General principles of antibacterial therapy

The following principles, many of which apply to drug therapy in general, are a guide to good practice with antibacter-ial agents.

1. Making a precise diagnosis

regarding the site of infection, the responsible organisms and their sensitivity to drugs.

2. Removing the barriers to cure (Ii any)

• surgical clearance of infection e.g., abscess

• removal of obstruction in urinary or respiratory tract etc.

3. Selection of the best drug Depends on

• specificity: ideally the antimicrobial activity of the drug should match that of the infecting organisms

• pharmacokinetic factors: to ensure that the chosen drug is capable of reaching the site of infection in adequate amount e.g., if the infection is in the cerebrospinal fluid, the drug must pass the blood-brain barrier.

• patient: may have history of allergy to that specific antibiotic or impaired routes of elimination e.g., renal failure.

4. Optimum dose frequency with appropriate route of administration of the drug

5. Continuation of therapy to complete the full duration e.g., Ciprofloxacin (Neofloxin) for 14 clays in enteric fever.

b. Test for cure

e.g., in urinary tract infections, disappearance of symptoms and signs occurs before the organisms are eradicated, as such microbiological proof is desirable.

7. Prophylactic chemotherapy

e.g., 3 gm Amoxycillin (12 Tycil capsules) orally 1 hour before dental, oral or upper respiratory tract procedures in patients who are at risk.

8. Carriers oi pathogenic organisms

e.g., 500 mg Ciprofloxacin (Neofloxin 500) orally bid for 30 days in chronic salmonella carriers.

Choice of antibiotics

Before selecting an antibiotic, the clinician should first consider two factors - the patient and the known or likely causative organism, Factors related to the patient which must be considered include history of allergy, renal and hepatic function, resistance

to infection (i.e. whether imrnunocomprornised). severity of illness, age and if female, whether pregnant, breast-feeding or taking an oral contraceptive.

The known or likely organism and its antibiotic sensitivity, in association with the above factors, will suggest one or more antibacterials, the final choice depending on the microbiological, pharmacological and toxicological properties.

Selection of antibiotics, in general, should be based on identification of the microbe and sensitivity tests. This process inevitably takes time and therefore therapy must usually be started on the basis of the 'Best Guess'. From this point of view, infections may be categorised in three.

/stCAegory ~

,--- ~/ j 0. • • "\~

2nd Category Moe meat.on 01 /\ treatment GHl be

made later if necessary, a her identification of microbe and

3rd Category

[;

sensitivity test. /-1

~//

First Category

Clinical diagnosis automatically decides on the antibiotic because the causative organism is always the same and is virtually sensitive to the same drug e.g, enteric fever is almost always caused by Salmonella typhi/paratyphi and Quinolone is the antibiotic of choice (Neofloxin or Isofloxin).

Second Category

The clinical diagnosis clearly identifies the infecting organisms but its sensitivity to anyone antibiotic can not be specifically assumed, e.g., in tuberculosis, multi-drug antitubercular regimen is given.

o :::r C> o· CD

.

C>

cg

=

~-

en

Third category

The clinical diagnosis can not identify the infecting organisms e.g., urinary tract infection.

(A) Reasonable choice of antibiotic by knowledge of the likely pathogens in the clinical situation e.g.. Co-trimoxazole (Megatrim OS) in lower urinary tract infection (coliform organisms)

(8) Gram staining tests - The antibiotic may be selected on the knowledge that the organism is a Gram-positive or Gramnegative coccus or bacillus.

Criteria for using a new antibiotic

• Antibacterial activity of the new agent is superior to, and likely to have a 'therapeutic advantage over, existing compounds.

• The new agent has improved efficacy against selected infections.

• The pharmacokinetics of the new antibiotic result in a therapeutic advantage (e.g. penetration of the intracellular sites); a prolonged half-life may also allow a more convenient once or twice daily dosage regimen.

• The new antibiotic is less toxic than the existing compounds.

• The new antibiotic is better tolerated; e.g., reduced gastrointestinal intolerance for oral agents.

Antil dnl! in a hBSJ: (her infe antil incr rapi antii rhos anti the inv£ The ther lP~e! aPFl disc

trea heW etne

Page

Page 09

•

Combination of antibiotics

Advantages

1. To achieve a synergistic effect.

e.g., Trimethoprim and Sulpharnethoxazole combination (Co-trimoxazole) is synergistic against some Gram-positive and Gram-negative organisms.

Synergy

When one antibiotic greatly enhances the activity of another, with more than a merely additive effect, this interaction is called synergy. Examples of mechanisms of synergy include the following:

a. Serial inhibition of microbial growth -

Fixed inhibition of Trimethoprirn (80 mg) and Sulfamethoxazole (400 mg) i.e. Megatrim OS will block successive steps in the synthesis of folic acid.

b. One antibiotic enhances the penetration of another - The synergistic interaction between penicillin and arninoglvcosides may be mediated by this mechanism.

2. To reduce the likelihood of emergence of drug resistance. e.g.. treatment of T8 requires at least two drugs, in an attempt to prevent the replication of pre-existing resistant organisms.

3. To treat infections in which multiple organisms are likely or proved.

e.g., treatment of intra-abdominal abscess by Cephalen (Cephalexin) to cover the gram-negative aerobes and Filmet (Metronidazole) to cover anaerobes.

4. To achieve broad spectrum of activity.

e.g., treatment of febrile leukopenic patient by two or sometimes three antibiotics to provide activity against grampositive and gram-negative organisms.

5. To treat severe infection.

e.g., at an initial stage when the causative agent is unknown.

Disadvantages I. An increased risk of drug toxicity

2. An increased risk of colonization with resistant organisms

3. Possibi I ity of antagon ism e.g., In men i ngitis, add ition of Tetracycline to Amoxycillin therapy interferes with the bactericidal action of Amoxycillin.

4. Higher costs: combination antibiotics are often more expensive than single agents.

5. False sense of security

Page 10

Chemoprophylaxis

Use of a drug to prevent infection by one organism of virtually uniform susceptibility is termed chemoprophylaxis which includes suppression of disease as well as prevention of infection. Approximately one-third of hospitalized patients receive antibiotics and. of these, about one-half receive prophylactic antibiotics, primarily for surgical procedures.

Chemoprophylaxis in medical conditions:

The basis for chemoprophylaxis in some selected medical conditions are as follows:

1. When the risk of infection is predictable or the consequences of sepsis are profound.

2. When the target organisms are predictably sensitive to the chosen drug(s).

3. When the prophylactic regimen is safe and well tolerated.

For example, Tycil (Amoxycillin) effectively prevents repeated attacks of Strep. pyogenes pharyngitis, thus avoiding recurrent episodes of rheumatic fever with the attendant risk of rheumatic heart disease and prophylactic Tycil (Amoxycillin) therapy is safe and effective against Strep. pyogenes.

The main categories may be summarised as follows:

1. True prevention of infection, e.g.. rheumatic fever prevention by Tycil (Amoxycillin).

2. Prevention of opportunistic infections, e.g.. in immunocompromised patients such as with treated leukaemia.

3. Suppression of existing infection before it causes overt disease, e.g.. prophylaxis in dirty compound fractures or in animal bites.

4. Prevention of exacerbations of a chronic infection, e.g., in chronic bronchitis.

5. Prevention of spread amongst contacts (in epidemics and/or sporadic cases), e.g., prophylactic Etrocin (Erythromycin) therapy in non-immune susceptible child contacts of pertussis.

" 1

Tabulated summary
Indication to Indication Antibacterial Adult dose
be prevented for prophylaxis agent indicated L
___j
Diphtheria Susceptible Etrocin I 500 mg 6 hourly
contacts (Erythromycin) {or 5 clays
Meningococcal Do Neofloxin I 500 mg single
infection (Ciprofloxacil~ dose __
Pertussis Do Etrocin 500 mg 6 hourly
(Erythromycin) fOf 7days
Rheumatic fever Following Tycil 250mg12
rheumatic fever (Arnoxvcillin) hourly
Endocarditis Heart valve Tycil 3 gm single dose,
lesion, septal (Amoxycillin) 1 hr before
defect, patent procedures like
ductus, or dental extraction,
prosthetic
valve Etrocin 1 gm, 1,5-2 hr
(Erythromycin) preoperativelv
and 500 mg 6
hrly postoperatively,
Tetanus Wound Etrocin 500 mg 6 hrly
or injury (Erythromycin) for 7 clays
Gas gangrene Wound Filmet 500 mg 8 hrly
or injury (Metronidazole) for 5 days
Chemoprophylaxis in surgery incr rapi anti thos amii the inv{ The ther pre~ app disc trea hay

efte

The principles guiding the use of antibacterials in this context are as follows:

1. VVhen the risk of infection is high because of bacteria in the viscus which is being operated on, e.g., the large bowel.

2. When the patient has a susceptible organ, e.g., diseased heart valves.

3. VVhen the patient is generally susceptible to infection, e.g.. patients who are neutropenic due to treatment of leukaemia.

Specific instances are given below:

I. Gastric surgery, e.g., Cephalen (Cephalexin) prophylaxis against gut organisms.

2. Colorectal surgerv, e.g., Cephalen (Cephalexin) and Filrnet (Metronidazole) prophylaxis against E. Coli, clostridia ilild bacteriodes.

3. Gynaecological surgery specially in vaginal/abdominal hysterectomy and perineal floor repair, e.g., Cephalen (Cephalexin) and Filmet (Metronidazole) prophylaxis against bacteriodes, streptococci, col iforms and anaerobes.

4. Orthopaedic surgery specially in joint replacement 01 limb amputation, e.g., Filmet (Metronidazole) prophylaxis against gas gangrene.

5. Insertion of prostheses, e.g.. prophylaxis in arthroplasty, valvoplasty.

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Antibacterial drugs against common organisms

The presentation of choices of specific agents for the treatment of various infections is always provocative of discussion and disagreement because such choices often represent the disti Ilate of personal experiences that may not duplicate those of others. In addition, the current availability of a number of drugs that are approximately equally effective makes an order of choice very difficult, if not impossible, To complicate matters, patterns of sensitivity of a number of microorganisms often vary with the clinical setting in which they are isolated.

It is important to stress that, as more information accumulates, as recently introduced drugs are used for longer periods, and as entirely new agents are developed, some of the recommendations will require modification not only in the order of choice but

even in the specific drugs that are suggested,

INFECTING ORGANISM ANTIBACTERIALS
Gram-positive cocci
Enterococcus
endocarditis (prophylaxis) Amoxycillin
C>
..a
<»
uncomplicated urinary tract Amoxycillin =
Vi'
3
infection en
• Staphylococcus aureus or
epidermic/is "
Q
non-pen ici II i nase-produci ng Cephalosporin, Erythromycin, ~
~
Azithromycin ct_
CD
penici II inase-produci ng Cloxacillin, Cephalosporin or :=>
Erythromycin -:::l
aOl
<D "'""
g, fil
Streptococcus pyogenes Amoxyci II i n, Azithromyci n :=> ::::;,
(I) =
c:I
(Group A) and Groups C & G) Erythromycin or
Streptococcus, Group B ) Cepha los pori n -u
a
r::r
Streptococcus, viridans group Cephalosporin CD
:3
<::n
(endocarditis)
5"~
Streptotoccus, anaerobic Metronidazole -,
~Cil
g<.g
• Streptococcus pneumoniae Amoxycillin, Azithromycin. ~,~
=>.Q
(pneumococcus) Erythromycin or ::IJ
3"~
Cephalosporin §~
Page 16 ~'i INFECTING ORGANISM ANTI BACTERIALS INFECTING ORGANISM ANTI BACTERIALS
Gram-negative cocci Other Gram-negative bacilli
• Neisseria gonorrhoeae Amoxycillin (+probenecid) or Borc/etella pertussis Erythromycin, Azithromycin
(gonorrhoea) Ciprofloxacin, Azithromycin (whooping cough)
• Brucella (brucellosis) Cotrimoxazole
Gram-positive bacilli Calymmatobacterium Amoxycillin or Cotrimoxazole
Bacillus anthracis (anthrax) Erythromycin, Azithromycin granulomatis
Clostridium perfringens Metronidazole (granuloma inguinale)
(gas gangrene) Garc/nerella vaginalis Metronidazole, Amoxycillin
(anerobic vaginosis)
Clostridium cJilficile Metronidazole
(pseudomembranous colitis) • Haemophilus ducrevi Erythromycin, Azithromycin
(chancroid) Cotrimoxazole or
Corynebacterium diphtheriae Erythromycin, Azithrornvcin Ciprofloxacin
(diphtheria) • Haemophilus intluenzae
Enteric Gram-negative bacilli epiglottitis, arthritis or other Amoxycillin, Azithromycin
• Bacteroides Metronidazole serious infections
oropharyngeal strains Upper respiratory infections Arnoxvcillin, Azithromycin
gastrointestinal strains and bronchitis
• Campylobacter jejuni Ciprofloxacin Legionella pneumophila Erythromycin, Azithromycin
Erythromycin, Azithromycin (legionnairesdisease) :J
cs:
C)§
~<J
'" -
= c
• Enterobacteriaceae • Pseudomonas aeruginosa en- c
:3 =
U> =
e.g., Enteiobacter aerogenes urinary tract infection Ciprofloxacin (or another ~
thos Escherichia coli quinolone) --n
Klebsiella pneumoniae other infections Ciproiloxacin Q
anti 0
Proteus spp. Vibrio cholerae (cholera) Ciprofloxacin, Cotrimoxazole =-
(he a
Lower urinary tract Cephalosporin, Ciprofloxacin CD
:::>
inv( Septicaemia Ciprofloxacin Chlamydiae ~~
The Chlamydia trachoma tis Erythromycin, Azithromycin $,,<
g_ ~
ther • Salmonella typhi (typhoid Ciprofloxacin, Cotrimoxazole trachoma 00.
= =
en
fever) inclusion conjunctivitis r
pfe~ • Other Sa/monella Ciprofloxacin urethritis
app • Shigella Ciprofloxacin lymphogranuloma venereum --u
a
(lli:sc • Yersinia enterocolitica Cotrimoxazole, Ciprofloxacin 0-
<l>
3
trea Chlamydia pneumoniae Erythromycin, Azithromycin en
hay 5'"=
effe Mycoplasma .-::::
Mycoplasma pneumoniae Erythromycin, Azithromycin u~
tu-
Ureaplasma urealyticum Erythromycin, Azithromycin g- §
r = c
....
::I
-cc
""'1il
• Resistance may be a problem; sensitivitv tests should be performed. §~
,j- ~'~
~~
Page Page 17 Page 18 Post Antibiotic Effect

The post antibiotic effect (PAE) is defined as the suppression of bacterial growth that persists after limited exposure of organisms to antimicrobial agents. Neofloxin appears to have a significant post antibiotic effect against Enterobactericeae, Pseudomonas aeruginosa and Staphylococcus aureus.

The longer the PAE, the lower the probability that growth of the infecting bacterium will resume during that fraction of the interdose interval where antimicrobial level falls below the tvllC. A long PAE provides the potential for administering the antimicrobial agent at longer intervals between doses. Quinolones have been shown to produce a prolonged (4h or more) PAE, in both Gram-negative and Gram-positive isolates. The low MIC of Neofloxin with higher concentration in serum and tissues would give rise to greater PAE for Neofloxin that could considerably prolong their action in-vivo, prevent rapid regrowth of bacteria and provide less frequent dosage interval.

Problems of antibacterial therapy

Inappropriate use of antibacterial therapy is uneconomic and increases the likelihood of toxicity and the development of drug reslstance, but is unfortunately still widespread. It includes

• use of an antibiotic in the absence of established, susceptible infection

• prescription of the wrong drug

• administration of the correct drug by the wrong route or in an incorrect dose

• inappropriate use of combined regimens in the absence of ~ynergistic activity or mixed infections

Ihe fact that harmful effects may follow the therapeutic or the propllrylactic use of anti-infective agents must never discourage tile physician from their administration in any situation in which they are definitely indicated. It should, however, make the physician very careful in their use when they are required. To do otherwise is to run the risk, at times, of converting a simple, beni:gill disease into one that may be serious or even fatal.

Superinfection Tabulated summary of side-effects of antibacterials
Superinfection may be defined as the appearance of ~ Cuttiov.iscul»
~ ::I ~~ ,-0 co ;:- I Hypotension
bacteriological and clinical evidence of a new infection during ~ 0 I"'" I'. C'
'"
i c ,....- '-" ~, ~, 2,'v\yocarditis
'" r-, r-, r-. r-. 1'. r-,
the chemotherapy of a primary one. It is relatively common and lOedem,l
potentially very dangerous because the microorganisms -;;; .c -: '.D' 0' ._,c' J"; 4 Tachvc.irrha.Sh.xk
c "'. "'. -.G_ ~ -..c . ...0
responsible for the new infection are very difficult to eradicate in '" LO .c 00 0' Uj co tn' r-, Dermatological
'" '" '.D '"' -s» .c '.D '.D .c
many cases. Superinfection by these organisms is due to removal 5 Epidermal necrosis
-;;; 6 Erythem,l nodosum
of the inhibitory influence of the flora that normally inhabits the <oJ :;;
'0;, ~ -t- 0 .,.-- 0\"' c..D~ .--~ r •. -; '..D~ c' 7 Ixfohation
0
oropharynx and other body orifices. "2 '"' lr; '...0 U; If') I..f') <.D 10 lr;: -.c~
0;~ ~~~ ~5{ ~, t"':'....o --.; ~ G'I~~, .-- L.(', 0'> 8 Pruritus
::I Lri 1'-', -..c "' '" -o Ir', t.J'";. 1.1]
'" cc' Q'1 ~ :;:; ~ 8"'1,,- 6 (Y'~ r ," rJ~ ~ y.,- ~i
z -r In o-, 1-1"'...0 ..,..., u; ..0 9 Urtic,lri,l
10 Rash
..s- II Photosensitivity
::I '"
<oJ -
~~ 12 Stovcns-lohnsnn
::I 0. I", t-; c. '"
~~ "T -T _,. "T syndrome
.,,: '" EnrioCi//J(,
0
Side-effects of antibacterials c_ 7 --t: 13 COltre/
::I .. co .o "T co -c
E .!: ~-t"_ "T. _,. "T. -r- --t: Hvpothvroichsm
.§.£" \"1 Lf'; ~, N N ("'I ~,
"1""'1"" -r- "T 7 7 "T 14 Hypoglyc acmia
Side-effects of antibacterial agents are often minor Eye/ENT
inconveniences, but can produce irreversible tissue damage and .!: :; "T. 7. 15 i\lystagrnus
i 0 0 ~ ~
-e- "T --t: 16 Optic neuritis
may occasionally prove fatal. 0. ~~ ~ ~ 0 i2-:' ~
:r -r 17 Visual disturbance
18 Photophobia. Tinnitus
0 M~C:C ~~ '0 19 Ototoxicity
Predictable reactions result ;;;_ M !"": ~
E '" ~ ~~ ~t·: 0' :;;~ ,:;::;~ ;:::
~ .:= :"""'l ~ Castrointestillal
from the known '" 0() Q"\~ -c' R; ~ .: ~ ~:5 ~ a\ r-,,'
J:_g N '" 0, ~
pharmacological actions of 20 r\norexia
7 21 Naus(\l/Vomiting
the drug and may be caused r~
00' NI..!:; r-v ~f ~' :"l r . N~ 1.6 co 22 Abdominal pain/
~, '" '" ~ ~, N ~ r.! ~
by indiviclual differences in Nt--. ,,_-. -ct"' ~, .: '<1"' r-, -~ "<t~ .- "c:t r. Discomiort/Dyspepsi'l
,_ N N 0,0, ,t r~ ("".[ N 010, 0) 0[ r1
i3 -~. ~' o~~ O-'M""'~' OM ~' ;i ~~
its pharmacokinetics or in the r-J N N ("'1 N N (',l r1 0101 21 Di.urhoea
pharmacodynamic response. 24 Pseudomembranous
colitis
These reactions should be -..,_ ;':'
~z '" l;n -o r-. 25 Taste abnorm,llily
avoidable or at least readily w w ~
26 Drv mouth
recognized. 0. 27 Clossltis/Stomatitis
Idiosyncratic reactions are .§ 28 CI blceding!
<oJ " UIn·ration
0
-e
novel, unexpected c ",-
w Haen7ateJ/ogicai
responses which pose a e ~ 0 29 I\granulocytosis ~l
(7\'""'"'1 0'
greater problem because ~G cr> ",' 0 0 cc: ""; 0': 30 Aplasti« ,In,wmi,l B·
I""--..~ ", t" .-- 0Cl, ::: p-
they are so uncommon. It Qi"S'o' ",' r- ...... ' :3;- 0 ~: ~~ ~~ 11 Eosinophilia m
QI.E ~n~ en ,0" co ;3
is impractical to screen for '32 Lour orvrosi, o»
av 13 Haeillolytic anaemia
an adverse event which o.:!
effe :s ::I' 34 Meg'llohlastic anaemia _-
~ => -
may occur in less than ~ '" ,___, "T.
',", >- 35 Methaeilloglo- ',_- -
"'Jl
1/10,000 patients. binaernia/ fit::
SulpiJaemoglobinaemia =_'S:O
c. a =
.s ~ '" c; =>.!]
_2 36 I:lI€eciing
.s ~ N ] ~
8" 0, -c, J7 lJihromlJo[yt!l[Jellia'/ :J
.~ :-E ~ 0"- :::J-.gj
x- Cii '0: .0 U
0 ~ PurpurJ en ..
0() c .s: ~ '2 22 §;~
::I E Q_ aJ C g 38 Coombs' positivity
15 '" Q.Q
« u :;: ~ u gj :J.
Pag6 Page 29 -!2g
Page 30 e Tabulated summary of side-effects of antibacterials

IIdV effe

Page

o c:-

" '"

E .~

§~

0Ll "

15

Page 31

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;:;( ~~

M ,-."'~ -.D-,~ -c I'; L1l-.c

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r-, ao '" ""

~~ ~~

~~ ~

N',", N N

.: ~-

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rr) ... i...:-i

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N L""l No!'"'-.!

N ~ .. ~~ ~

0; -:

tn -c

-t"- C; M rr-, IIi ._..r; "," r·," ""'JI." Lt"',-..o

'" -"',

M"~" 0 Lij w-, -.c .--~ Lrl' d,

I./"'lIJ'l I';

6 -:t"- CO-

Ir, t,~ I..f',

N~L1"'i- co r-l ,'"'.I l'J ,..--"'f"-f'-...<""'1l'J N 0" '-"j--.D('"'l ~j l'J

Hepatic

39 Hepatotoxicity

40 Abnormal biochemical liver (unction

41 Jaundice

Immunological 42 Anaphvlaxis

43 t\ngioneurotic oedema 44 Bronchospasm

45 Serum sickness

46 Systemic lupus erythematosus

!'vtuseuloskelet,71

47 Jvlyalgia/ Myopathy/Arthralgia

Neurological 48 Coma

49 Convulsion

50 Encephalopathy

S I Benign intr.uranial hypertension

52 Drowsiness1

Ti redness/Weakness 53 DizzineSl

')4 Contusion

55 Headache

56 Malaioe

57 Neuromuscular blockade

58 Neuropathy/Cranial nerve palsv

59 Paresthesia

60 tvleningeal irritation 61 Kernicterus

62 Insomnia

63 Psychosis

Renal

64 Nephrotoxicity

65 Interstitial nephritio 66 Uraemia/Increased serum creatinine

67 Alluria

68 Haernaturia/ Crystalluria

69 Urine discolouratioll

Miscellaneous

70 Dvspnoea/Apnoea

71 Chills/Fever/Sweating 72 Pulrnouarv eosinophrilia

13 Metabolic ,lCidosis

Drug, interactions involving antibacterials

Mechanisms:

Enzyme II1duction : Hepatic enzyme inducers interfere with the hepatic metabolism of many other lipid-soluble drugs (e.g. oral contraceptive)' reducing their plasma levels. This effect takes about 2-3 weeks to complete and persists as long as the inducer is taken.

Enzyme inhibition: Some antibiotics can inhibit the metabolism of other drugs, for example Ciprofloxacin, Erythromycin, Metronidazole, etc.

The clinical effect is almost immediate because it depends only on the presence of both drugs at the active enzyme sites in the liver. There is a gradual increase in the concentration of the drug with inhibited metabolism, and maximal toxic effects occur within 1 week (i.e. after 4-5 half-lives of the drug with inhibited metabolism). When the inhibitor is withdrawn, the plasma level of the drug falls and its therapeutic effect may be attenuated.

Changes in gsstroitnesune! flora: Women on oral contraceptive therapy may be put at risk of pregnancy if prescribed an antibiotic for a minor infection. The mechanism is thought to involve disruption of the entero-hepatic cycling of the hormonal components by removal of the gut bacteria responsible for their deconjugation. Antibacterials have been shown to reduce the bacterial iinactivation of digoxin in the gut lumen, thus increasing its bioavailability in a few patients.

Interference with gastrointestinal ebsotptiot: : Concomitant antacid administration may interfere with Ciprofloxacin absorption.

Decressed renal excretion: Potentially nephrotoxic antibacterials may produce a vicious cycle of increasing renal damage (e.g. aminoglycosidesl

LJ a

0" mE

en'

Page 32

Antibacterial Inleracting drug Probable mechanism Clinical effect
I~moxycillin Otal contraceptives, Reduced Contraceptive failure
oecoojugation in gut
Probenecid Inhibition of active Increased circulating drug
renal tubular secretion
Warfarin ? Altered intestinal Potentiared
flora which synthesize anticoagulation
vitamin K Probenecid

Nephrotoxicity 'Contraceptive fai lure

Cephalexin

i'iephrotoxic drugs Additive/synergistic Oral contraceptives Intestinal hurry lnterference with steroid deconjugatiorn

in gu~

Competitionfor active Cephalosporin ,toxicity

renal transport

ld\i

He

Macrolides BwmO€riptine Enzyme inhibition Llrug toxicity
Carbamazepine Do no,
( vdosporin .00 !Yo
[Jigoxin Decreased gut lncreased digoxin
metabolism bioavailability
IDi'sopy,ramide Do Drug Itoxicity
Ergotamine ?Enzyme inhibitlon Ergotism
lheopJ\y,lIine Do [Jru:g toxicity
Warfarin Do Potentiated
anticoagulation
Melronid.lwi'e AI'c0hoi Inhibition oj Disulfiram reaction
acetaldehyde oxidase
Cimetidine Inzvme inhibition Metronidazole loxicit'f
Disulfiram Do PsyGi\otic reartions
Lithium Lithium retention Drug. toxicity
Phenobarbitone Do Treatment failure
~hen\10in Do Drug toxicity
Warfarin Do Potentiated
anticoagulation
Huoro- 'Anfacid Reduced absorption Treatment failure
quinolones lfheophylline Enz~'me inhibition Drug toxicity
Warfarin .00 Potentiated
anticoagulation
Zinc. calcium Reduced absorption Treatment failure
Cotrimoxazole Sul'phonyl'urea Enzyme inhibition Hvpoglvcaernia
Warfarin Do Potentiated
anticoagulation
I ~yrimethamine Additive Ivtegaloblastic anaemia
, ~hen\10in Enzvrne inhibition Drug toxicity
Iii
Page 33 Resistance

The development of resistance to antibacterials usually involves a stable genetic change, heritable from generation to generation. Any of the mechanisms that result in alteration of bacterial genetic composition can operate. While mutation is frequently the cause, resistance to antibacterial agents may be acquired through transfer of genetic material from one bacterium to another by transduction, transformation, or conjugation,

Major mechanisms of resistance to antibacterial agents

Type of resistance Antibacterial class Specific resistance mechanism
Altered target r~-Iactam Altered or new binding
antibiotics proteins
Erythromycin Ribosomal RNA methylation
Quinolones Altered DNA gyrase
Cotrimoxazole New drug insensitive
dihydropteroate synthase
(sulfonamide) and
dihydrofolate reductase
(trimethoprim)
IDet.oxi fy i ng r~-Iactam ~-Iactamase
el~lynie antibiotics
I)e.(reasedl uptake
• Dtmlnished g-Iactam Alteration in outer membrane
permeability antibiotics. proteins
Quinolones
i; Active efflux Erythromycin New membrane transport
system Page 34