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.

KPC,MBLs,NDM-1 感染症の治療法って?

多剤耐性菌感染患者の治療戦略をどうするか?
来るであろう未来に向けて、現時点の知識を復習。今後のエビデンスが強く求められる分野です。
 

 

立ち向かうは…5レンジャー
 
  • ceftazidime-avibactam
  • colistin
  • aztreonam
  • tigecycline
  • fosfomycin
 
重症の場合
 
2つ以上のコンビネーション技か…⁉︎
さらに高用量、持続投与なども駆使して…
 
  • carbapenem (especially if the meropenem MIC ≤8mcg/mL)
  • polymyxin
  • tigecycline
  • gentamicin
  • Ceftazidime-avibactam 
おそらくコンビネーションも非常に厳しいと思う。新薬開発が求められます。
 
しかし、製薬会社の立場は…です。
抗菌薬開発しても耐性菌が出現する。
開発した抗菌薬を使用促進しないと、利益確保難しい。しかし、制限せざる得ない。
 
2/17 eu POLITICO の耐性菌イベントに対する
Tweetに難しさを感じました。
 
"Pharma industry is asking for DELINKAGE of the use of antibiotics & the volume as a financing incentive! WOW! "
 
"We need a delinking of revenue from volume use of antibiotics"
 
 
重症MDRP治療案を再掲
  • Ticarcillin + tobramycin + rifampin 
  • Polymyxin B + rifampin
  • A fluoroquinolone + either ceftazidime or cefepime
  • Ceftazidime + colistin
  • Clarithromycin + tobramycin
  • Azithromycin + one of the following : tobramycin, doxycycline, trimethoprim, or rifampin
  • Colistin + rifampin
  • Fosfomycin + a carbapenem
ESBLs 敗血症治療案も再掲
  • カルバペネム ◎
  • セフェピム 高用量 ◯
  • ゾシン △
ESBLs 敗血症以外で重症でなければ
  • CMZ △
ESBLs 尿路関連感染で重症でなければ
  • FOM △
 
伊勢志摩サミットにおいて、感染症対策が主要な議題の一つです。成果を期待したいです。
 
以下、UpToDate より引用
 
The carbapenem-hydrolyzing beta-lactamase is an important emerging mechanism of antimicrobial resistance among nosocomial gram-negative pathogens. These enzymes are classified on the basis of their amino acid homology; Classes A, B, and D are of greatest clinical importance.
 
The clinically most important of the Class A carbapenemases is the Klebsiella pneumoniae carbapenemase (KPC) group, which has been implicated in several outbreaks. 
 
Class B beta-lactamases are known as the metallo-beta-lactamases (MBLs), which are named for their dependence upon zinc for efficient hydrolysis of beta-lactams. The New Delhi metallo-beta-lactamase (NDM-1) is an important emerging carbapenemase in this group. 
 
Class D beta-lactamases are referred to as OXA-type enzymes because of their preferential ability to hydrolyze oxacillin (rather than penicillin). 
 
Implementation of the lower 2010 Clinical and Laboratory Standards Institute (CLSI) breakpoints for carbapenem susceptibility improves the detection of carbapenemase-producing Enterobacteriaceae. Identifying strains of P. aeruginosa or A. baumannii with carbapenemases can be difficult. Isolates resistant to penicillins, cephalosporins, and carbapenems with retained susceptibility to aztreonam should be suspected of carrying an MBL. 
 
Use of broad spectrum cephalosporins and/or carbapenems is an important risk factor for the development of colonization or infection with carbapenemase-producing organisms, although prior receipt of carbapenems is not essential for acquisition of these strains.
 
Carbapenemase-producing organisms can cause clinical infections or asymptomatic colonization. Carbapenemase-producing bacteria have been implicated in a variety of infections, including bacteremia, ventilator-associated pneumonia, urinary tract infection, and central venous catheter infection.
 
Selection of antibiotic therapy should be tailored according to the antimicrobial susceptibility test result. In particular, additional antibiotic susceptibility testing should be requested for ceftazidime-avibactam, colistin, aztreonam, tigecycline, and fosfomycin.
 
Patients with uncomplicated urinary tract infections can often be successfully treated with a single active agent
For patients with serious infections (including bacteremia), we suggest combination therapy with two or more active antimicrobial agents instead of monotherapy (Grade 2C).
 Potential agents to use in the combination regimen include a carbapenem (especially if the meropenem MIC ≤8mcg/mL), a polymyxin, tigecycline, or gentamicin. Ceftazidime-avibactam is another treatment option to use in a combination regimen, if the isolate is susceptible, although clinical experience with this agent for carbapenem-resistant infections is limited.
 
Polymyxins are the cornerstones of therapy for carbapenem-resistant A. baumannii and P. aeruginosa and are generally used in combination with another agent.
 
Patients infected or colonized with carbapenemase-producing bacteria should be placed on contact precautions. Screening high-risk patients to detect rectal colonization may also be helpful in controlling transmission.
 
TREATMENT
 
The optimal treatment of infection due to carbapenemase-producing organisms is uncertain, and antibiotic options are limited. Management of patients with infections due to carbapenemase-producing organisms should be done in consultation with an expert in the treatment of multidrug resistant bacteria.
 
Therapy for carbapenemase-producing Enterobacteriaceae — 
 
The location and severity of infection influence regimen selection for carbapenem-resistant Enterobacteriaceae (CRE), as do results of susceptibility testing . Isolates causing uncomplicated urinary tract infections can often be successfully treated with an aminoglycoside or fosfomycin, assuming the isolates retain susceptibility to one of these agents. For patients with more serious infections (including bacteremia) caused by CRE, we suggest using combination antimicrobial therapy. The optimal combination is uncertain. For most serious infections, a polymyxin-based (colistin or polymyxin B) regimen should be used. Meropenem, especially if the isolate has an MIC to meropenem ≤8 mcg/mL, or tigecycline can be added to form a combination regimen. Ceftazidime-avibactam is an alternative agent to use as part of a combination regimen if the isolate is susceptible, although experience with this agent to treat serious infections with CRE is limited. Adding aztreonam may be useful for patients whose isolates carry a metallo-beta-lactamase and demonstrate in vitro susceptibility to this agent. However, clinical experience with aztreonam for treatment of serious infections due to MBL-producing bacteria is very limited. Another potential strategy in difficult cases is high-dose, extended infusion of a carbapenem (that is used in a combination regimen). 
 
The rationale for using two or more agents includes the high mortality associated with serious CRE infections, evidence suggesting that combination therapy is associated with reduced mortality, the concern for emergence of resistance during monotherapy, and the lack of clearly effective single-drug alternatives. Several observational studies have suggested that treatment with combination therapy may improve mortality. 
As an example, in a retrospective study of 661 patients with an infection due to K. pneumoniae confirmed by polymerase chain reaction to harbor the KPC gene, definitive therapy with combination therapy was associated with a lower 14-days mortality compared with therapy with a single-active agent (30.2 versus 38.4 percent)
This difference was particularly evident among the 447 patients with bacteremia, who had mortality rates of 32 versus 51.3 percent with combination therapy versus monotherapy, respectively. 
Most combination regimens included a carbapenem; when the isolate had a meropenem MIC ≥16 mg/L, mortality rates among those who received a combination regimen with meropenem and those who received monotherapy were not statistically different. 
An earlier analysis of a smaller subset of these patients reported that patients treated with a combination of a polymyxin plus tigecycline had a mortality rate of 30 percent (7 of 23), while the regimen of colistin, tigecycline, and extended-infusion meropenem (a dose of 2 grams infused over three or more hours every eight hours) was associated with the lowest mortality rate (2 of 16 [12.5 percent]). 
A systematic review of 20 observational studies also concluded that combination therapy may offer a survival advantage in severely ill patients . Additionally, in vitro studies have demonstrated synergy with combination regimens.
Unfortunately, emergence of polymyxin- or tigecycline-resistant, carbapenemase-producing K. pneumoniae has been reported, and development of resistant K. pneumoniae in patients receiving polymyxin therapy has been documented. Infection with a polymyxin-resistant strain has been found to be an independent risk factor for mortality.
However, use of a single active agent, such as an aminoglycoside or fosfomycin, in uncomplicated urinary tract infections is supported by several small studies. In one study of a panel of 81 carbapenem-resistant Enterobacteriaceae of various types and species, 60 percent tested susceptible to fosfomycin. In a small prospective study of 11 patients, an intravenous preparation of fosfomycin was used to successfully treat various carbapenem-resistant K. pneumoniae infections. Of note, intravenous fosfomycin is not available in many countries, including the United States and Australia.
 
Therapy for carbapenem-resistant A. baumannii and P. aeruginosa 
 
Carbapenem-resistant A. baumannii and P. aeruginosa are typically resistant to all beta-lactams and fluoroquinolones. The intrinsic resistance of these organisms further limits antibiotic options. Although sulbactam has been used to treat some infections due to A. baumannii, most multidrug-resistant isolates of A. baumannii have reduced susceptibility to this agent . In vitro activity of ceftazidime-avibactam is similar to ceftazidime alone for most A. baumannii and many P. aeruginosa. Aminoglycosides may be useful, particularly for urinary tract infections, assuming susceptibility is retained for one of these antibiotics. Aztreonam may also be considered for MBL-possessing P. aeruginosa, but supporting clinical data is lacking. P. aeruginosa are intrinsically resistant to tigecycline, the emergence of tigecycline-resistant A. baumannii has been reported. Most multidrug-resistant A. baumannii and P. aeruginosa retain susceptibility for the polymyxins. Therefore, the polymyxins (ie, colistin and polymyxin B) are usually the cornerstones for therapy. Combination therapy is also advised when polymyxins are used to treat multidrug-resistant A. baumannii and P. aeruginosa.
 
Detailed discussion of the management of multi-drug resistant A. baumannii and P. aeruginosa are found in detail elsewhere. 
 
For ventilator-associated pneumonia due to these organisms, adjunctive use of aerosolized colistin has been evaluated. This is also discussed in detail elsewhere.