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an antibiotic (trade name Vancocin) effective against some bacterial infections (同)Vancocin

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/07/30 09:35:40」(JST)

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Crystal structure of a short peptide L-Lys-D-Ala-D-Ala (bacterial cell wall precursor, in green) bound to vancomycin (blue) through hydrogen bonds. Reported by Knox and Pratt in Antimicrob. Agents. Chemother., 1990 1342-1347

Vancomycin INN /væŋkɵˈmaɪsɨn/ is an antibiotic useful for the treatment of a number of bacterial infections. It is of the glycopeptide antibiotic class and is effective mostly against Gram-positive bacteria. Vancomycin was first isolated in 1953 at Eli Lilly, from a soil sample collected from the interior jungles of Borneo by a missionary. It is a naturally occurring antibiotic made by the soil bacterium Actinobacteria species Amycolatopsis orientalis (formerly designated Nocardia orientalis). It is a complex chemical compound and an example of a comparatively rare halo-organic natural compound, containing two covalently bonded chlorine atoms (see green "balls" in ball-and-stick model, right).

The compound was industrially produced by fermentation and given the generic name vancomycin, derived from the term "vanquish". The original indication for vancomycin was for the treatment of penicillin-resistant Staphylococcus aureus, a use kept alive for many years because that compound had to be given intravenously and thus provided bacteria fewer opportunities to evolve resistance, and because organisms were relatively slow to evolve/adapt to it, even in experiments.

Vancomyin is primarily used for the treatment of serious infections caused by Gram-(+) bacteria known or suspected to be resistant to other antibiotics. The Infectious Disease Society of America recommends vancomycin as a first-line treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and meningitis infections caused by methicillin-resistant S. aureus.^[1] Orally administered vancomycin is recommended as a treatment for intestinal infection with Clostridium difficile, a common side effect of treatment with broad-spectrum antibiotics.^[2]

It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.^[3]

1 Medical uses
2 Side effects
- 2.1 Nephrotoxicity
- 2.2 Ototoxicity
- 2.3 Interactions with other nephrotoxins
3 Dosing considerations
- 3.1 Intravenous vs oral administration
- 3.2 Red man syndrome
- 3.3 Therapeutic drug monitoring
4 Biosynthesis
5 Spectrum of susceptibility
6 Pharmacology and chemistry
- 6.1 Mechanism of action
7 Usage in plant tissue culture
8 Antibiotic resistance
- 8.1 Intrinsic resistance
- 8.2 Acquired resistance
9 History
10 See also
11 References

Medical uses

Vancomycin is indicated for the treatment of serious, life-threatening infections by Gram-positive bacteria unresponsive to other less-toxic antibiotics. In particular, vancomycin should not be used to treat methicillin-sensitive Staphylococcus aureus because it is inferior to penicillins such as nafcillin.^[4]^[5] )

The increasing emergence of vancomycin-resistant enterococci has resulted in the development of guidelines for use by the Centers for Disease Control Hospital Infection Control Practices Advisory Committee. These guidelines restrict use of vancomycin to the following indications:^[6]^[7]

Treatment of serious infections caused by susceptible organisms resistant to penicillins (methicillin-resistant S. aureus]] *MRSA) and multiresistant Staphylococcus epidermidis (MRSE)) or in individuals with serious allergy to penicillins
Treatment of pseudomembranous colitis caused by Clostridium difficile; in particular, in cases of relapse or where the infection is unresponsive to metronidazole treatment (for this indication, vancomycin is given orally, rather than by its typical intravenous (IV) route)
For treatment of infections caused by Gram-positive microorganisms in patients with serious allergies to beta-lactam antimicrobials.^[7]
Antibacterial prophylaxis for endocarditis following certain procedures in penicillin-hypersensitive individuals at high risk^[7]
Surgical prophylaxis for major procedures involving implantation of prostheses in institutions with a high rate of MRSA or MRSE^[7]
Early in treatment as an empiric antibiotic for possible MRSA infection while waiting for culture identification of the infecting organism

Side effects

Although vancomycin levels are usually monitored, in an effort to reduce adverse events, the value of this is not beyond debate.^[8] Peak and trough levels are usually monitored, and, for research purposes, the area under the concentration curve is also sometimes used. Toxicity is best monitored by looking at trough values.^[9]

Common adverse drug reactions (≥1% of patients) associated with IV vancomycin include: local pain, which may be severe, and thrombophlebitis.

Damage to the kidneys and to the hearing were a side effect of the early impure versions of vancomycin, and these were prominent in the clinical trials conducted in the mid-1950s.^[10]^[11] Later trials using purer forms of vancomycin found nephrotoxicity is an infrequent adverse effect (0.1–1% of patients), but this is accentuated in the presence of aminoglycosides.^[12]

Rare adverse effects (<0.1% of patients) include: anaphylaxis, toxic epidermal necrolysis, erythema multiforme, red man syndrome, superinfection, thrombocytopenia, neutropenia, leukopenia, tinnitus, and dizziness and/or ototoxicity.^[6]

Vancomycin can induce platelet-reactive antibodies in the patient, leading to severe thrombocytopenia and bleeding with florid petechial hemorrhages, ecchymoses, and wet purpura.^[13]

Vancomycin has traditionally been considered a nephrotoxic and ototoxic drug, based on observations by early investigators of elevated serum levels in renally impaired patients who had experienced ototoxicity, and subsequently through case reports in the medical literature. However, as the use of vancomycin increased with the spread of MRSA beginning in the 1970s, the previously reported rates of toxicity were recognized as not being observed. This was attributed to the removal of the impurities present in the earlier formulation of the drug, although those impurities were not specifically tested for toxicity.^[10]

Nephrotoxicity

Subsequent reviews of accumulated case reports of vancomycin-related nephrotoxicity found many of the patients had also received other known nephrotoxins, in particular, aminoglycosides. Most of the rest had other confounding factors, or insufficient data regarding the possibility of such, that prohibited the clear association of vancomycin with the observed renal dysfunction.

In 1994, the use of vancomycin monotherapy was clearly documented in only three of 82 available cases in the literature.^[14] Prospective and retrospective studies attempting to evaluate the incidence of vancomycin-related nephrotoxicity have largely been methodologically flawed and have produced variable results. The most methodologically sound investigations indicate the actual incidence of vancomycin-induced nephrotoxicity is around 5–7%. To put this into context, similar rates of renal dysfunction have been reported for cefamandole and benzylpenicillin, two reputedly non-nephrotoxic antibiotics.

In addition, evidence to relate nephrotoxicity to vancomycin serum levels is inconsistent. Some studies have indicated an increased rate of nephrotoxicity when trough levels exceed 10 µg/ml, but others have not reproduced these results. Nephrotoxicity has also been observed with concentrations within the "therapeutic" range, as well. In essence, the reputation of vancomycin as a nephrotoxin is overstated, and it has not been demonstrated that maintaining vancomycin serum levels within certain ranges will prevent its nephrotoxic effects, when they do occur.

Ototoxicity

Attempts to establish rates of vancomycin-induced ototoxicity are even more difficult due to the scarcity of quality evidence. The current consensus is that clearly related cases of vancomycin ototoxicity are rare. The association between vancomycin serum levels and ototoxicity is also uncertain. While cases of ototoxicity have been reported in patients whose vancomycin serum level exceeded 80 µg/ml, cases have been reported in patients with therapeutic levels, as well. Thus, whether therapeutic drug monitoring of vancomycin for the purpose of maintaining "therapeutic" levels will prevent ototoxicity also remains unproven.

Interactions with other nephrotoxins

Another area of controversy and uncertainty concerns the question of whether, and, if so, to what extent, vancomycin increases the toxicity of other nephrotoxins. Clinical studies have yielded variable results, but animal models indicate some increased nephrotoxic effect probably occurs when vancomycin is added to nephrotoxins such as aminoglycosides. However, a dose- or serum level-effect relationship has not been established.

Dosing considerations

Intravenous vs oral administration

Vancomycin must be given intravenously (IV) for systemic therapy, since it is not absorbed from the intestine. It is a large hydrophilic molecule that partitions poorly across the gastrointestinal mucosa. Due to short half-life, it is often injected twice-daily.^[15]

The only indication for oral vancomycin therapy is in the treatment of pseudomembranous colitis, where it must be given orally to reach the site of infection in the colon. Following oral administration, the fecal concentration of vancomycin is around 500 µg/ml^[16] (sensitive strains of C. difficile have a mean inhibitory concentration of ≤2 µg/ml^[17])

Inhaled vancomycin has also been used (off-label), via nebulizer, for treatment of various infections of the upper and lower respiratory tract.

The caustic nature of vancomycin makes IV therapy using peripheral lines a risk for thrombophlebitis. Ideally, central lines or infusion ports should be used.^[18]

Red man syndrome

Vancomycin is recommended to be administered in a dilute solution slowly, over at least 60 minutes (maximum rate of 10 mg/minute for doses >500 mg)^[6] due to the high incidence of pain and thrombophlebitis and to avoid an infusion reaction known as the "red man syndrome" or "red neck syndrome". This syndrome, usually appearing within 4–10 min after the commencement or soon after the completion of an infusion, is characterized by flushing and/or an erythematous rash that affects the face, neck, and upper torso. These findings are due to nonspecific mast cell degranulation and are not an IgE-mediated allergic reaction. Less frequently, hypotension and angioedema may also occur. Symptoms may be treated or prevented with antihistamines, including diphenhydramine, and are less likely to occur with slow infusion.^[19]^[20]^:120–1

Therapeutic drug monitoring

Plasma level monitoring of vancomycin is necessary due to the drug's biexponential distribution, intermediate hydrophilicity, and potential for ototoxicity and nephrotoxicity, especially in populations with poor renal function and/or increased propensity to bacterial infection. Vancomycin activity is considered to be time-dependent; that is, antimicrobial activity depends on the duration that the serum drug concentration exceeds the minimum inhibitory concentration of the target organism. Thus, peak serum levels have not been shown to correlate with efficacy or toxicity; indeed, concentration monitoring is unnecessary in most cases. Circumstances in which therapeutic drug monitoring is warranted include: patients receiving concomitant aminoglycoside therapy, patients with (potentially) altered pharmacokinetic parameters, patients on haemodialysis, patients administered high-dose or prolonged treatment, and patients with impaired renal function. In such cases, trough concentrations are measured.^[6]^[14]^[21]^[22]

Target ranges for serum vancomycin concentrations have changed over the years. Early authors suggested peak levels of 30–40 mg/l and trough levels of 5–10 mg/l,^[23] but current recommendations are that peak levels need not be measured and that trough levels of 10-15 or 15–20 mg/l, depending on the nature of the infection and the specific needs of the patient, may be appropriate.^[24]^[25]

Biosynthesis

Figure 1: Modules and domains of vancomycin assembly

Vancomycin biosynthesis occurs via different nonribosomal protein synthases (NRPSs).^[26] The enzymes determine the amino acid sequence during its assembly through its 7 modules. Before vancomycin is assembled through NRPS, the amino acids are first modified. L-tyrosine is modified to become the β-hydroxychlorotyrosine (β-hTyr) and 4-hydroxyphenylglycine (HPG) residues. On the other hand, acetate is used to derive the 3,5 dihydroxyphenylglycine ring (3,5-DPG).^[27]

Figure 2: Linear heptapeptide, which consists of modified aromatic rings

Nonribosomal peptide synthesis occurs through distinct modules that can load and extend the protein by one amino acid through the amide bond formation at the contact sites of the activating domains.^[28] Each module typically consists of an adenylation (A) domain, a peptidyl carrier protein (PCP) domain, and a condensation (C) or elongation domain. In the A domain, the specific amino acid is activated by converting into an aminoacyl adenylate enzyme complex attached to a 4'phosphopantetheine cofactor by thioesterification^[29]^[30] The complex is then transferred to the PCP domain with the expulsion of AMP. The PCP domain uses the attached 4'-phosphopantethein prosthetic group to load the growing peptide chain and their precursors.^[31] The organization of the modules necessary to biosynthesize Vancomycin is shown in Figure 1. In the biosynthesis of Vancomycin, additional modification domains are present, such as the epimerization (E) domain, which isomerizes the amino acid from one stereochemistry to another, and a thioesterase domain (TE) is used as a catalyst for cyclization and releases of the molecule via a thioesterase scission.

Figure 3: Modifications necessary for vancomycin to become biologically active

A set of multienzymes (peptide synthase CepA, CepB, and CepC) are responsible for assembling the heptapeptide. (Figure 2). The organization of CepA, CepB, and Cep C closely resembles other peptide synthases such as those for surfactin (SrfA1, SrfA2, and SrfA3) and gramicidin (GrsA and GrsB).^[28] Each peptide synthase activates codes for various amino acids to activate each domain. CepA codes for modules 1, 2, and 3. CepB codes for modules 4, 5, and 6, and CepC codes for module 7. The three peptide synthases are located at the start of the region of the bacterial genome linked with antibiotic biosynthesis, and spans 27 kb.^[28]

After the linear heptapeptide molecule is synthesized, vancomycin has to undergo further modifications, such as oxidative cross-linking and glycosylation, in trans^{[clarification needed]} by distinct enzymes, referred to as tailoring enzymes, to become biologically active (Figure 3). To convert the linear heptapeptide, eight enzymes, open reading frames (ORFs) 7, 8, 9, 10, 11, 14, 18, 20, and 21 are used. The enzymes ORF 7, 8, 9, and 20 are P450 enzymes. ORF 10 and 18 show to nonheme haloperoxidases^{[clarification needed]}. And ORF 9 and 14 are identified as putative hydroxylation enzymes.^[32] With the help of these enzymes, β-hydroxyl groups are introduced onto tyrosine residues 2 and 6, and coupling occurs for rings 5 and 7, rings 4 and 6, and rings 4 and 2. In addition, a haloperoxidase is used to attach the chlorine atoms onto rings 2 and 6 via an oxidative process.^[28]

Spectrum of susceptibility

Vancomycin is considered a last resort medication for the treatment of septicemia and lower respiratory tract, skin, and bone infections caused by Gram-positive bacteria. The MIC susceptibility data for a few medically significant bacteria are:

Staphylococus aureus: 0.25 - 4.0 μg/ml
Staphylococcus aureus (methicillin resistant or MRSA): 1 - 138 μg/ml
Staphylococcus epidermidis: ≤0.12 - 6.25 μg/ml

^[33]

Pharmacology and chemistry

Vancomycin is a branched tricyclic glycosylated nonribosomal peptide produced by the Actinobacteria species Amycolatopsis orientalis (formerly designated Nocardia orientalis).

Vancomycin exhibits atropisomerism — it has multiple chemically distinct rotamers owing to the rotational restriction of some of the bonds. The form present in the drug is the thermodynamically more stable conformer, so has more potent activity.^{[citation needed]}

Mechanism of action

Vancomycin acts by inhibiting proper cell wall synthesis in Gram-positive bacteria. Due to the different mechanism by which Gram-negative bacteria produce their cell walls and the various factors related to entering the outer membrane of Gram-negative organisms, vancomycin is not active against Gram-negative bacteria (except some nongonococcal species of Neisseria).

The large hydrophilic molecule is able to form hydrogen bond interactions with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides. Under normal circumstances, this is a five-point interaction. This binding of vancomycin to the D-Ala-D-Ala prevents cell wall synthesis of the long polymers of N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG) that form the backbone strands of the bacterial cell wall, and it prevents the backbone polymers that do manage to form from cross-linking with each other.^[34]

Mechanism of vancomycin action and resistance: This diagram shows only one of two ways vancomycin acts against bacteria (inhibition of cell wall cross-linking) and only one of many ways that bacteria can become resistant to it.

Vancomycin is added to the bacterial environment while it is trying to synthesize new cell wall. Here, the cell wall strands have been synthesized, but not yet cross-linked.
Vancomycin recognizes and binds to the two D-ala residues on the end of the peptide chains. However, in resistant bacteria, the last D-ala residue has been replaced by a D-lactate, so vancomycin cannot bind.
In resistant bacteria, cross-links are successfully formed. However, in the nonresistant bacteria, the vancomycin bound to the peptide chains prevents them from interacting properly with the cell wall cross-linking enzyme.
In the resistant bacteria, stable cross links are formed. In the sensitive bacteria, cross-links cannot be formed and the cell wall falls apart.

Usage in plant tissue culture

Vancomycin is one of the few antibiotics used in plant tissue culture to eliminate Gram-positive bacteria infection. It has relatively low toxicity to plants.^[35]

Antibiotic resistance

Intrinsic resistance

A few Gram-positive bacteria are intrinsically resistant to vancomycin: Leuconostoc and Pediococcus species, but these organisms rarely cause diseases in humans.^[36] Most Lactobacillus species are also intrinsically resistant to vancomycin,^[36] with the exception of L. acidophilus and L. delbruekii, which are sensitive.^[37] Other Gram-positive bacteria with intrinsic resistance to vancomycin include Erysipelothrix rhusiopathiae, Weissella confusa, and Clostridium innocuum.^[38]^[39]^[40]

Most Gram-negative bacteria are intrinsically resistant to vancomycin because their outer membrane is impermeable to large glycopeptide molecules^[41] (with the exception of some non-gonococcal Neisseria species).^[42]

Acquired resistance

Evolution of microbial resistance to vancomycin is a growing problem, in particular, within healthcare facilities such as hospitals. While newer alternatives to vancomycin exist, such as linezolid (2000) and daptomycin (2003), the widespread use of vancomycin makes resistance to the drug a significant worry, especially for individual patients if resistant infections are not quickly identified and the patient continues the ineffective treatment. Vancomycin-resistant Enterococcus emerged in 1987. Vancomycin resistance evolved in more common pathogenic organisms during the 1990s and 2000s, including vancomycin-intermediate Staphylococcus aureus (VISA) and vancomycin-resistant Staphylococcus aureus (VRSA).^[43]^[44] Agricultural use of avoparcin, another similar glycopeptide antibiotic, may have contributed to the evolution of vancomycin-resistant organisms.^[45]^[46]^[47]^[48]

One mechanism of resistance to vancomycin involves the alteration to the terminal amino acid residues of the NAM/NAG-peptide subunits, under normal conditions, D-alanyl-D-alanine, to which vancomycin binds. The D-alanyl-D-lactate variation results in the loss of one hydrogen-bonding interaction (4, as opposed to 5 for D-alanyl-D-alanine) possible between vancomycin and the peptide. This loss of just one point of interaction results in a 1000-fold decrease in affinity. The D-alanyl-D-serine variation causes a six-fold loss of affinity between vancomycin and the peptide, likely due to steric hindrance.^[49]

In enterococci, this modification appears to be due to the expression of an enzyme that alters the terminal residue. Three main resistance variants have been characterised to date among resistant Enterococcus faecium and E. faecalis populations:

VanA - Enterococcal resistance to vancomycin and teicoplanin; inducible on exposure to these agents
VanB - lower-level enterococcal resistance; inducible by vancomycin, but strains may remain susceptible to teicoplanin
VanC - least clinically important; enterococci resistant only to vancomycin; constitutive resistance

2011: A variant of vancomycin has been tested at the Scripps Research Institute that binds to the resistant D-lactic acid variation in vancomycin-resistant bacterial cell walls, and also binds well to the original target (vancomycin-susceptible bacteria), and thus reinstates potent antimicrobial activity.^[50]

History

Vancomycin was first isolated in 1953 by Edmund Kornfeld (working at Eli Lilly) from a soil sample collected from the interior jungles of Borneo by a missionary.^[51] The organism that produced it was eventually named Amycolatopsis orientalis.^[10] The original indication for vancomycin was for the treatment of penicillin-resistant Staphylococcus aureus.^[10]^[11]

The compound was initially called compound 05865, but was eventually given the generic name vancomycin, derived from the term "vanquish".^[10] One advantage that was quickly apparent is that staphylococci did not develop significant resistance despite serial passage in culture media containing vancomycin. The rapid development of penicillin resistance by staphylococci led to the compound's being fast-tracked for approval by the Food and Drug Administration in 1958. Eli Lilly first marketed vancomycin hydrochloride under the trade name Vancocin^[11]

Vancomycin never became the first-line treatment for S. aureus for several reasons:

It possesses poor oral bioavailability; it must be given intravenously for most infections.
β-Lactamase-resistant semisynthetic penicillins such as methicillin (and its successors, nafcillin and cloxacillin) were subsequently developed, which have better activity against non-MRSA staphylococci.
Early trials used early impure forms of vancomycin ("Mississippi mud"), which were found to be toxic to the ears and to the kidneys;^[52] these findings led to vancomycin's being relegated to the position of a drug of last resort.^[11]

In 2004, Eli Lilly licensed Vancocin to ViroPharma in the U.S., Flynn Pharma in the UK, and Aspen Pharmacare in Australia. The patent expired in the early 1980s; the FDA authorized the sale of several generic versions in the USA, including from manufacturers Bioniche Pharma, Baxter Healthcare, Sandoz, Akorn Strides, and Hospira.^[53]

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^ Smith, TL; Pearson, ML; Wilcox, KR; Cruz, C; Lancaster, MV; Robinson-Dunn, B; Tenover, FC; Zervos, MJ; Band, JD (February 1999). "Emergence of vancomycin resistance in Staphylococcus aureus. Glycopeptide-Intermediate Staphylococcus aureus Working Group". The New England Journal of Medicine (PDF|format= requires |url= (help)) 340 (7): 493–501. doi:10.1056/NEJM199902183400701. PMID 10021469.
^ McDonald, LC; Killgore, GE; Thompson, A; Owens Jr, RC; Kazakova, SV; Sambol, SP; Johnson, S; Gerding, DN (December 2005). "An epidemic, toxin gene-variant strain of Clostridium difficile". The New England Journal of Medicine (PDF|format= requires |url= (help)) 353 (23): 2433–41. doi:10.1056/NEJMoa051590. PMID 16322603.
^ Acar, J.; Casewell, M.; Freeman, J.; Friis, C.; Goossens, H. (2000). "Avoparcin and virginiamycin as animal growth promoters: A plea for science in decision-making". Clinical Microbiology and Infection 6 (9): 477–82. doi:10.1046/j.1469-0691.2000.00128.x. PMID 11168181.
^ Bager, F; Madsen, M; Christensen, J; Aarestrup, F.M (1997). "Avoparcin used as a growth promoter is associated with the occurrence of vancomycin-resistant Enterococcus faecium on Danish poultry and pig farms". Preventive Veterinary Medicine 31 (1–2): 95–112. doi:10.1016/S0167-5877(96)01119-1. PMID 9234429.
^ Peter J Collignon (1999). "Vancomycin-resistant enterococci and use of avoparcin in animal feed: is there a link?". Med J Aust 171 (3): 144–146. PMID 10474607.
^ Lauderdale, TL; Shiau, YR; Wang, HY; Lai, JF; Huang, IW; Chen, PC; Chen, HY; Lai, SS; Liu, YF (2007). "Effect of banning vancomycin analogue avoparcin on vancomycin-resistant enterococci in chicken farms in Taiwan". Environmental microbiology 9 (3): 819–23. doi:10.1111/j.1462-2920.2006.01189.x. PMID 17298380.
^ Pootoolal J, Neu J, Wright GD (2002). "Glycopeptide antibiotic resistance". Annu Rev Pharmacol Toxicol 42: 381–408. doi:10.1146/annurev.pharmtox.42.091601.142813. PMID 11807177.
^ Xie, J; Pierce, JG; James, RC; Okano, A; Boger, DL (September 2011). "A Redesigned Vancomycin Engineered for Dual d-Ala-d-Ala and d-Ala-d-Lac Binding Exhibits Potent Antimicrobial Activity Against Vancomycin-Resistant Bacteria". J. Am. Chem. Soc. 133 (35): 13946–9. doi:10.1021/ja207142h. PMC 3164945. PMID 21823662.
^ Shnayerson, Michael; Plotkin, Mark (2003). The Killers Within: The Deadly Rise of Drug-Resistant Bacteria. Back Bay Books. ISBN 978-0-316-73566-7.
^ Griffith RS. (1981). "Introduction to vancomycin". Rev Infect Dis 3: S200–S204. PMID 7043707.
^ Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations

UpToDate Contents

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1. バンコマイシン過敏症 vancomycin hypersensitivity
2. バンコマイシン：成人への非経口投与と血清濃度のモニタリング vancomycin parenteral dosing and serum concentration monitoring in adults
3. バンコマイシン低感受性黄色ブドウ球菌による菌血症 staphylococcus aureus bacteremia with reduced susceptibility to vancomycin
4. バンコマイシン耐性腸球菌の疫学、予防および管理 epidemiology prevention and control of vancomycin resistant enterococci
5. コアグラーゼ陰性ブドウ球菌による感染症の治療 treatment of infections due to coagulase negative staphylococci

English Journal

Glycin-rich antimicrobial peptide YD1 from B. amyloliquefaciens, induced morphological alteration in and showed affinity for plasmid DNA of E. coli.

Rahman MS1, Choi YH1, Choi YS1, Yoo JC2.
AMB Express.AMB Express.2017 Dec;7(1):8. doi: 10.1186/s13568-016-0315-8. Epub 2017 Jan 3.
Antimicrobial peptides (AMPs), low-molecular-weight proteins with broad-spectrum antimicrobial activity, are the most promising candidates for the development of novel antimicrobials. A powerful cationic glycine-rich AMP YD1 (MW ~ 1.0 kDa) was purified from Bacillus amyloliquefaciens CBSYD1 isola
PMID 28050849

Safety assessment of Tetragenococcus halophilus isolates from doenjang, a Korean high-salt-fermented soybean paste.

Jeong DW1, Heo S2, Lee JH3.
Food microbiology.Food Microbiol.2017 Apr;62:92-98. doi: 10.1016/j.fm.2016.10.012. Epub 2016 Oct 4.
We assessed the safety of 49 Tetragenococcus halophilus strains isolated from doenjang in Korea. Minimum inhibitory concentration assays showed that all strains can be considered as susceptible to ampicillin, erythromycin, penicillin G, tetracycline, and vancomycin, but resistant to ciprofloxacin ba
PMID 27889172

Prevalence and molecular characterization of Clostridium difficile isolates from a pig slaughterhouse, pork, and humans in Taiwan.

Wu YC1, Chen CM2, Kuo CJ3, Lee JJ4, Chen PC5, Chang YC6, Chen TH7.
International journal of food microbiology.Int J Food Microbiol.2017 Feb 2;242:37-44. doi: 10.1016/j.ijfoodmicro.2016.11.010. Epub 2016 Nov 12.
Clostridium difficile causes antibiotic-associated diarrhea in both humans and animals. The ribotype 078, predominant in food animals, is associated with community-acquired C. difficile infection, and C. difficile is suggested to be a foodborne pathogen. Recently, the C. difficile ribotype 078 linea
PMID 27870984

Japanese Journal

Clinical and Microbiological Characteristics of Vancomycin-Resistant Enterococci with the VanD Phenotype and vanA Genotype

Song Joon Young,Cheong Hee Jin,Seo Yu Bin [他]
Japanese Journal of Infectious Diseases 66(1), 1-5, 2013-01-00
NAID 40019556992

当科における脊椎インストゥルメントサージャリーの術後感染対策 (西日本脊椎研究会特集号)

山田圭,佐藤公昭,密川守 [他]
Journal of spine research : official journal of the Japanese Society for Spine Surgery and Related Research 3(12), 1580-1586, 2012-12-00
NAID 40019553763

Related Pictures

Vancomycin Intravenous : Uses, Side Effects, Interactions, Pictures, Warnings & Dosing Diminishing Returns: The

★リンクテーブル★

リンク元	「抗菌薬」「バンコマイシン」「レジオネラ属」「急性尿細管間質性腎炎」「殺菌性抗生物質」
拡張検索	「vancomycin-intermediate Staphylococcus aureus」「vancomycin-resistant enterococci」

「抗菌薬」

Vancomycin
Systematic (IUPAC) name
	(1S,2R,18R,19R,22S,25R,28R,40S)- 48- {[(2S,3R,4S,5S,6R)- 3- {[(2S,4S,5S,6S)- 4- amino- 5- hydroxy- 4,6- dimethyloxan- 2- yl]oxy}- 4,5- dihydroxy- 6- (hydroxymethyl)oxan- 2- yl]oxy}- 22- (carbamoylmethyl)- 5,15- dichloro- 2,18,32,35,37- pentahydroxy- 19- [(2R)- 4- methyl- 2- (methylamino)pentanamido]- 20,23,26,42,44- pentaoxo- 7,13- dioxa- 21,24,27,41,43- pentaazaoctacyclo[26.14.2.23,6.214,17.18,12.129,33.010,25.034,39]pentaconta- 3,5,8(48),9,11,14,16,29(45),30,32,34,36,38,46,49- pentadecaene- 40- carboxylic acid
Clinical data
Trade names	Vancocin
AHFS/Drugs.com	monograph
MedlinePlus	a604038
Licence data	US FDA:link
Pregnancy cat.	B2 (AU) B (PO) / C (IV)(US)
Legal status	Prescription Only (S4) (AU) POM (UK) ℞-only (US)
Routes	IV, oral
Pharmacokinetic data
Bioavailability	Negligible (oral)
Metabolism	Excreted unchanged
Half-life	4–11 hours (adults); 6-10 days (adults, impaired renal function)
Excretion	Renal
Identifiers
CAS number	1404-90-6
ATC code	A07AA09 J01XA01
PubChem	CID 14969
DrugBank	DB00512
ChemSpider	14253
UNII	6Q205EH1VU
KEGG	D00212
ChEBI	CHEBI:28001
ChEMBL	CHEMBL262777
Chemical data
Formula	C66H75Cl2N9O24
Mol. mass	1449.3 g.mol-1
	SMILES C[C@H]1[C@H]([C@@](C[C@@H](O1)O[C@@H]2[C@H]([C@@H]([C@H](O[C@H]2Oc3c4cc5cc3Oc6ccc(cc6Cl)[C@H]([C@H](C(=O)N[C@H](C(=O)N[C@H]5C(=O)N[C@@H]7c8ccc(c(c8)-c9c(cc(cc9O)O)[C@H](NC(=O)[C@H]([C@@H](c1ccc(c(c1)Cl)O4)O)NC7=O)C(=O)O)O)CC(=O)N)NC(=O)[C@@H](CC(C)C)NC)O)CO)O)O)(C)N)O;
	InChI InChI=1S/C66H75Cl2N9O24/c1-23(2)12-34(71-5)58(88)76-49-51(83)26-7-10-38(32(67)14-26)97-40-16-28-17-41(55(40)101-65-56(54(86)53(85)42(22-78)99-65)100-44-21-66(4,70)57(87)24(3)96-44)98-39-11-8-27(15-33(39)68)52(84)50-63(93)75-48(64(94)95)31-18-29(79)19-37(81)45(31)30-13-25(6-9-36(30)80)46(60(90)77-50)74-61(91)47(28)73-59(89)35(20-43(69)82)72-62(49)92/h6-11,13-19,23-24,34-35,42,44,46-54,56-57,65,71,78-81,83-87H,12,20-22,70H2,1-5H3,(H2,69,82)(H,72,92)(H,73,89)(H,74,91)(H,75,93)(H,76,88)(H,77,90)(H,94,95)/t24-,34+,35-,42+,44-,46+,47+,48-,49+,50-,51+,52+,53+,54-,56+,57+,65-,66-/m0/s1 ; Key:MYPYJXKWCTUITO-LYRMYLQWSA-N ;
(what is this?) (verify)

　　[★]

英: antibacterial drug, antibacterial
関: 抗生剤、薬理学、抗菌薬一覧、抗細菌薬

first aid step 1 2006 p.165

定義

細菌/微生物に静菌作用、殺菌作用を示す物質。結果として、人において病原性を除去する目的で使用される。
このうち、微生物によって産生される物質を抗生物質と呼ぶ

作用機序による分類

細胞壁合成阻害：βラクタム系抗菌薬(ペニシリン系抗菌薬、セフェム系抗菌薬、モノバクタム系抗菌薬、カルバペネム系抗菌薬)
核酸合成阻害　：ニューキノロン系抗菌薬、メトロニダゾール
タンパク質合成阻害

30S：アミノグリコシド系抗菌薬、テトラサイクリン系抗菌薬
50S：マクロライド系抗菌薬、クリンダマイシン、クロラムフェニコール、ストレプトグラミン系抗菌薬、オキソゾリニドン系抗菌薬(リゾネリド)

代謝拮抗：サルファ剤(サルファメソキサゾール、トリメトプリム)

first aid step 1 2006 p.165

	Mechanism of action	Drugs
1	Block cell wall synthesis by inhibition of peptidoglycan cross-linking	penicillin, ampicillin, ticarcillin, piperacillin, imipenem, aztreonam, cephalosporins
2	Block peptidoglycan synthesis	bacitracin, vancomycin, cycloserine
3	Disrupt bacterial/fungal cell membranes	polymyxins
4	Disrupt fungal cell membranes	amphotericin B, nystatin, fluconazole/azoles
5	Block nucleotide synthesis	sulfonamides, trimethoprim
6	Block DNA topoisomerases	quinolones
7	Block mRNA synthesis	rifampin
8	Block protein synthesis at 50S ribosomal subunit	chloramphenicol, erythromycin/macrolides, lincomycin, clindamycin, streptogramins (quinupristin, dalfopristin), linezolid
9	Block protein synthesis at 30S ribosomal subunit	aminoglycosides, tetracyclines, spectinomycin 　ATuSi　→　あつし

薬物動態

濃度依存性：アミノグリコシド系抗菌薬、ニューロキノロン系抗菌薬
時間依存性：βラクタム系抗菌薬

治療期間

小児

尾内一信 ; 第 39 回日本小児感染症学会教育講演 2 小児感染症の抗菌薬療法 -耐性菌時代の適正使用-

感染臓器・臨床診断	原因菌	投与期間（抗菌薬）
髄膜炎	インフルエンザ菌	7-10日
	肺炎球菌	10-14日
	髄膜炎菌	7-10日
	GBS，腸内細菌，リステリア	21日
中耳炎	＜2 歳	10日
中耳炎	2 歳≦	5-7日
咽頭炎	A 群連鎖球菌	10日(ペニシリン系薬)
咽頭炎	A 群連鎖球菌	5日(セフェム系薬)
肺炎	肺炎球菌，インフルエンザ菌	解熱後3-4日
	黄色ブドウ球菌	3-4週間
	マイコプラズマ，クラミジア	10-21日
腎臓、膀胱炎、腎盂腎炎	大腸菌，プロテウス，腸球菌	3日
腎臓、膀胱炎、腎盂腎炎	大腸菌，プロテウス，腸球菌	14日
骨髄炎	黄色ブドウ球菌	21日
骨髄炎	連鎖球菌，インフルエンザ菌	14日

主要な感染症の抗菌薬投与期間

感染レジマニュ p.27

骨	骨髄炎		4-6週
耳鼻咽喉	中耳炎		5-7日
	副鼻腔炎		5-14日
	A群溶連菌咽頭炎		10日
肺	肺炎	肺炎球菌	7-10日 or 解熱後3日間
		インフルエンザ菌	10-14日
		マイコプラズマ	14日(7-10日)
		レジオネラ	21日
	肺化膿症		28-42日
心臓	感染性心内膜炎	α連鎖球菌	2-4週
		黄色ブドウ球菌	4-6週
消化管	腸炎	赤痢菌	3日
		チフス	14日(5-7日)
		パラチフス
	腹膜炎	特発性	5日
		二次性	10-14日
胆肝膵	肝膿瘍	細菌性	4-8週
		アメーバ性	10日
尿路	膀胱炎		3日
	急性腎盂腎炎		14日(7-10日)
	急性腎盂腎炎・再発		6週
	慢性前立腺炎		1-3ヶ月
髄腔	髄膜炎	インフルエンザ菌	7-10日
		髄膜炎菌
		肺炎球菌	10-14日
		リステリア	21日
敗血症	敗血症	コアグラーゼ陰性ブドウ球菌	5-7日
		黄色ブドウ球菌	28日(14日)
		グラム陰性桿菌	14日(7-14日)
		カンジダ	血液培養陰性化後, 14日

ソース不明

シャント感染：黄色ブドウ球菌：頭蓋内デバイスの感染の場合、髄液培養陰性+10日間

妊婦に避けるべき抗菌薬

Antibiotics to avoid in pregnancy
Sulfonamides––kernicterus.
Aminoglycosides––ototoxicity.
Fluoroquinolones––cartilage damage.
Erythromycin––acute cholestatic hepatitis in mom

(and clarithromycin––embryotoxic).

Metronidazole––mutagenesis.
Tetracyclines––discolored teeth, inhibition of bone growth.
Ribavirin (antiviral)––teratogenic.
Griseofulvin (antifungal)––teratogenic.
Chloramphenicol––“gray baby.”
SAFE Moms Take Really Good Care.

使っても良い

YN.H-24

βラクタム系
エリスロマイシン、アジスロマイシン

参考

抗菌薬インターネットブック

まとまっていてよい

http://www.antibiotic-books.jp

抗菌薬一覧

「バンコマイシン」

　　[★]

英: vancomycin, VCM
化: 塩酸バンコマイシン vancomycin hydrochloride
商: Vancocin, Luphocin、バンマイシン
関: 抗菌薬一覧、テイコプラニン、メトロニダゾール

first aid step1 2006 p.140,165,166,169,173,207

抗菌薬

グリコペプチド系抗生物質

特徴

Streptomyces orientalisから分離
経腸管的に吸収されないため骨髄移植時の消化管内消毒に用いられる。

構造

作用機序

細胞壁合成阻害作用(block peptidoglycan synthesis)
細胞内で作られたmurein monomerの重合を妨げる？

薬理作用

抗菌スペクトル

MRSAを含むほとんどのグラム陽性菌と一部の嫌気性菌に抗菌作用を示す
殺菌的に作用(bactericidal antibiotics)

動態

腸管からほとんど吸収されない→腸管殺菌のための経口投与、点滴静注による全身投与で用いられる

適応

感染性腸炎
骨髄移植時の消化管内殺菌

[US?]MRSA(methicillin-resistant Staphylococcus aureus), penicillin-resistant Sreptococcus pneumoniae

適応菌種

メチシリン耐性黄色ブドウ球菌、クロストリジウム・ディフィシル

注意

禁忌

副作用

nephrotoxicity, ototoxicity, thrombophlebitis, diffuse flushing(red man syndrome) (first aid step1 2006 p.169)

重大な副作用

添付文書

1)ショック：0.1%未満(血圧低下、不快感、口内異常感、喘鳴、眩暈、便意、耳鳴り、発汗等)
2)注射用塩酸バンコマイシン製剤：アナフィラキシー様症状、急性腎不全、間質性腎炎、汎血球減少、無顆粒球症、血小板減少、皮膚粘膜眼症候群(Stevens-Johnson症候群)、中毒性表皮壊死症(Lyell症候群)、剥脱性皮膚炎、第8脳神経障害、偽膜性大腸炎、肝機能障害、黄疸

その他

1)過敏症(発熱、発疹、潮紅、悪寒、蕁麻疹、そう痒)
2)血液(好酸球増多、白血球減少、血小板減少)
3)肝臓(AST・ALT・Al-P上昇)
4)消化器(下痢：48%、悪心：28%、嘔吐：34%、食欲不振)　←骨髄移植時の消化管内殺菌における発現頻度
5)腎臓(BUN・クレアチニンの上昇)
6)その他(口内炎、舌炎)

「レジオネラ属」

　　[★]

英: Legionella
同: Legionella属、レジオネラ
関: レジオネラ科 Legionellaceae、グラム陰性桿菌

特徴

ヒト呼吸器感染症原因菌となる水中の好気性グラム陰性桿菌の一属
グラム陰性桿菌
グラム染色されにくい　→　ヒメネス染色、アクリジンオレンジ染色
BCYE-α寒天培地
細胞内増殖性　(細胞内寄生性細菌と同じ, 結核菌、チフス菌、リステリア菌)

レジオネラ症の代表的菌種レジオネラ属菌

Legionella pneumophila serotype 1　← 最も頻度が高い
Legionella pneumophila serotype 6
Legionella pneumophila other
Legionella micdadei
Legionella bozemanii
Legionella dumffii
Legionella gormanii
Legionella longbeachae
Legionella others

培養

標準的な選択培地：buffered charcoal yeast extract agar(BCYE agar) supplemented with polymyxin, anisomycin, vancomycin, and dyes

レジオネラ属による感染症

レジオネラ症

レジオネラ肺炎：4類感染症

治療

「急性尿細管間質性腎炎」

　　[★]

英: acute tubulointerstitial nephritis
同: 急性間質性腎炎 acute interstitial nephritis, AIN
関: 尿細管間質性腎炎

原因

薬剤性

antibiotics (lactams, sulfonamides, quinolones, vancomycin, erythromycin, minocycline, rifampin, ethambutol, acyclovir)
NSAIDs,COX-2阻害薬
利尿薬(thiazides, furosemide, triamterene)
抗てんかん薬(フェニトイン、フェノバルビタール、カルバマゼピン、バルプロ酸)
その他(カプトプリル、H2受容体阻害薬、プロトンポンプ阻害薬、mesalazine、indinavir、アロプリノール)

感染症

細菌(Streptococcus、Staphylococcus、Legionella、Salmonella、Brucella、Yersinia、Corynebacterium diphtheriae)
ウイルス(Epstein-Barr virus、cytomegalovirus、Hantavirus、polyomavirus、HIV)
その他(レプトスピラ、リケッチア、マイコプラズマ)

特発性

「殺菌性抗生物質」

　　[★]

英: bactericidal antibiotics
関: 抗菌薬

penicillin, cephalosporins, vancomycin, aminoglycosides, fluoroquinolones, metronidazole

「vancomycin-intermediate Staphylococcus aureus」

　　[★] バンコマイシン低感受性黄色ブドウ球菌 VISA

「vancomycin-resistant enterococci」

　　[★] バンコマイシン耐性腸球菌 VRE

[1] "www.idsociety.org".

[2] "www.idsociety.org".

[3] "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014.

[4] Small PM, Chambers HF (1990). "Vancomycin for Staphylococcus aureus endocarditis in intravenous drug users". Antimicrob Agents Chemother 34 (6): 1227–31. doi:10.1128/AAC.34.6.1227. PMC 171789. PMID 2393284.

[5] Gonzalez C, Rubio M, Romero-Vivas J, Gonzalez M, Picazo JJ (1999). "Bacteremic pneumonia due to Staphylococcus aureus: a comparison of disease caused by methicillin-resistant and methicillin-susceptible organisms". Clin Infect Dis 29 (5): 1171–7. doi:10.1086/313440. PMID 10524959.

[AMH2006-6] Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3

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