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SECONDRY METABOLITE

*Ishwar Chandra

[email protected](M.tech Biotechnology, amity institute of biotechnology Amity University)

INTRODUCTION

Secondary metabolites, also known as natural products, are those products (chemical compounds) of

metabolism that are not essential for normal growth, development or reproduction of an organism. In

this sense they are "secondary". The function or importance of these compounds to the organism's

development is usually of ecological nature as they are used as defence against predators (herbivores,

pathogens etc.), for interspecies competition, and to facilitate the reproductive processes. Contrary to

primary metabolites these compounds are not ubiquitous in the living organisms who produce them nor

are they necessarily expressed continuously. Although plants are better known as a source of secondary

metabolites, bacteria, fungi and many marine organisms (sponges, tunicates, corals, snails) are very

interesting sources, too. Secondary metabolites can be classified by their chemical structure or physical

properties into one or more of the following groups: alkaloids, terpenoids, polyketides, aliphatic,

aromatic, and heteroaromatic organic acids, phenols, iridoids , steroids, saponins, peptides, ethereal

oils, resins and balsams. Secondary metabolites are the natural plant products, which are not involved in

the metabolic processes of plants such as photosynthesis. They are also called as secondary plant

products.

Functions

These secondary metabolites help a plant in defense from predators, and sometimes they help in

reproduction processes like pollination. These plant products called as secondary metabolites are

more useful for human mankind as they protect us from many diseases and disorders. Plants

produce a variety of secondary metabolites.

Some of the important secondary metabolites are given below



Plant defense- When there is fungal invasion, plants release hydrogen peroxide which helps the

plant in defense against many antigens. Hydrogen peroxide is produced by a plant and it moves

to the cell wall. Cell wall is the site of invasion. It comes in contact with the enzyme peroxidase

and breaks down pectinase. Thus the foreign harmful substance is rendered useless and hydrogen

peroxide helps in the defense mechanism of plants.

Nature of ochratoxin A

Ochratoxins are a group of mycotoxins produced as secondary metabolites by several fungi of

the Aspergillus or Penicillium families and are weak organic acids consisting of a derivative of

an isocoumarin (Figure 1). The family of ochratoxins consists of three members, A, B, and C

which differ slightlyfrom each other in chemical structures. These differences, however, have

marked effects on their respective toxic potentials. Ochratoxin A is the most abundant and hence

the most commonly detected member but is also the most toxic of the three.1,2,3 It is a potent

toxin affecting mainly the kidney. As in other mycotoxins, ochratoxin A can contaminate a wide

variety of foods as a result of fungal infection in crops, in the field during growth, at harvest, in

storage and in shipment under favourable environmental conditions especially when they are not

properly dried. Ochratoxin A may be present in a foodstuff even when the visible mould is not

seen.



Figure 1. Ochratoxin A

Occurrence and common food products involved

Ochratoxin A is found mainly in cereal and cereal products. This group of commodities has been

reported to be the main contributors to ochratoxin A exposure in exposure assessments carried

out by the European Commission4,5, accounting for 50% of total dietary exposure of ochratoxin

A in European countries (SCOOP task 3.2.7, 2002). Besides cereals and cereal products,

ochratoxin A is also found in arange of other food commodities, including coffee, cocoa, wine,

beer, pulses, spices, dried fruits, grape juice, pig kidney and other meat and meat products of

non-ruminant animals exposed to feedstuffs contaminated with this mycotoxin. Ruminant

animals such as cows and sheep are generally resistant to the effects of ochratoxin A due to

hydrolysis to the non-toxic metabolites by protozoa in the stomachs before absorption into the

blood.

Associated fungal species and geographical distributions

The frequency of the occurrence of the different species of ochratoxinA- producing fungi differs

according to the geographical regions and in the commodities affected. The Penicillium species

that is associated with ochratoxin A production, Penicillium verrucosum,is a common storage

fungus and is the source of ochratoxin A in crops in the cool temperate regions such as Canada,

eastern and north western Europe and parts of South America. It grows only at temperatures

below 30°C and at a lower water activity7. Penicillium species may produce ochratoxin at

temperatures as low as 5°C.In contrast, Aspergillus species appears to be limited to conditions of

high humidity and temperature growing in the tropical and subtropical climates and is the source

of contamination for coffee and cocoa beans, spices, dried vine fruit, grape juice and wine.

Aspergillus ochraceus is the best known species of ochratoxin ±producing Aspergillus. It grows

at moderate temperatures and at a high water activity and is a significant source of ochratoxin Ain cereals. It infects coffee beans usually during sun-drying causing contamination in green

coffee. Aspergillus carbonarius is highly resistant to sunlight and survives sun-drying because of

its black spores and therefore grows at high temperatures. It is associated with maturing fruits

and is the source of ochratoxin A in grapes, dried vine fruits, and wine and is also another source



of ochratoxin A in coffee. Another closely related species, Aspergillus niger, is another minor

source of ochratoxin A production in infected coffee beans and dried vine fruits

.Chemistry and effects of processing.

Ochratoxin A is a moderately stable molecule and is able to survive most food processing to

some extent and may thus occur in consumer products. Processing may involve boiling, baking,

roasting or fermentation, and the degree to which it is destroyed will further depend on other

parameters such as pH, temperature and the other ingredients present. Ochratoxin A is only

partly destroyed during cooking and bread making. Baking and roasting have been reported to

reduce the toxin content by a mere 20%.9,10 However, physical treatment of grain, such as

scouring while cleaning the grain prior to milling, can result in a >50% reduction of ochratoxin

A contamination in the resultant wheat flour. Milling seems to have no or only a minor effect on

the level of ochratoxin A.11

Sources of human exposure

Dietary intake represents the main source of ochratoxin A in human. Human exposure to

ochratoxin A occurs mainly through consumption of contaminated crops or food derived from

animals exposed to contaminated feedstuffs. Occupational exposures from inhalation of dust at

grain storage warehouses are uncommon. Levels of ochratoxin A in human can be measured by

detection of ochratoxin A in human blood and breast milk. A collaborative survey carried out by

13 member states in European Commission in 1995 (SCOOP task 3.2.2) estimated ochratoxin A

intakes in human based on plasma levels of the toxin as a biomarker and found that similar levels

were obtained by estimations from dietary exposure from food surveys. This suggests that the

main sources of ochratoxin A are the known dietary sources covered in the food surveys.

Toxicity and health implications

Metabolism



11. Ochratoxin A is absorbed from the gastrointestinal tract. In mostspecies, ochratoxin A is

absorbed from the stomach as a result of its acidic properties12. Absorption also takes place in

the small intestine particularly in the proximal jejunum. In non-ruminant species such as pigs,

chickens, rabbits and rats,around half of the ingested ochratoxin A may be absorbed.13,14 The

absorbed ochratoxin A is distributed via blood, mainly to the kidneys, and at lower

concentrations to the liver, muscle and fat, with a proportion metabolised into thenon-toxic

metabolite ochratoxin alpha and other less toxic minor metabolites atvarious sites in different

species12, and a significant proportion excretedunchanged. Ochratoxin A has a long serum half -

life in non-ruminant animals andin humans (72-120 h in pigs, 840 h in a human subject) on the

basis of its strong binding to serum macromolecules. In ruminant species such as the cow,

effective hydrolysis of ochratoxin A to the non-toxic ochratoxin alpha takes place in the four

stomachs in the presence of the ruminant protozoa6 rendering the species resistant to the effects

of the toxin. Transfer to the milk has been demonstrated in rats, rabbits and humans. In contrast,

little ochratoxin A is transferred to the milk of ruminants, again due to metabolism of this

mycotoxin by the rumen microflora.

Acute toxicity

The acute toxicity of ochratoxin A is relatively low, although large species differences and

sensitivity are seen with oral LD50 values ranging widely in different species. Oral LD50 values

has been demonstrated to range from 0.2 mg/kg bw in dogs, 1 mg/kg bw in pigs, 3.3 mg/kg bw

in chicken, and 46-58 mg/kg bw in mouse. Dogs and pigs have been reported to be the most

sensitive species15. Effects of acute poisoning such as multifocal haemorrhages in various

organs and fibrin thrombi in the spleen, brain, liver, kidney and heart have been reported

following single dose administration. Nephrosis, hepatic and lymphoid necrosis, and enteritis

with villous atrophy have also been observed in the test species. At present, there are no

documented cases of acute toxicity reported in humans. Chronic toxicity The subchronic and

chronic effects of ochratoxin A are of greatest concern. Ochratoxin A has been shown to be

nephrotoxic, hepatotoxic, teratogenic and immunotoxic to several species of animals and

carcinogenic in mice and rats causing tumours of the kidney and liver.

Nephrotoxicity



In particular, its role in chronic nephropathies has been extensively documented in many

mammalian species. Ochratoxin A is considered the causal agent in nephropathies observed in

several species of agricultural animals, particularly in pigs. It has produced nephrotoxic effects in

all species of single - stomach animals studied so far, even at the lowest level tested (200 g/kg

feed in rats and pigs). Ochratoxicosis in farm animals such as pigs and poultry may lead to

pathological changes in the kidney such as tubular atrophy, interstitial fibrosis and hyalinised

glomeruli. The main target site of ochratoxin A toxicity is the renal proximal tubule, where it

exerts cytotoxic and carcinogenic effects. Significant sex and species differences in sensitivity to

nephrotoxicity have been observed where pigs have been found to be a more sensitive species

compared with rats or mouse. In human, dietary exposure to ochratoxin A in parts of Bulgaria,

Romania and the former Yugoslavia may have association with Balkan endemic nephropathy, a

chronic progressive kidney disease, that is characterised by progressive hypercreatinaemia,

uraemia, hypertension and oedema.

Other toxicities

. Ochratoxin A has been known to cause hepatic damage and hepatic necrosis in experimental

animals. It is a potent teratogen in mice, rats, hamsters and chicken. Both teratogenic and

reproductive effects have been demonstrated. Ochratoxin A has been reported to be an

immunosuppressor and affects the immune system in a number of mammalian species. It was

able to cause inhibition of protein biosynthesis and inhibition of macrophage migration

Carcinogenicity

Ochratoxin A was tested for carcinogenicity by oral administration in mice and rats. Increased

incidence of hepatocellular tumours in mice of each sex, and association with renal-cell

adenomas and carcinomas have been reported in male mice and in rats of each sex fed with

ochratoxin A. In 1993, the International Agency for Research on Cancer (IARC) classified

ochratoxin A as possible human carcinogen (Group 2B) and concluded that there was sufficient

evidence in experimental animals for the carcinogenicity of ochratoxin A and inadequate

evidence in humans for the carcinogenicity of ochratoxin A.19 The doses at which

carcinogenicity were observed in rodents had been reported to be higher than those that caused

nephrotoxicity.



Genotoxicity

Ochratoxin A has been shown to induce DNA damage, DNA repair, and chromosomal

aberrations in mammalian cells in vitro as well as DNA damage and chromosomal aberrations in

mice treated in vivo. However, the mechanism for genotoxicity is unclear and there was no

evidence that it is mediated by direct interaction with DNA.

Observations in humans

Human exposure, as demonstrated by the occurrence of ochratoxin A in blood, and in human

milk, has been observed in various countries in Europe. Ochratoxin A was found more frequently

and high concentrations in blood samples obtained from people living in regions where the fatal

human kidney disease, Balkan Endemic Nephropathy, occurs. A highly significant relationship

has been observed between Balkan endemic nephropathy and tumours of the urinary tract,

particularly with tumours of the renal pelvis and ureters. Nevertheless, similar average

concentrations have been found in some other European countries where this disease is not

observed. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) concluded in

2001 that the epidemiological and clinical data available do not provide a basis for calculatingthe likely carcinogenic potency in human and that Balkan Endemic Nephropathy may involve

other nephrotoxic agents.

Level of safe intake of ochratoxin A

Following the evaluations carried out in 1990, 1995 and 2001 for ochratoxin A, JECFA has

established a provisional tolerable weekly intake (PTWI) of 100 ng/kg bw/wk for this substance

The European Commission¶s Scientific Committee for Food (SCF), after reviewing its opinion

on ochratoxin A, concluded in 1998 that it would be prudent to reduce exposure to ochratoxin A

as much as possible, ensuring that exposures are towards the lower end of the range of tolerable

daily intakes which has been estimated by other bodies, at a level below 5 ng/kg bw/ day.21

Tolerable intake, which can be expressed in daily, weekly (e.g. PTWI) or monthly basis is an

estimate of the amount of a contaminant that can be ingested over a lifetime without appreciable



risk. An intake above PTWI does not automatically mean that health is at risk. Transient

excursion above the PTWI would have no health consequences provided that the average intake

over long period is not exceeded as the emphasis of PTWI is a lifetime exposure.. Values for the

estimated dietary exposures to ochratoxin A in European countries range from 0.13 to 4.6 ng/kg

bw per day (i.e. 0.91 to 32.2 ng/kg bw per week) with the major source being cereal and cereal

products (SCOOP task 3.2.2 and SCOOP 3.2.7). Following the evaluation in 2001 by JECFA,

the mean total intake of ochratoxin A at the international level was estimated to be 45 ng/kg bw

per week based on aggregated data. This was assessed on the basis of data on mean consumption

combined with weighted mean level of contamination

Codex draft limit

In the recent sessions of the Codex Committee of Food Additives and Contaminants (CCFAC),

there had been active discussions on setting the draft maximum level for ochratoxin A in raw

wheat, barley, rye and derived products. A draft maximum level of 5 g/kg is now held at step 7,

pending for JECFA to conduct a more comprehensive risk assessment by 2006. In the 37th

session of CCFAC held in April 2005, ochratoxin A was considered a high priority item for

evaluation by JECFA, with particular reference to ochratoxin A levels in cereals, exposure

assessment, and effects of processing on residual levels in foods.

Legal limits in some countries

Legal limits of ochratoxin A have been set in a number of food commodities including cereals

and cereal products, dried vine fruits, roasted and soluble coffee, wine, grape juice, and foods for

infants and children by the European Commission under EC regulation 466/2001 22 , 472/2002

23 , 24 and 123/200525. The updated limits set for different food items are listed in Annex 1.

Study on ochratoxin A in food

Studies on levels of ochratoxin A in food, so far, have been conducted mainly in the West.

Consequentially, international data accumulated at present are confined principally to the

Western diet. Little is known about levels of ochratoxin A with regards to the rice - based Eastern

diet pertaining to the weather conditions in countries in the East. The present study was carried

out to evaluate the local situation of the levels of ochratoxin A in food, and to estimate the

dietary exposure to ochratoxin A in secondary school students population in Hong Kong in order



to assess if there is any associated health risk. In this study, the potentials for any risks to health

posed by ochratoxin

VANCOMYSIN

is a glycopeptide antibiotic used in the prophylaxisand treatment of infections caused by Gram-

positivebacteria. It has traditionally been reserved as a drug of "last resort", used only

after treatment with other antibiotics had failed, although the emergence of vancomycin-resistant

organisms means that it is increasingly being displaced from this role by linezolidand

the carbapenems.

Systematic (IUPAC) name

unable to be assigned

Identifiers

CAS number 1404-90-6

ATC code A07AA09 J01XA01

PubChem 14969

DrugBank APRD01287

Chemical data

Formula

C66H75Cl2N9O24

Mol. mass 1449.3 g.mol-1

Pharmacokinetic data

Bioavailability Negligible (oral)

Metabolism Excreted unchanged

Half life 411 hours (adults)

6-10 days (adults, impaired renal

function)

Excretion Renal

Therapeutic considerations

Pregnancy cat.

B2 ( Au), B (U.S.)

Legal status

S4 (Au), POM (UK ), -only (U.S.)

Routes IV, oral



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

History

Vancomycin was first isolated by EC Kornfeld (working at Eli Lilly) from a soil sample

collected from the interior jungles of Borneo by a missionary. The organism that produced it was

eventually named Amycolatopsis Orientalis. The original indication for vancomycin was for

the treatment of penicillin-resistant Staphylococcus aureus.

[1][2]

The compound was initiallylabelled compound 05865, but was eventually given the generic name, vancomycin (derived

from the word "vanquished"). One advantage that was quickly apparent was 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 being fast-tracked for approval by the FDA in 1958. Eli Lilly first



marketedvancomycin hydrochloride under the trade name Vancocin.[1]

Vancomycin never

became first line treatment for Staphylococcus aureus for several reasons:

1. The drug must be given intravenously, because it is not absorbed orally.

2. -lactamase-resistant semi-synthetic penicillins such as methicillin (and its

successors,nafcillin and cloxacillin) were subsequently developed.

3. Early trials using early impure forms of vancomycin ("Mississippi mud") which were

found to be toxic to the ears and to the kidneys;[3]

these findings led to vancomycin being

relegated to the position of a drug of last resort.

In 2004, Eli Lilly licensed Vancocin to ViroPharma in the U.S., Flynn Pharma in the UK

andAspen Pharmacare in Australia. The patent expired in the early 1980s and generic versions of

the drug are also available under various trade names.

Pharmacology and chemistry

It is a branched tricyclic glycosylated nonribosomal peptide produced by the fermentation of

the Actinobacteria species Amycolatopsis orientalis (formerly designated Nocardia orientalis).

Vancomycin acts by inhibiting proper cell wall synthesis in Gram- positive bacteria. The

mechanism inhibited, and various factors related to entering the outer membrane of Gram-

negative organisms mean that vancomycin is not active against Gram-negative bacteria(except

some non-gonococcal species of Neisseria). Specifically, vancomycin prevents incorporation of

N-acetylmuramic acid (NAM)- and N-acetylglucosamine (NAG)- peptide subunits into

the peptidoglycan matrix; which forms the major structural component of Gram- positive cell

walls. The large hydrophilic molecule is able to form hydrogen bond interactions with the

terminal D-alanyl-D-alanine moieties of the NAM/NAG- peptides. Normally this is a five- point

interaction. This binding of vancomycin to the D-Ala-D-Ala prevents the incorporation of the

NAM/NAG- peptide subunits into the peptidoglycan matrix. Vancomycin

exhibitsatropisomerism ² it has two chemically distinct rotamers owing to the rotational

restriction of the chlorotyrosine residue (on the right hand side of the figure). The form present in

the drug is the thermodynamically more stable conformer, and, importantly, has more potent

activity.



Clinical use Indications

Vancomycin is indicated for the treatment of serious, life-threatening infections by Gram-

positive bacteria which are 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-

resistantenterococci has resulted in the development of guidelines for use by the Centers for

Disease Control (CDC) Hospital Infection Control Practices Advisory Committee. These

guidelines restrict use of vancomycin to the following indications:[6]

y treatment of serious infections caused by susceptible organisms resistant

to penicillins(methicillin-resistant Staphylococcus aureus and multi-

resistant Staphylococcus epidermidis (MRSE)) or in individuals with serious allergy

to penicillins

y pseudomembranous colitis (relapse or unresponsive to metronidazole treatment)

y For treatment of infections caused by gram- positive microorganisms in patients who have

serious allergies to beta-lactam antimicrobials.

(http://wonder.cdc.gov/wonder/prevguid/m0039349/m0039349.asp)

y antibacterial prophylaxis for endocarditis following certain procedures in penicillin-

hypersensitive individuals at high risk y surgical prophylaxis for major procedures involving implantation of prostheses in

institutions with a high rate of MRSA or MRSE

Adverse effects

Common adverse drug reactions (1% of patients) associated with IV vancomycin include: local

pain, which may be severe and/or 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. Later trials using purer forms of vancomycin found

that nephrotoxicity is an infrequent adverse effect (0.1±1% of patients), but that this is

accentuated in the presence of aminoglycosides.[7]

Rare adverse effects (<0.1% of patients)

include: anaphylaxis, toxic epidermal necrolysis, erythema multiforme, red man syndrome (see

below), superinfection, thrombocytopenia, neutropenia, leucopenia, tinnitus, dizziness and/or



ototoxicity (see below).[6]

Lately it has been emphasized that vancomycin can induce platelet -

reactive antibodies in the patient, leading to severe thrombocytopenia and bleeding with

florid petechial hemorrhages, ecchymoses, and wet purpura. [8]

Dosing considerations

Intravenous vs oral administration

Vancomycin needs to be given intravenously (IV) for systemic therapy since it does not cross

through the intestinal lining. It is a large hydrophilic molecule which partitions poorly across the

gastrointestinal mucosa. The only indication for oral vancomycin therapy is in

the treatment ofpseudomembranous colitis, where it must be given orally to reach the site of

infection in the colon. Inhaled vancomycin has also been used (off -label), via nebulizer,

for treatment of various infections of the upper and lower respiratory tract.

Red man syndrome

Vancomycin must be administered in a dilute solution slowly, over at least 60 minutes

(maximum rate of 10 mg/minute for doses >500 mg).[6]

This is due to the high incidence

ofpain and thrombophlebitis and to avoid an infusion reaction known as the red man

syndromeor red neck syndrome. This syndrome, usually appearing within 4±10 minutes after the

commencement or soon after the completion of an infusion, is characterised by flushing and/or

and an erythematous rash that affects the face, neck and upper torso. Less

frequently,hypotension and angioedema may also occur. Symptoms may be treated

with antihistamines, including diphenhydramine.[9]

Therapeutic drug monitoring

Vancomycin activity is considered to be time-dependent ± that is, antimicrobial activity depends

on the duration that the drug level exceeds the minimum inhibitory concentration (MIC) of the

target organism. Thus, peak levels have not been shown to correlate with efficacy or toxicity ±

indeed concentration monitoring is unnecessary in most cases. Circumstances wheretherapeutic

drug monitoring (TDM) is warranted include: patients receiving concomitant aminoglycoside

therapy, patients with (potentially) altered pharmacokinetic parameters, patients



on haemodialysis, during high dose or prolonged treatment, and patients with impairedrenal

function. In such cases, trough concentrations are measured.[6][10][11][12]

Toxicity

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

seventies, it was recognised that the previously reported rates of toxicity were 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.[2]

Nephrotoxicity

Subsequent reviews of accumulated case reports of vancomycin-related nephrotoxicity found

that many of the patients had also received other known nephrotoxins,

particularlyaminoglycosides. 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, Cantu and colleagues found that the use of vancomycin

monotherapy was clearly documented in only three of 82 available cases in the

literature.[10]

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 that 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. Additionally, 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. Essentially, the reputation of vancomycin as a nephrotoxin is over -stated, 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, it also remains unproven that therapeutic drug monitoring of vancomycin for the purpose

of maintaining "therapeutic" levels will prevent ototoxicity.

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 that there probably is some increased nephrotoxic

effect when vancomycin is added to nephrotoxins such as aminoglycosides. However, a dose- or

serum level-effect relationship has not been established.

Antibiotic resistance Intrinsic resistance

There are a few gram- positive bacteria that are intrinsically resistant to vancomycin: these

areLeuconostoc and Pediococcus species, but these organisms are rare causes of disease in

humans.[13]

Most Lactobacillus species are also intrinsically resistant to vancomycin[13]

(the

exception is L. acidophilus[14]

). Most gram-negative bacteria are intrinsically resistant to

vancomycin because of their outer membrane is impermeable to large glycopeptide

molecules[15]

(with the exception of some non-gonococcal Neisseria species).[16]

Acquired resistance

Acquired microbial resistance to vancomycin is a growing problem, particularly within health

care facilities such as hospitals. With vancomycin being the last-line antibiotic for serious Gram-

positive infections there is the growing prospect that resistance will result in a return to the days

when fatal bacterial infections were common. Vancomycin-resistant enterococci (VRE) emerged

in 1987. Vancomycin resistance emerged in more common pathogenic organisms during

the 1990s and 2000s, including vancomycin-intermediate Staphylococcus



aureus(VISA), vancomycin-resistant Staphylococcus aureus (VRSA), and vancomycin-

resistantClostridium difficile.[17][18] There is some suspicion that agricultural use of avoparcin,

another similar glycopeptide antibiotic, has contributed to the emergence of vancomycin-

resistant organisms. One mechanism of resistance to vancomycin appears to be alteration to the

terminal amino acid residues of the NAM/NAG- peptide subunits, normally D-alanyl-D-alanine,

which vancomycin binds to. Variations such as D-alanyl-D-lactate and D-alanyl-D-serine result

in only a 4- point hydrogen bonding interaction being possible between vancomycin and the

peptide. This loss of just one point of interaction results in a 1000-fold decrease in affinity.

InEnterococci this modification appears to be due to the expression of an enzyme which alters

the terminal residue. Three main resistance variants have been characterised to date among

resistant Enterococcus faecium and E. faecalis populations.

y VanA - resistance to vancomycin and teicoplanin, inducible on exposure to these agents

y VanB - lower level resistance, inducible by vancomycin but strains may remain

susceptible to teicoplanin

y VanC - least clinically important, resistance only to vancomycin, constitutive resistance

The development and use of novel antibiotics such as linezolid and daptomycin is expected to

delay, but not halt, the emergence of bacteria resistant to all available antibiotics.



References

1. ^ a b

Moellering, RC Jr. (2006). "Vancomycin: A 50-Year Reassessment". Clin Infect

Dis42: S3±S4. PubMed.

2. ^ a b

Donald P. (2006). "Vancomycin: A History". Clin Infect Dis 42: S5-S12. PMID

16323120.

3. ^ Griffith RS. (1981). "Introduction to vancomycin". Rev Infect Dis 3: S2004.

4. ^ Small PM, Chambers HF (1990). "Vancomycin for Staphylococcus aureus endocarditis

in intravenous drug users". Antimicrob Agents Chemother 34: 1227±31. PMI

D 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: 1171±7. PMID

10524959.

6. Google search

7. Boosrags .com

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