Hugo W.B., Russel A.D.(ed). Pharmaceutical Microbiology
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5 Use of microorganisms as models of mammalian
drug metabolism
The safety and efficacy of a drug must be exhaustively evaluated prior to its approval
for use in the treatment of human diseases. Investigations of the manner in which a
drug is metabolized are extremely valuable since they provide information on its mode
of action, why it exhibits toxicity and how it is distributed, excreted and stored in the
body. Traditionally, drug metabolism studies have relied on the use of animal models
and, to a lesser extent, liver microsomal preparations, tissue culture and perfused organ
systems. Each of these models has certain advantages and disadvantages. Animals in
particular are expensive to purchase and maintain and there is considerable pressure
from animal welfare groups to curb the use of animals in scientific research.
The use of microbial systems as in vitro models for drug metabolism in humans
has been proposed since there are many similarities between certain microbial enzyme
systems and mammalian liver enzyme systems. The major advantages of using micro-
organisms is their ability to produce significant quantities of metabolites that would
otherwise be difficult to obtain from animal systems or by chemical synthesis, and the
considerable reduction in operating costs compared with animal studies.
Microbial drug metabolism studies are usually carried out by firstly screening a
large number of microorganisms for their ability to metabolize a drug substrate. The
organism is usually grown in a medium such as peptone glucose in flasks which are
shaken to ensure good aeration. Drugs as substrates are generally added after 24 hours
of growth and are then sampled for the presence of metabolites at intervals up to 14
days after substrate addition. Once it has been determined that a microorganism can
metabolize a drug, the whole process can be scaled up for the production of large
quantities of metabolites for the determination of their structure and biological properties.
As an example of this the metabolism of the antidepressant drug imipramine can be
considered. In mammalian systems, this is metabolized to five major metabolites:
2-hydroxyimipramine, 10-hydroxyimipramine, iminodibenzyl, imipramine-/V-oxide
and desipramine (Fig. 25.11). For microbial metabolism studies, a large number of
fungi are screened, from which several are chosen for the preparative scale production
of imipramine metabolites. Cunninghamella blakesleeana produces the hydroxylated
metabolites 2-hydroxyimipramine and 10-hydroxyimipramine; Aspergillus flavipes and
Fusarium oxysporum f. sp. cepae yield the N-oxide derivative and iminodibenzyl,
respectively; whilst the pharmacologically active metabolite desipramine is produced
by Mucor griseocyanus together with the 10-hydroxy and iV-oxide metabolites. By
scaling up this procedure, significant quantities of the metabolites that are formed during
the mammalian metabolism can be obtained.
Microorganisms thus have considerable potential as tools in the study of drug
metabolism. Whilst they cannot completely replace animals they are extremely useful
as predictive models for initial studies.
6 Insecticides
Like animals, insects are susceptible to infections which may be caused by viruses,
fungi, bacteria or protozoa. The use of microorganisms to spread diseases to particular
Additional pharmaceutical applications of microorganisms 487
Fig. 25.11 Structure of imipramine and its metabolites.
insect pests offers an attractive method of bio-control, particularly in view of the ever-
increasing incidence of resistance to chemical insecticides. However, any micro-
organism used in this way must be highly virulent, specific for the target pest but non-
pathogenic to animals, man or plants. It must be economical to produce, stable on
storage and preferably rapidly acting. Bacterial and viral pathogens have so far shown
the most promise.
Perhaps the best studied, commercially available insecticidal agent is
B. thuringiensis. This insect pathogen contains two toxins of major importance. The
(^-endotoxin is a protein present inside the bacterial cell as a crystalline inclusion
within the spore case. This toxin is primarily active against the larvae of lepidopteran
insects (moths and butterflies). Its mechanism of action is summarized in Fig. 25.12.
Commercially available preparations of B. thuringiensis are spore-crystal mixtures
prepared as dusting powders. They are used primarily to protect commercial crops
from destruction by caterpillars and are surprisingly non-toxic to man and animals.
Although the currently available preparation has a rather narrow spectrum of activity,
a variant B. thuringiensis strain has recently been isolated and found to produce a
different 5-endotoxin with activity against coleopteran insects (beetles) rather than
lepidopteran or dipteran (flies and mosquitoes) insects.
The second B. thuringiensis toxin, the /3-exotoxin has a much broader spectrum
encompassing the Lepidoptera, Coleoptera and Diptera. It is an adenine nucleotide,
probably an ATP analogue which acts by competitively inhibiting enzymes which
catalyse the hydrolysis of ATP and pyrophosphate. This compound, however, is toxic
when administered to mammals so that commercial preparations of the B. thuringiensis
5-endotoxin are obtained from strains which do not produce the j8-exotoxin.
Strains of B. sphaericus pathogenic to mosquitoes were isolated several years ago.
More recently, strains of this organism with increased toxicity to mosquitoes have
been isolated and might have considerable potential as control agents.
Other insect pathogens are currently being evaluated for activity against insects
which are vectors for diseases such as sleeping sickness, as well as those which cause
damage to crops. Viruses may well have the greatest potential for insect control since
they are host-specific and highly virulent, and one infected insect can release vast
numbers of virus particles into the environment. They have already been used with
considerable success against the spruce sawfly and pine moth.
Concluding remarks
Microorganisms are not always the killers they are made out to be. In fact, mankind
has been remarkably adept at harnessing microbes for a variety of purposes. In many
instances, e.g. antibiotics by whole or partial synthetic production (Chapter 7) and
various forms of vaccines, products have been obtained to turn the tables on infecting
organisms. Other products have been used for a variety of purposes (including
many non-pharmaceutical or non-medical ones, outside the scope of this chapter).
Microorganisms have also been employed for specific assay purposes and different
types of chemical transformations, as well as in genetic engineering (Chapter 24).
Immobilized microorganisms have now been used with considerable success in the
partial synthesis of steroids and antibiotics and in the production of the antiviral
compound adenine arabinoside (Chapter 5).
There are reports of the benefits of botulinum toxin in the treatment of cerebral
palsy in children. The toxin, produced by Clostridium botulinum, is a powerful and
deadly poison, but is also an effective muscle relaxant. It is not licensed for use as such
in the UK but is undergoing clinical trials. Current evidence suggests that repeat
injections are necessary some 4-6 months after the first.
Additional pharmaceutical applications of microorganisms 489
Recent studies on the therapeutic uses of toxins have demonstrated also that:
1 botulinum toxin can be used to study synapse remodelling and that enzyme-
inactivated toxin can be employed to deliver other molecules into motor nerve ending.
2 Pseudomonas cytotoxin hybrids destroy cancer cells and have given promising
results in tumour destruction.
3 Cholera toxin and related toxins act as immune modulators, with potential use as
adjuvants and as therapeutic agents in the treatment of immunologically mediated human
disease.
A cautionary note must still be added, however: problems of toxicity remain and
these must be overcome before widespread therapeutic usage is feasible.
The beneficial harnessing of microbes is likely to continue well into the next century.
8 Further reading
Ames B.N., McCann J. & Yamasaki E. (1975) Methods for detecting carcinogens and mutagens with
the Salmonella/mammalian microsome mutagenicity test. Mutat Res, 31, 347-364.
Breeze A.S. & Simpson A.M. (1982) An improved method using acetyl-coenzyme A regeneration for
the enzymic inactivation of aminoglycosides prior to sterility testing. J Appl Bacteriol, 53, 277-
284.
Clark A.M., McChesney J.D. & Hufford CD. (1985) The use of microorganisms for the study of drug
metabolism. Med Res Rev, 5, 231-253.
Conference (1973) Streptokinase in clinical practice. Postgrad Med J, 49, 3-142.
Data J.L. & Nies A.S. (1974) Dextran 40. Ann Intern Med, 81,500-504.
Davis G., Green M.J. & Hill H.A.O. (1986) Detection of ATP and creatinine kinase using an enzyme
electrode. Enzyme Microb Tech, 8, 349-352.
Demain A.L., Somkuti G.A., Hunter-Cevera J.C. & Rossmore H.W. (1989) Novel Microbial Products
for Medicine and Agriculture. Amsterdam: Elsevier.
Doenicke A., Grote B. & Lorenz W. (1977) Blood and blood substitutes. Br J Anaesth, 49, 681—
688.
Fukui S. & Tanaka A. (1982) Immobilized microbial cells. Annu Rev Microbiol, 36, 145-172.
Harvey A. (ed.) (1993) Drugs from Natural Products. Pharmaceuticals andAgrochemicals. Chichester:
Ellis Horwood.
Hewitt W. & Vincent S. (1989) Theory and Application of Microbiological Assay. London: Academic
Press.
Hutt A.J., Kooloobandi A. & Hanlon G.W. (1993) Microbial metabolism of 2-arylpropionic acids:
Chiral inversion of ibuprofen and 2-phenylpropionic acid. Chirality, 5, 596-601.
Jones R.L. & Grady R.W. (1983) Siderophores as antimicrobial agents. Eur J Clin Microbiol, 2, 411-
413.
Kier D.K. (1985) Use of the Ames test in toxicology. Reg Toxicol Pharmacol, 5, 59-64.
Mackowiack P.A. (1979) Clinical uses of microorganisms and their products. Am J Med, 67,293-306.
Priest EG. (1992) Biological control of mosquitoes and other biting flies by Bacillus sphaericus and
Bacillus thuringiensis. J Appl Bacteriol, 72, 357-369.
Queener S.W. (1990) Molecular biology of penicillin and cephalosporin biosynthesis. Antimicrob Agents
Chemother, 34, 943-948.
Reid E. & Wilson D. (eds) (1990) Analysis for Drugs and Metabolites including Anti-infective Agents.
Methodological Surveys in Biochemistry and Analysis, vol. 20. Royal Society of Chemistry.
Scientific American (1981) Issue on industrial microbiology, vol. 245, No. 3. (An excellent series of
papers describing the manufacture by microorganisms or products useful to mankind.)
Smith R.V. & Rosazza J.P. (1975) Microbial models of mammalian metabolism. / Pharm Sci, 64,
1737-1759.
Turner A.P.F. & Pickup J.C. (1985) Diabetes mellitus: biosensors for research and management.
Biosensors, 1, 85-115.
Verall M.S.(1985) Discovery and Isolation of Microbial Products. Chichester: Ellis Horwood.
490 Chapter 25
Weinberg E.D. (1984) Iron withholding: a defence against infection and neoplasia. Physiol Rev, 64,
65-107.
White L.O. & Reeves D.S. (1983) Enzymatic assay of aminoglycoside antibiotics. In: Antibiotics:
Assessment of Antimicrobial Activity and Resistance (eds A.D. Russell & L.B. Quesnel), pp. 199-
210. Society for Applied Bacteriology Technical Series No. 18. London: Academic Press.
White R.J. (1982) Microbiological models as screening tools for anticancer agents: potentials and
limitations. Annu Rev Microbiol, 36,415-433.
Additional pharmaceutical applications of microorganisms 491
Index
Note: page numbers in italics refer to
figures, those in bold refer to tables
[A
w
] see water activity
abortion
brucellosis 29
listeriosis 28
abscesses, fibrin deposition 83-4
acanthamoeba keratitis 207
Acanthamoeba spp. 207
accelerated electron radiation 401,
403,405
acetic acid 235
/V-acetyl-3-0-1 -carboxyethyl-
glucosamine 5
iV-acetylglucosamine 5
acetyltransferases 188
acid-fast stain for bacterial spores 12
Acinetobacter 30
acquired immune deficiency syndrome
see AIDS
Acremonium chrysogenum 157, 158
acridine dyes 174, 226
acriflavine 226,249
actinomycetes
cloning host 462
industrial water supplies 342
active immunity 304-5, 328-9
acute phase proteins 281
acycloguanosine see acyclovir
acyclovir (acycloguanosine) 70,
126-7, 130, 174
adaptation, drug resistance 133
additive effects of drug
combinations 128
adenosine arabinoside 125
adenosine deaminase deficiency
467
adenosine triphosphatase 258
adenosine triphosphate (ATP) 17
firefly light-emitting system 25
microbial 372
non-microbial 25
adenovirus 57,63
oncogenic 72
adenyl cyclase 86
adenylyltransferases 188
adhesins, antibodies against 79
adult T-cell leukaemia/lymphoma
syndrome 72
adverse drug reactions 135-6
aflatoxins 49,372
agglutinins 79
B. pertussis 81
AIDS
Candida albicans infection 44
cryptococcal meningitis 47
fungal infections 114
Mycobacterium avium intracellular
276
Pneumocystis carinii pneumonia
117, 178
secondary infections 72
trimetrexate treatment 178
air, filtered 432-3
air supply for clean areas 432-4
air-filtration systems 341,433
air-sampling machine 340
albumin, human serum 464
Alcaligenes spp. 342, 346
alcohols 210,213-14
aliphatic 213
aralkyl 213-14
fusel 40
membrane-active agents 178
preservatives 213-14
properties 209
aldehydes 210,214-16
antiviral activity 57
properties 209
sporicidal action 204
toxicity 208
alexidine 216-17
alkyl polyguanides 204
alkyl quaternaries 204
allergies 279
allografts 301
allylamines, synthetic 122
Alternaria spp. 347
alveolar region, macrophages 78
amantadine hydrochloride 124,125
Ames test 484-5
6-p-amidinopenicillanic acid 93, 94,
95
amikacin 106, 707, 108
aminacrine 226
D-amino acids 163
amino acids 472-3
bioassays 481-2
amino groups 259
aminoacyl-tRNA 172
aminoglycoside-aminocyclitol
antibiotics 106-8, 169, 171
active uptake 171
energy-dependent phase of uptake
171
energy-independent phase of uptake
171
resistance 188-9,190
ribosomal target site alteration 189
aminoglycoside-modifying enzymes
189,190
aminoglycosides 131, 133,481
burn wounds 144
cystic fibrosis infections 140
enzymatic inactivation 133
toxicity 135
6-aminopenicillanic acid (6-APA) 92,
93
amoebiasis, intestinal 108
cyclic AMP 86
amphoterocin B 114,115
action 179
combination with 5-flucytosine
134
ampicillin 93, 94, 95
candidiasis superinfection 136
Gram-negative bacteria lysis 167
Haemophilus influenzae resistance
145
kidney infection 141
typhoid fever 142
«-amyl alcohol 40
amylase 83
anaphylactic reactions 299
anaphylaxis 135
anaphylotoxins 292
anionic surfactants 357
ankylosing spondylitis 301
antagonism 128
anthelmintics, imidazole derivatives
120, 121
anthrax 27
vaccine 311
anti-inflammatory drugs 301
anti-sense agents 466
antibacterial agents, non-antibiotic
cell wall targetting 256
cellular targets 260, 261
cytoplasm effects 258-9
cytoplasmic membrane activity
257-8
mode of action 256-9, 260, 261,
262
multitarget reactors 259, 262
antibacterial agents, semi-solid
248-9
antibiotic policies 145-7
costs 146
drug resistance 146
free prescribing 146-7
restricted dispensing/reporting
147
antibiotic resistance see resistance
antibiotics
activity spectrum 182
aminoglycoside-aminocyclitol
106-8, 170,171, 188-9,190
antifungal 114,775
assays 479-81
p-lactams 92-3, 94, 95-8, 99,
100-4
combination 134-5
definition 91-2
enzymic inactivation 486
glycopeptide 111-12
macrolides 108-11
manufacture 149-50
benzylpenicillin 149,150-8
cephalosporin C 149, 158, 759,
160
fermentation 149,150
Index 493
Index
Note: page numbers in italics refer to
figures, those in bold refer to tables
[A
w
] see water activity
abortion
brucellosis 29
listeriosis 28
abscesses, fibrin deposition 83-4
acanthamoeba keratitis 207
Acanthamoeba spp. 207
accelerated electron radiation 401,
403,405
acetic acid 235
/V-acetyl-3-0-1 -carboxyethyl-
glucosamine 5
iV-acetylglucosamine 5
acetyltransferases 188
acid-fast stain for bacterial spores 12
Acinetobacter 30
acquired immune deficiency syndrome
see AIDS
Acremonium chrysogenum 157, 158
acridine dyes 174, 226
acriflavine 226,249
actinomycetes
cloning host 462
industrial water supplies 342
active immunity 304-5, 328-9
acute phase proteins 281
acycloguanosine see acyclovir
acyclovir (acycloguanosine) 70,
126-7, 130, 174
adaptation, drug resistance 133
additive effects of drug
combinations 128
adenosine arabinoside 125
adenosine deaminase deficiency
467
adenosine triphosphatase 258
adenosine triphosphate (ATP) 17
firefly light-emitting system 25
microbial 372
non-microbial 25
adenovirus 57,63
oncogenic 72
adenyl cyclase 86
adenylyltransferases 188
adhesins, antibodies against 79
adult T-cell leukaemia/lymphoma
syndrome 72
adverse drug reactions 135-6
aflatoxins 49,372
agglutinins 79
B. pertussis 81
AIDS
Candida albicans infection 44
cryptococcal meningitis 47
fungal infections 114
Mycobacterium avium intracellular
276
Pneumocystis carinii pneumonia
117, 178
secondary infections 72
trimetrexate treatment 178
air, filtered 432-3
air supply for clean areas 432-4
air-filtration systems 341,433
air-sampling machine 340
albumin, human serum 464
Alcaligenes spp. 342, 346
alcohols 210,213-14
aliphatic 213
aralkyl 213-14
fusel 40
membrane-active agents 178
preservatives 213-14
properties 209
aldehydes 210,214-16
antiviral activity 57
properties 209
sporicidal action 204
toxicity 208
alexidine 216-17
alkyl polyguanides 204
alkyl quaternaries 204
allergies 279
allografts 301
allylamines, synthetic 122
Alternaria spp. 347
alveolar region, macrophages 78
amantadine hydrochloride 124,125
Ames test 484-5
6-p-amidinopenicillanic acid 93, 94,
95
amikacin 106, 707, 108
aminacrine 226
D-amino acids 163
amino acids 472-3
bioassays 481-2
amino groups 259
aminoacyl-tRNA 172
aminoglycoside-aminocyclitol
antibiotics 106-8, 169, 171
active uptake 171
energy-dependent phase of uptake
171
energy-independent phase of uptake
171
resistance 188-9,190
ribosomal target site alteration 189
aminoglycoside-modifying enzymes
189,190
aminoglycosides 131, 133,481
burn wounds 144
cystic fibrosis infections 140
enzymatic inactivation 133
toxicity 135
6-aminopenicillanic acid (6-APA) 92,
93
amoebiasis, intestinal 108
cyclic AMP 86
amphoterocin B 114,115
action 179
combination with 5-flucytosine
134
ampicillin 93, 94, 95
candidiasis superinfection 136
Gram-negative bacteria lysis 167
Haemophilus influenzae resistance
145
kidney infection 141
typhoid fever 142
«-amyl alcohol 40
amylase 83
anaphylactic reactions 299
anaphylaxis 135
anaphylotoxins 292
anionic surfactants 357
ankylosing spondylitis 301
antagonism 128
anthelmintics, imidazole derivatives
120, 121
anthrax 27
vaccine 311
anti-inflammatory drugs 301
anti-sense agents 466
antibacterial agents, non-antibiotic
cell wall targetting 256
cellular targets 260, 261
cytoplasm effects 258-9
cytoplasmic membrane activity
257-8
mode of action 256-9, 260, 261,
262
multitarget reactors 259, 262
antibacterial agents, semi-solid
248-9
antibiotic policies 145-7
costs 146
drug resistance 146
free prescribing 146-7
restricted dispensing/reporting
147
antibiotic resistance see resistance
antibiotics
activity spectrum 182
aminoglycoside-aminocyclitol
106-8, 170,171, 188-9,190
antifungal 114,775
assays 479-81
p-lactams 92-3, 94, 95-8, 99,
100-4
combination 134-5
definition 91-2
enzymic inactivation 486
glycopeptide 111-12
macrolides 108-11
manufacture 149-50
benzylpenicillin 149,150-8
cephalosporin C 149, 158, 759,
160
fermentation 149,150
Index 493
P-lactams 149-50
penicillin V 149,158
mechanisms of action 162-79
chromosome function/replication
173-6
protein synthesis 169-70,163,
171-6
microorganisms in partial synthesis
477
polypeptide 111
production from microorganisms
470,
473
rifamycins 106
semisynthesis 92
sources 92
synthesis 92
tetracyclines 104-6
antibodies 283
binding 80
feedback 296
maternally-acquired 327
passive acquired immunity 303
pre-formed 328
secretory 327
transplacental passage 302
antibody-dependent cell-mediated
cytotoxicity (ADCC) 297
antifungal agents 114,115
disinfectant powders 249
antigen 283
antigen-antibody complexes 86
antigen-presenting cells 294
antigens 284
cross-reactive 298
antilymphocyte serum 301
antimessages 69
antimicrobial action, target sites 163
antimicrobial agents/drugs
acid 210,212-13
adverse reactions 135-6
anatomical site of infection 133
chemoprophylaxis 136-7
choice 202-8
chemical agent properties 203
microbial challenge 203
vegetative bacteria 204
clinical use 130-1, 137^45
combinations 226-7
dilution 449
distribution 133
environmental factors 208
generic substitution 146
host factors 131
intended application 207-8
lipid solubility 133
liquid
antifungal activity 244-5
bacteriostasis estimation 242-4
virucidal activity testing 245-8
membrane filtration 449
neutralizing agents 240
non-antibiotic 229-32
bacterial spore resistance 270-2
fungal resistance 274-5
protozoal resistance 275
resistance 263^1, 265, 266-76
viral resistance 275, 276
see also biocides
organism susceptibility 131,752
pharmacological factors 131,133
preservatives 365-8
properties 209
resistance 133-4
selection 131,133
semi-solid 243
specific inactivation 448
sterility testing 448-9
superinfection 136
synergism 227
synthetic 115-22,123
therapeutic concentrations 133
toxicity 208
types of compound 208,210-11,
212-21, 222, 223-7
antimycobacterial drugs, resistance
196-7
antiseptics 202,230
antibacterial activity 205
antifungal activity 205, 206
a-antitrypsin 461,463
antitubercular drugs 117-18
antiviral drugs 124-8, 174
API system 20
arabinogalactan 168
arabinose 168
arabinosyl transferase enzyme 168
Archaebacteria 4
Arthus reaction 300
2-arylpropionic acid 478
ascospores 40,41
Neurospora crassa 48
aseptic areas for manufacture of sterile
products 435-6
Ashbya gossypii 471
L-asparaginase 476
Aspergillus flavipes 487
Aspergillus flavus 49
Aspergillus fumigatus 49
Aspergillus niger 205, 486
Aspergillus oryzae 49
Aspergillus parasiticus 49
Aspergillus spp. 49-50
building contamination 349
glass container contamination 348
isolated from air 340
packaging contamination 348
assay methods
plate 481
urease 371
asthma, extrinsic 291
athlete's foot 51
atmosphere
chemical disinfection 341, 342
compressed air 342
disinfection 250-1
filtration 341
microbial content 340-1
microbial count reduction 341-2
microbiological quality checking
340
microbiological standard
requirements 341
microorganism fall-out in
manufacturing process 428
suspended particles 340
ultraviolet irradiation 341,342
attenuation 279
Aurebasidium pullulans 351
Aurebasidium spp. 349
autoclave see steam sterilizer
autoclaving, instruments 425
autografts 301
autoimmune destruction 86
autoimmunity 279,298-9
autolysins 167
avoparcin 198-9
azalides
action on ribosomes 169
protein synthesis inhibition 172
azathioprine 301
azidothymidine see zidovudine (AZT)
azithromycin 110,118,172
AZT see zidovudine (AZT)
aztreonam 102,103
B cells 285, 296
baby hamster kidney (BHK) cell
monolayers 246
bacillary dysentery 29, 57
bloody flux 82
MacConkey's medium 18
bacille Calmette-Gu6rin (BCG)
vaccine 297, 306,311, 333,
336
efficiency 326
potency 316
sterility tests 317
Bacillus anthracis 10, 27
Bacillus brevis 27
Bacillus cereus 27, 76
biocide resistance 264
emetic toxin 85
penicillinase production 477
Bacillus licheniformis 27
Bacillus megaterium 342
Bacillus polymyxa 27
Bacillus pumilus 386
Bacillus spnaericus 488
Bacillus spp.
antibiotic source 92
isolated from air 340
packaging contamination 348
properties 27
raw materials for manufacturing
process 347
spore 11
transfer from manufacturing process
operators 346
Bacillus stearothermophilus 386,
387,443
Bacillus subtilis 27
biocide resistance 264
cloning host 460, 462
contamination of non-sterile
products during manufacture
380
PKU screening 483
sterilization reference organism
386,
388
water supply 342
Bacillus thuringiensis 488,489
bacitracin 27,92,111
resistance 196
bacteraemia 84,282
bacteraemic shock 376
see also endotoxic shock
bacteria 3-4
acid-fast organisms 32
acquired resistance to biocides
272-4
494 Index
adaptation to intrinsic resistance
272
aerobes 16
aggregates 4
anaerobes 16, 17
binary fission 14,21,22
biochemical tests 20
bioluminescence 25
bond energy 17
carbohydrate metabolism 17
cell counts 20-1
cell envelope 86
colony-forming units (CFU) 21
conjugation 14-15
culture media 17
direct epifluorescent filtration
technique (DEFT) 23
DNA 14
electric conductivity 24-5
energy storage 17
facultative 16
flow cytometry 23-4
growth 15-25
consumable determinants 15-16
curves 22-3
energy provision 17-18
environmental determinants 16-
17
gas requirements 15, 16
inhibition 16-17
mean generation time 21-2
measurement 20-2
media 16, 17
pH 16
requirements 15-17
temperature 16
water requirement 15-16
identification 18-20
isolated from air 340
light-scattering/-absorbing units 21
luminous 25
media 16, 17, 18-20
metabolic pathways 18
micro-calorimetry 24
microaerophilic 16
microscopy 23
oxygen requirement 16
quick detection methods 23-5
reproduction 14-15
resistance to biocides 264, 265,
266
sexual reproduction 10
toxins 14
transduction 15
transformation 14, 15
vegetative 204
viable counts 21
water storage 343
see also Gram-negative bacteria;
Gram-positive bacteria
bacterial cell
appendages 10
capsules 10
envelope 266
pigment 10
polysaccharide backbone 5
proteins of outer layer 8
shape 4
size 4
slime 10
structure 4-5, 6, 7-10
wall 164-8
crosslinking 166
peptide bond formation 166
bacterial cell wall 4
lysis by disinfectants 256
non-antibiotic antibacterial agent
activity 256
bacterial chromosome 9-10
bacterial culture
death curve 230,231
growth curve 230, 231
pH effects on growth 235
bacterial infections
epithelial tissue 80
gastrointestinal 141-3
systemic 80
bacterial spores 11-13
acid-fast stain 12
antimicrobial agent choice 204
biocide resistance 270-2
coat 12
dehydration 11-12
development 271
formation process 11-12
germination 12-13,271
heat resistance 11-12,13, 397
mature 271
outgrowth 12-13,271
susceptibility 271
bacterial vaccines 307-8,311-12
combined 310
fermentation 307-8
processing of bacterial harvest 308
safety tests 316
seedlot system 307
single component 310,311-12
bactericidal activity of semi-solid
antibacterials 248-9
bactericides 131,229
multidose injections 414
quantitative suspension tests 239
bacteriophages see phages
bacteriostasis
cup-plate technique 243
ditch-plate technique 242-3
estimation 242-4
gradient-plate technique 244
serial dilution 242
solid dilution method 243
bacteriostats 229
semi-solid antibacterial agents 248
bacteriuria 140, 141
Bacteroides fragilis 30
aztreonam resistance 102
phages 248
Bacteroides spp. 30
Baird-Parker medium 19
baker's yeast 35
base-pair mutation 484
BCG vaccine see bacille Calmette-
Gu6rin (BCG) vaccine
benzalkonium chloride 417, 419
benzoic acid 210, 212
benzyl alcohol 213
D-benzylpenicillenic acid 104
benzylpenicillin 92,93
brain abscess 145
degradation products 96
Gram-negative bacteria
lysis 167
protection 7
hydrolysis 477
manufacture 149
carbon source 155
cell removal 157
contaminants 155-6
crude extract treatment 157-8
defoaming agents 153-4
extraction 157-8
fed nutrients 155-6
fermentation control 154-7
fermenter 152-4
GMP 158
inoculum preparation 151
inoculum transfer to vessel 154
instrumentation 154
isolation 157
lactose 155
media additions 154
nitrogen source 155
organism 150-1
oxygen supply 152-3
PAA stimulation 156-7
pH 156
production strains 151
sampling 154
sulphate supply 155
temperature control 153, 156
termination of fermentation 157
biguanides 210,216-17
mycobacterial resistance 269
properties 209
biliary excretion 133
binary fission of bacteria 14
bio-control 488-9
bioburden
determination 440
measurement 372
reduction in pharmaceutical
products 371
biocide-degrading enzymes,
constitutive 266
biocides 230
bacterial resistance 10, 264, 265
intrinsic 264, 265, 266
cationic 268,269
insusceptibility 263
relative microbial responses 263-4
see also antimicrobial agents/drugs,
non-antibiotic
biofilms 77
physiological (phenotypic)
adaptation to intrinsic
resistance 272
production 264
biological indicators of sterility 442,
443,445-6
bioluminescence 25
preservatives 254
biotin 472
bisbiguanides 178
see also chlorhexidine
bismuth sulphite agar 19
bisphenols 222,224
bisulphites 262
Black Death 28
black fluids 222, 223
blepharitis 79
blood substitute, dextran 10,471
Index 495
blow/fill/seal units 436
blue-green algae 3,4
. boils 26, 143
bone marrow 284
multipotential cells 285
suppression 135-6
Bordetella pertussis 28-9,80,334
non-invasive pathogen 81-2
vaccine production 308
see also pertussis; whooping cough
Borrelia burgdorferi 32
Borrelia recurrentis 32
Borrelia vincenti 32
botulinum
antitoxin 318
toxin in medical use 489,490
botulism 27, 76, 85
bovine spongiform encephalopathy
(BSE) 73,207,323-4
sterilization 386
see also prions
brain abscess 145
Branhamella catarrhalis 26
Branhamella spp. 26
Brevundimonas diminuta 445-6
brewer's yeast 35
brilliant green 226
P-bromopenicillanic acid 103
bronchiectasis 138
bronchitis 138
chronic 29
bronchodilators 416
bronchopneumonia 30
bronchoscope, disinfection 276
bronopol 214
thiol group reaction 259
Brucella abortus 29, 80, 81
Brucella melitensis 29
Brucella suis 29
buildings 349-50
Burkitt's lymphoma 72
burns, infected wounds 144
cadexomer-I
2
220
calcium alginate 422
Campylobacter
antimicrobial agent choice 204
gastrointestinal infections 142
Campylobacter jejuni 31
Campylobacter spp. 30-1
cancer chemotherapy 476
Candida albicans 35,44-7
amphoterocin B activity 114
antimicrobial agent choice 205
cell wall 44-5
flucytosine activity 122
gene isolation 45
germ tube formation 46,47
HO gene 47
hyphal form 45
mating type switching 46, 47
morphological switching 45-6
mutants 45
phenotypic switching 45
positive control for sterility testing
449
Candida parapsilosis 44
Candida spp., contaminated medicines
356
candidiasis
intestinal 114
ketoconazole 122
superinfection 136
candidosis, vaginal 44,46
capacity use-dilution test 238
capreomycin 111,118
capsids 54,57
assembly 69
capsomeres 54-6,57
1-carbacephems 101, 102
1-carbapenems 101-2
see also carbapenems
carbapenems 167
see also 1-carbapenems
carbenicillin 93, 94,95
burn wounds 144
gentamicin combination 108
carbohydrate metabolism 17
carbolic acid see phenol
carboxypeptidase 167
carbuncle 143
carcinogen screening 62,484-6
catgut, sterilized surgical 423
cationic compounds 268, 269
cationic surfactants 224-5, 358
pH effects on antibacterial activity
236
CD4+ cells 72, 73
CD8 expression 296
cefacetrile 98,99
cefaclor 97, 98,100
cefamandole 97, 98,100
cefibuten 97, 99,100
cefixime 97
cefotaxime 96, 97, 99,100
kidney infection 141
PBP binding 167
cefoxitin 97, 98,100
cefpodixime 97, 99,100
ceftazidime 96, 99,100
PBP binding 167
ceftizoxime 96, 99,100
ceftriaxone 96, 99,100
cefuroxime 96, 97, 98,100
ceilings 349
clean areas 430, 434
cell membrane see cytoplasmic
membrane
cell surface, pH effects on antibacterial
activity 236
cell wall see bacterial cell wall
cell-mediated immunity 283, 293-6
cellulitis 143
cellulose, oxidized 422
central nervous system
infections 144-5
secondary disease 86
cephalexin 97, 98,100
PBP binding 167
cephaloridine 167
cephalosporin C 477
manufacture 149, 158,159, 160
cephalosporins 92,93-7,131
activity spectrum 97
p-lactam ring interaction with
transpeptidases 167
|3-lactamase susceptibility 97
biosynthetic genes 156-7
enzymatic inactivation 133
half-life 97
PBP binding 167
peptidoglycan crosslinking 166-8
pharmacokinetic properties 97
resistance 192
structure-activity relationships 96-
7
cephamycins 157
cephapirin 97,98
cephradine 97, 98,100
changing facilities, clean areas 433
cheese ripening 49
chemical indicators of sterility 442-3,
444
chemoprophylaxis 136-7
Chick-Martin test 237, 238
chickenpox outbreaks 88, 325
chimeras 455
chiral inversion 478-9
chitin
Candida albicans 44
S. cerevisiae cell wall 43, 44
Chlamydia psittaci 31
Chlamydia spp. 31
Chlamydia trachomatis 31
chloramine 218
chloramphenicol 91,92,112,113,
133,
190-1
action on ribosomes 170
bone marrow suppression 135-6
drug-resistant ribosomes 190
efflux proteins 190
enzymatic inactivation 133
mammalian cell penetration 172
protein synthesis inhibition 171-2
ribosome effects 172
typhoid fever treatment 137
chloramphenicol acetyltransferases
(CATs) 112,190
chlorbutol 213-14
ophthalmic preparations 419
chlorhexidine 210,216-17,258
bacterial spore activity 271
cytoplasm coagulation 259
E. coli sensitivity 267
mechanism of action 258,260
microbial attack 359
microorganism sensitivity 265
mycobacterial resistance 269
ophthalmic preparations 417,419
properties 209
Proteus resistance 268
S. marcescens resistance 268
Sacch. cerevisiae sensitivity 274
chlorine 217-18
antiviral activity 57
compounds 209,210
gas 345
thiol group reaction 259
chlorine-releasing agents, thiol group
reaction 259
chlorocresol 222, 224, 253
chloroform 219,367-8
p-chloromercuribenzoate 259
chloroxylenol 209, 211, 222, 224,
268
potentiators 258
chlortetracycline 105
cholera 28,283
antibiotic treatment 142
contaminated medicine 356
496 Index