カルバペネム：過去、現在、未来

Carbapenems: Past, Present, and Future
Krisztina M. Papp-Wallace　et al
Antimicrobial agent and chemotherapy

切り札中の切り札の抗菌薬、カルバペネムに関するreview
定義：・the 4:5 fused ring　lactam of penicillins with a double bond between C-2 and C-3　but with the substitution of carbon for sulfur at C-1.

・MDRの出現等により耐性が出現している。
the recent emergence of multidrug-resistant (MDR) pathogens seriously　threatens this class of lifesaving drugs. Several recent studies clearly show that resistance to carbapenems is increasing throughout the world

・Thienamycin（チエナマイシン）: Streptomyces cattleyaから分離された最初のカルバペネム。生体内での安定性の悪さから臨床実用には至らなかったが、以後のカルベペネム系薬の開発に影響。
thienamycin was found to be unstable in　aqueous solution, sensitive to mild base hydrolysis (above Ph　8.0), and highly reactive to nucleophiles, such as hydroxylamine,
cysteine, and even thienamycin’s own primary amine

・その後Imipenemが開発、thienamycinの不安定性を解消、1985年に登場。一方で腎毒性軽減作用、DHP-I（腎臓近位尿細管上皮細胞の刷子縁膜上に存在）に対する不活性化のため配合剤（シラスタチン：DHP-I阻害薬、有機アニオン輸送系の阻害作用　ベタミプロン：有機アニオン輸送系の阻害薬）が必要
注：イミペネム単剤では有機アニオン輸送系を介した近位尿細管上皮細胞へのイミペネムの取り込みにより腎毒性を認める。
Imipenem and a closely related carbapenem,　panipenem (compound 5), identified later, were more-stable　derivatives of thienamycin and less sensitive to base hydrolysis　in solution。In 1985, imipenem (originally called　MK0787) became the first carbapenem available for the treatment　of complex microbial infections. Imipenem, like its parent,　thienamycin, demonstrated high affinity for PBPs and stability　against -lactamases. However, both imipenem and　panipenem were susceptible to deactivation by dehydropeptidase　I (DHP-I), found in the human renal brush border. Therefore, coadministration with an inhibitor, cilastatin　(compound 6) or betamipron (compound 7), was necessary

・その後、カルバペネム骨格の1位にβメチル位を有し、安全性及びDHP-Iに対する安定性の欠点を補った抗菌薬が開発。
meropenem, biapenem, ertapenem, and doripenem(compounds 8 to 11)。A major advance in this　“synthetic journey” was the addition of a methyl group to the　1- position (Fig. 2A). This modification was found to be　protective against DHP-I hydrolysis (62). Several carbapenems　were identified with this modification in the subsequent 2 decades;　many were similar to the currently available carbapenems,　having a 1--methyl and a pyrrolidine ring at C-2

CARBAPENEMS: CHEMISTRY AND BIOLOGY
the carbon atom at the C-1 positionがカルベペネムの抗菌力、スペクトラム、βラクタマーゼに対する安定性に対して重要。
又、hydroxyethyl R2　side chain aidsもβラクタマーゼに対する抵抗性

the carbon atom at the C-1 position was found to play　a major role in the potency and spectrum of carbapenems and　in their stability against -lactamases. We have also　since learned that a strategically positioned hydroxyethyl R2　side chain aids in resistance to hydrolysis by -lactamases。

Mechanism of action
ポーリンを通過し、複数のPBPに結合し細胞壁合成阻害。
Generally speaking, carbapenems enter Gram-negative bacteria　through outer membrane proteins (OMPs), also known as　porins. A key factor of the　efficacy of carbapenems is their ability to bind to multiple　different PBPs. Since cell wall formation is a dynamic“three-dimensional process” with formation and autolysis occurring　at the same time, when PBPs are inhibited, autolysis　continues

Microbiological activity
一般的にはイミペネム・パニペネム・ドリペネムはグラム陽性球菌に強く、メロペネム、ビアペネム、エルタペネム、ドリペネムはグラム陰性桿菌に強い。
In general, imipenem, panipenem,　and doripenem are potent antibiotics against Gram-positive　bacteria. Meropenem, biapenem, ertapenem,　and doripenem are slightly more effective against Gram-negative　organisms

エルタペネムはスペクトラムが狭くイミペネム、メロペネム程、緑膿菌に活性がない。メロペネムはAcinetobacter baumanniiに対してイミペネム、ドリペネム程活性がない。ドリペネムはP.aeruginosa, ,A.baumanniiに対してMICが低い。ドリペネムはカルバペナーゼに対して最も感受性が低い。
Important considerations here　are the following: (i) ertapenem has a more limited spectrum,　because it is not as active as imipenem or meropenem against　P. aeruginosa (164); (ii) meropenem is not as potent as imipenem　or doripenem against Acinetobacter baumannii (164);　(iii) doripenem has lower MICs than do imipenem and meropenem　versus P. aeruginosa and A. baumannii. In addition, doripenem is the carbapenem least susceptible to hydrolysis by carbapenemases; hydrolysis of doripenem is 2- to 150-fold slower than that of imipenem

Pharmacology and clinical use
経口吸収率は悪い。イミペネム、エルタペネムは筋肉注射が可能である。排泄は主に腎排泄である。
all clinically available carbapenems have low　oral bioavailability and thus do not cross gastrointestinal membranes　readily and must be administered intravenously; imipenem-　cilastatin and ertapenem can also be delivered intramuscularly。As with other-lactams, all of these carbapenems are eliminated predominately　by renal excretion

MECHANISMS OF RESISTANCE　AGAINST CARBAPENEMS
ポーリン・effluex pumps、βラクタマーゼ、PBPsの変異により耐性が増加。（グラム陽性球菌ではPBPsの変異、グラム陰性桿菌ではβラクタマーゼ）
Mechanisms of resistance to carbapenems include production　of -lactamases, efflux pumps, and mutations that alter the　expression and/or function of porins and PBPs。
An increasing number　of class A carbapenemases (e.g., KPC and GES enzymes),
class B metallo--lactamases (e.g., VIM, IMP, and NDM　-lactamases), and class D carbapenemases have recentlyemerged. In addition, overproduction　of class C -lactamases, such as CMY-10 and PDC -lactamases,　which are not robust carbapenemases, can lead to carbapenem　resistance,

NOVEL CARBAPENEMS: ANYTHING IN THE PIPELINE?
・抗緑膿菌、抗MRSA用カルバペネム
Antipseudomonal and/or anti-MRSA carbapenems
Tomopenemが期待されたが中止

・抗MRSAカルバペネム
Specific anti-MRSA carbapenems
下記が検討中
15i (compound 13) and CP5484　(compound 14) may offer interesting possibilities

・経口カルバペネム　Oral carbapenems
Tebipenemが日本で初めて発売（・・・それは誇れる事？）
Tebipenem-pivoxil (compound 15) is the world’s first oral　carbapenem in development in Japan (Fig. 9). Tebipenempivoxil　is active against MDR S. pneumoniae (MIC
0.06　mg/liter) and other Gram-positives, as well as the Enterobacteriaceae
. Tebipenem-pivoxil’s spectrum does　not include MRSA and P. aeruginosa

・Trinem carbapenems
ペニシリン・セファロスポリン・カルバペネムの３つの基幹をもつ
中々、発展が難しい。　

河野先生著（カルベペネムをどう使うか）で補足
・カルベペネム骨格の1位のβメチル基：DHP-1に対する安定性に重要であると共に、H.influenzaeに対する抗菌力増強
・2位側鎖の塩基性：塩基性が弱い程、腎毒性、中枢毒性を軽減、外膜透過性に影響。DHP-Iに対する安定性は低下する。高い程、中枢神経毒性。（ビアペネムが高い塩基性で毒性が低いのは2位側鎖をピラゾロトリアゾリウム基に変換した結果、2位側鎖の塩基性が弱い事によりメロペネムは大量投与が可能となっている。DHP-Iに対する安定性は1位のβメチル基により保持70％　）
・分子量：小さい程、グラム陰性桿菌の外膜（ポーリン）通過に影響（ertapenemは高い分子量のためブドウ糖非発酵グラム陰性桿菌に対する活性が弱い）