrome toxin-1.Linezolid has excellent tissue distribution and may be administered parenterally or orally due to its high bioavailability.

Linezolid has received US Food and Drug Administration (FDA) approval for treatment of nosocomial pneumonia and complicated skin and skin structure infections due to susceptible pathogens including MRSA.The efficacy of linezolid was illustrated in a study of 220 adults with known or suspected MRSA infection in whom skin and soft tissue infection was the most common diagnosis. Linezolid and vancomycin had equivalent clinical cure rates overall (73 percent) and in the subgroup with MRSA bacteremia (56 and 50 percent, respectively).

Ceftaroline 

The active metabolite of ceftaroline, a fifth-generation cephalosporin, exhibits bactericidal activity against gram-positive organisms (including MRSA, vancomycin-intermediate S. aureus (VISA), and macrolide-resistant S. pyogenes) as well as gram-negative pathogens (including Enterobacteriaceae but not Pseudomonas species or extended-spectrum beta-lactamase producers)

Telavancin

Telavancin is a semisynthetic lipoglycopeptide that inhibits cell wall synthesis and disrupts cell membrane permeability. It is bactericidal against MRSA, VISA, and vancomycin-resistant S. aureus (VRSA). It has a half-life of seven to nine hours, permitting once-daily dosing. Telavancin is excreted by the kidneys, and, thus, dosage adjustments are required in cases of renal failure. Telavancin has a higher rate of toxicity (including taste disturbance, nausea, vomiting, and renal dysfunction) than vancomycin.

Dalbavancin

Dalbavancin is a semisynthetic lipoglycopeptide that inhibits cell wall synthesis. It has a half-life of 6 to 12 days, which permits once-weekly dosing (initial dose 1000 mg followed by 500 mg dose one week later). At present, dalbavancin may prove useful in the treatment of complicated skin and skin structure infections when parenteral therapy is indicated and when patients appear to be otherwise ready for discharge. Outpatient monitoring will still be necessary.

Oritavancin

Oritavancin is a semisynthetic glycopeptide that inhibits cell wall synthesis and has activity against staphylococci and enterococci, including vancomycin-resistant strains. It was approved by the FDA for treatment of acute bacterial skin and skin structure infections in 2014.The drug has a half-life of 100 hours, allowing for single-dose therapy for skin and skin structure infections.
In a randomized trial, nearly 1000 patients with acute wound infection, cellulitis, erysipelas, or major cutaneous abscess with signs and symptoms of systemic inflammation warranting intravenous therapy were randomly assigned to receive a single dose of oritavancin (1200 mg intravenously followed by intravenous placebo for 7 to 10 days) or vancomycin (1g or 15 mg/kg body weight intravenously for 7 to 10 days).There was no difference in early clinical response rates (defined as the cessation of spread of skin involvement and the absence of fever at 48 to 72 hours) between the two regimens (82 percent with oritavancin and 79 percent with vancomycin). Success rates overall and for infections due to MRSA were also similar with the two regimens. The most frequently reported adverse effects were nausea, headache, and diarrhea.

Tedizolid

Tedizolid is an oxazolidinone drug with an oral and a parenteral formulation that was approved by the FDA for the treatment of acute bacterial skin and skin structure infections in 2014. It appears to be comparable to linezolid for this purpose.In contrast with linezolid, it is administered once daily. JAMATedizolid phosphate vs linezolid for treatment of acute bacterial skin and skin structure infections: the ESTABLISH-1 randomized trial. - PubMed - NCBI

Tigecycline

Tigecycline is a glycylcycline antibiotic derived from minocycline with in vitro activity against many gram-positive pathogens (including MRSA, vancomycin-resistant enterococci, and penicillin-resistant Streptococcus pneumoniae), many gram-negatives (important exceptions include Pseudomonas and Proteus species), anaerobes, and atypical species.

Teicoplanin

Teicoplanin is a glycopeptide; it has the same spectrum of activity and similar efficacy as vancomycin. However, teicoplanin has a longer half-life than vancomycin and can be administered once daily with more rapid infusion rates than vancomycin. It can also be given intramuscularly, facilitating outpatient management.
Teicoplanin tends to be better tolerated than vancomycin. This was illustrated in a meta-analysis of 11 clinical trials including 1276 patients. Efficacy was similar in the two groups, but there were significantly fewer episodes of red man syndrome and other adverse events in patients treated with teicoplanin (13.9 versus 21.0 percent with vancomycin).A meta-analysis noted a lower risk of nephrotoxicity with teicoplanin than with vancomycin.

Quinupristin-dalfopristin 

Quinupristin-dalfopristin is a streptogramin antibiotic with FDA approval for the treatment of vancomycin-resistant enterococcal infections and complicated skin and skin structure infections due to methicillin-susceptible S. aureus. Quinupristin-dalfopristin also has activity against MRSA and vancomycin-intermediate S. aureus isolates.

Adjunctive agents

Rifampin

Rifampin is a bactericidal agent that inhibits DNA-dependent RNA polymerase; it should not be used as a single agent due to the rapid emergence of resistance.Rifampin has been used in combination with other anti-staphylococcal agents in the treatment of prosthetic device infections or bone infections .However, its use must be tempered with the concerns regarding toxicity, drug-drug interactions, and the possible emergence of rifampin resistance.

Rifampin dosing is variable throughout the literature, ranging from 600 mg daily (single dose or in two divided doses) to 900 mg daily (in two or three divided doses). Additional study is needed to define the role of rifampin in management of MRSA infections.

Fusidic acid

Fusidic acid inhibits protein synthesis by blocking aminoacyl-sRNA transfer to protein. Emergence of resistance has been described in the setting of monotherapy and therefore should not be used as a single agent. It is effective when used in combination with other drugs such as rifampin.Use of fusidic acid together with statins is associated with risk of rhabdomyolysis. Fusidic acid is not available in the United States.