Adverse Reactions to Antibacterial Agents - Australian Society for

“FIRST DO NO HARM”HIPPOCRATES 450-355 BCESome 140,000 Australians are hospitalised each year due to an adverse drug reaction from prescription medicines. Most of these are preventable. Some 2-3% of all hospital admissions are the result of an adverse reaction to medication, with up to 30 percent of these events occurring in people 75 years and above.

Since the advent of the sulfonamides in the 1930s, the penicillins in the 1940s, followed by ‘newer’ antibiotics, people have talked in terms of life-saving, ‘wonder drugs’ and other effusive exclamations attributing near magical properties to these substances. This was of course before the concept of resistance was understood. However, to this day there is a belief in society that despite the resistance problems, at least we are dealing with safe medicines.

The ideal antibiotic would be one that has one hundred percent efficacy against the particular infection being

treated and cause no effect whatsoever on the host. Whilst this ideal seems to be imbedded in the belief systems of many lay people, and to some extent in the psyche of hopefully a small minority of health professionals, the reality is quite different. Far from being pharmacologically inactive, most antibiotics have a range of potential side effects ranging from trivial to life-threatening. These unwanted effects are interchangeably and variously termed, ‘side effects’, ‘adverse drug reactions’ or ‘adverse drug events’.

The World Health Organisation defines an adverse drug reaction as ‘any response to a drug which is noxious, unintended and occurs at doses used for prophylaxis, diagnosis, or therapy”2.

Adverse reactions are divided into two major types, A and B.3,4

Type A reactions include normal or augmented responses to drugs, for example hypoglycaemia due to a sulfonylurea or orthostatic hypotension due to an antihypertensive agent. Many

Type A reactions arise from secondary pharmacological effects of a drug, such as anticholinergic effects with some first-generation antihistamines, tricyclic antidepressants and mirtazepine, or neuromuscular blockade with aminoglycoside antibiotics. These are usually dose-dependent and predictable and are often recognised before a drug is marketed. They may occur after a long latency, such as carcinogenesis or effects on reproduction. Examples include adenocarcinoma in the daughters of women exposed to diethylstilboestrol during pregnancy in the 1950s, or the development of gout with the long-term use of thiazide diuretics.2,3,5,6

Type B reactions (hypersensitivity or allergic reactions-further classified into Types I, II, III and IV-see table 2) are unrelated to any known pharmacological action(s). They are often caused by immunological and pharmacogenetic mechanisms, are generally unrelated to dosage and are more likely to cause serious illness or death. Examples include anaphylaxis with penicillins, aplastic anaemia with chloramphenicol, and malignant hyperthermia with anaesthetic agents. Table 1 lists some common adverse reactions reported with antibacterial agents. Table 2 compares Type A and B adverse reactions.

ASA Newsletter, June 2004

Australian Society for Antimicrobials

Newsletter No. 21 June 2005

Adverse Reactions to Antibacterial Agents

Also in this issueAntimicrobials 2005 in Review ....................................................................... 8

Responses to recent ASA Picture Quizzes ....................................................... 9

ASA Journal Club .......................................................................................... 10

Picture Quiz June 2005 .................................................................................. 13

Meeting Calendar ........................................................................................... 14

Department of Pharmacy Practice, Victorian College of Pharmacy (Faculty of Pharmacy) Monash University, VIC

Louis Roller

2 ASA Newsletter, June 2005

Table 1: Common adverse effects of antibacterial therapy3-7

• Allergic reactions: eg penicillins, sulfonamides, many others

• Superimposed infections: eg broad-spectrum antimicrobials

• Moniliasis: eg broad-spectrum antimicrobials • Gastro-intestinal tract upset including mild diarrhoea:

virtually all antibiotics (special care with tetracyclines) • Blood dyscrasias: eg, chloramphenicol, sulfonamides,

many others • Neurotoxic: eg aminoglycosides, fluoroquinolones • Nephrotoxic: eg aminoglycosides, some cephalosporins,

bacitracin, many others • Interactions with other drugs: eg, fluoroquinolones,

macrolides, tetracyclines, rifampicin, nitrofurantoin, metronidazole

• Pseudomembranous colitis: virtually all antibiotics can cause this life-threatening situation (particularly lincosamides)

• Deleterious foetal effects: o category B3 (macrolides, fluoroquinolones,

quinupristin+dalfopristin, trimethoprim) 2

o category C (capreomycin, rifabutin, rifampicin,trimethoprim+sulfamethoxazole)

o category D (aminoglycosides, bleomycin, tetracyclines)

Table 2: Comparison between Type A and Type B adverse drug reactions3,4,6

Type A Type Bpharmacologically

predictableyes no

dose-dependent yes noincidence high lowmorbidity high lowmortality low high

management dose reaction may be sufficient

stop drug

ANTIBACTERIAL HYPERSENSITIVITYDrugs can activate the immune system in undesirable ways resulting in adverse drug reactions. These reactions are generally categorised as “drug allergy” or “hypersensitivity”. These reactions manifest as skin reactions, glomerulo-nephritis, oedema, anaphylactoid reactions, fever and eosinophilia. The underlying mechanism of allergic sensitisation to drugs was clarified by the discovery of the IgE class of immunoglobulins and by a better understanding of the process of sensitisation and activation of blood basophils and tissue mast cells. Drug reactions mediated by immune response may have different mechanisms. Thus, any of the four major types of hypersensitivity can be associated with an allergic drug reaction as shown in table 3.

Table 3: Classic hypersensitivity reactions3,4,5,6

Several of these hypersensitivity reactions may occur simultaneously. Some adverse reactions to antibacterials may be mistakenly classified as allergic or immune when they are actually genetic deficiency states or are idiosyncratic and not mediated by immune mechanisms (eg, haemolysis due to fluoroquinolones, primaquine, quinine, nitrofurantoin and sulfonamides in patients with glucose-6-phosphate dehydrogenase deficiency; or aplastic anaemia due to chloramphenicol or some sulfonamides).4

Some of the clinical manifestations of allergic drug reactions and aspects of an appropriate drug history are shown in tables 4 and 5 respectively.

Adverse Reactions to Antibacterial Agents... Cont

Type Antibody Mechanism Examples and causative agents

I IgE anaphylactic true systemic anaphylactic

reactions

antigen-antibody on mast cells

leading to histamine,

leukotriene, platelet activating

factor release

penicillins, cephalosporins represents class eg of the hapten

hypothesis

II IgG

IgM

Cytotoxic haemolytic anaemia

antigen-specific antibodies

directed against antigens on cell

surface

penicillins, quinine

III IgG

IgM

immune complex mediated

serum sickness

immune complexes

interact with antibodies

penicillins, cephalosporins,

isoniazid, phenytoin

IV T cells delayed hypersensitivity

typically seen with topical therapies

rather than systemic (contact dermatitis)

generally takes more than 12

hours to develop antigen interacts

directly with sensitised T cells

Characterised by rash which worsens

on subsequent or repetitive

administration

3ASA Newsletter, June 2005

Table 4: Clinical features of allergic drug reactions3,6,8

• Have no correlation with known pharmacological properties of the drug

• Require an induction period on primary exposure but not on re-administration

• Can occur with doses far below the therapeutic range• Often include a rash, angioedema, serum sickness,

anaphylaxis and asthma• Occur in a relatively small proportion of the population• Disappear on cessation of therapy and reappear after re-

administration of a small dose of the suspected drug (s) of similar chemical structure

• Desensitisation may be possible

Table 5: Detailed drug history2,4,6,9

• Prior allergic and medication encounters• Nature and severity of reaction• Temporal relationships between drugs and reactions

(dose, date initiated, duration)• Prior exposure to structurally related medicines

subsequent to the initial reaction• Effect of drug discontinuation• Response to treatment• Prior diagnostic treatment or rechallenge• Route of administration (eg preservative in

formulations)• Other medical problems if any

A UK study used national hospital discharge statistics from 1990-1 and 2000-1 to identify trends in admissions for four allergic conditions (anaphylaxis, angioedema, food allergy, and urticaria) in over 49,000 admissions that occurred during the 11-year study period. Total admissions increased from 1,960 in 1990-1 to 6,752 in 2000-1. The largest increases in rates were for anaphylaxis and food allergy. Anaphylaxis rates rose from six to 41 per million, and food allergy rates rose from five to 28 per million over this period. Admissions for urticaria and angioedema rose more modestly, from 20 to 43 per million and 10 to 17 per million respectively. The authors suggest that these changes could be caused by increasing exposure to environmental risk factors (such as peanuts and other foods, latex, or a greater range of medicines), to an increased susceptibility to these allergens in the population, or to a combination of these factors.10

Antibacterial hypersensitivity is common and most frequently involves beta-lactam agents.2,5,6 While many non-specific reactions are labelled as ’allergic’, true type I (IgE-mediated) antibiotic hypersensitivity is indicated by the development of urticaria, angioedema, bronchospasm, or anaphylaxis (with objectively demonstrated hypotension, hypoxia or tryptase elevation) within one hour of drug administration. Some instances of ‘pseudo-allergy’ (eg

anaphylactoid responses to vancomycin infusions such as ‘red-man syndrome’) involve direct release of vasoactive mediators by non-IgE-mechanisms. While not truly allergic, these responses may still be ameliorated by preventative antihistamines, in combination with slowing of the infusion rate.2,6,9

DIAGNOSIS OF ANTIMICROBIAL HYPERSENSITIVITYDefinitive diagnosis of antibiotic hypersensitivity can only be achieved with immediate penicillin reactions. Negative skin test results using major and minor determinants reassure patients and carers that the risk of life-threatening penicillin allergy is negligible. However, 80 to 90 percent of those individuals who report prior type I penicillin hypersensitivity are not found to be allergic after skin testing or oral-challenging. Furthermore, negative skin tests do not exclude the possibility of a non-type I rash reaction. For non beta-lactam drugs, the diagnosis of drug hypersensitivity is a clinical one. In cases of suspected drug allergy, elevation of mast cell tryptase measured on a serum sample collected between one and six hours after a clinical reaction is highly specific for an episode of mast cell degranulation.2,3,6,9

BETA-LACTAM HYPERSENSITIVITYBetween 1 to 10 percent of beta-lactam courses result in manifestations of hypersensitivity. Most reactions are late, non-IgE mediated and involve rash. Other later manifestations include fever, haemolysis and serum sickness-like reactions. The minority of reactions are immediate hypersensitivity reactions. Anaphylactic responses to penicillin occur approximately once in every 10 000 courses administered, with 10 percent of these reactions being fatal, most often associated with parenteral rather than oral administration. Most of these reactions occur in people without a history of prior beta-lactam allergy. Notwithstanding this, a detailed history of beta-lactam reaction should always be sought before a course of beta-lactam is commenced.2,3,5,9

A history of an immediate hypersensitivity reaction (urticaria, angioedema, bronchospasm, or anaphylaxis within one hour of drug administration) contraindicates further exposure to penicillin and other beta-lactams apart from aztreonam. Late manifestations are only a relative contraindication. Rashes, especially with amoxycillin or ampicillin are much less predictive of future reactions. Between three to six percent of patients hypersensitive to penicillin exhibit cross-reactivity with cephalosporins and a smaller number to carbapenems.2,3,6,9 Aztreonam is the only beta-lactam that may be given to people with severe penicillin hypersensitivity because of its lack of cross-reactivity with other beta-lactams.Desensitisation regimes are currently available for beta-lactams and sulfonamides2. Protocols for a host of other antimicrobials (eg quinolones, macrolides, vancomycin, clindamycin, pentamidine, anti-tuberculous drugs) have been empirically derived and tested in limited clinical settings. In



these circumstances, a specialist in immunology/allergy should be contacted to discuss any proposed desensitisation program.

SULPHA DRUG HYPERSENSITIVITY In a study of 969 patients with an allergic reaction after a sulfonamide antibiotic, about 10 percent had an allergic reaction after subsequently receiving a sulfonamide non-antibiotic (eg, hydrochlorothiazide, celecoxib). Of 19,257 who had no allergic reaction after a sulfonamide antibiotic, 1.6% had an allergic reaction after receiving a non-antibiotic sulphonamide agent. However, the risk of allergic reactions was even greater after the receipt of a penicillin among patients with a prior hypersensitivity reaction to a sulfonamide antibiotic, as compared with patients with no such history. The authors concluded that there is an association between hypersensitivity after the receipt of sulfonamide antibiotics and a subsequent allergic reaction after the receipt of a sulfonamide non-antibiotic, but the association appears to be due to a predisposition to allergic reactions rather than to cross-reactivity with sulfonamide-based drugs.11

ADVERSE DRUG REACTION REPORTINGMany countries have data collecting centres to accumulate reports of suspected adverse drug reactions. In Australia, there is the Adverse Drug Reaction Committee which is under the auspices of the Australian Therapeutics Good Administration. It produces quarterly reports in the Australian Adverse Drug Reaction Bulletin which is distributed free of charge to all prescribers and undergradutes of medicine, dentisty and pharmacy (see references 12-21 for several recent ADRAC reports related to antibacterilas). The Bulletin invites all prescribers and pharmacists to ‘fill in a blue form’ whenever they suspect an adverse reaction has occurred.It is difficult to define precisely the frequency of adverse reactions to antimicrobials because a variety of methods are utilised to collect the data. Where possible, adverse effects are classified as: Frequent (incidence >1 in 100), Infrequent (incidence >1 in 1000 and <1 in 100), Rare (incidence <1 in 1000). Table 7 contains examples of adverse reactions of antibacterial antibiotics currently available in Australia.


Aminoglycosides (amikacin, gentamicin, neomycin, netilimicin, paromomycin, tobramycin, streptomycin)Frequent nephrotoxicity, neurotoxicity, ototoxicity (auditory and vestibular) in varying degreesInfrequent hypersensitivityRare neuromuscular blockade (can lead to respiratory depression)AztreonamFrequent rash, phlebitis and thrombophlebitis (at injection site), diarrhoea, nausea, vomiting, abnormal taste,

elevated transaminases (transient), eosinophiliaInfrequent headache, diizziness, gastrointestinal bleeding, abdominal cramps and bloating, oral ulcerationRare anaphylaxis, pseudomembranous colitis, angioedema, bronchospasm, shock, elevated transaminases,

jaundice, neutropenia, thrombocytopenia, elevated INRCarbapenems (ertapenem, imipenem, meropenem)Frequent thrombophlebitis (at injection site), nausea, diarrhoea, vomitingInfrequent blood dyscrasias, seizures, psychiatric disturbances, encephalopathy, fever, rash, itch, paraesthesia,

headache, dizziness, somnolence, confusion, tremorRare pseudomembranous colitis, hepatitis, anaphylaxis, erythema multiforme, angioedema, Stevens-

Johnson syndrome, tachycardia, renal toxicityCephalosporins (cefaclor, cefepime, cefotoxime, cefotetan, cefoxitin, cefpirome, ceftazidime, ceftriaxone, cefuroxime axetil, cephalothin, cephamandole, cephazolin)Frequent diarrhoea, nausea, rash, drug fever, electrolyte disturbance, pain and inflammation at injection site,

pseudomembranous colitisInfrequent vomiting, headache, dizziness, oral and vaginal thrushRare anaphylactic shock, interstitial nephritis, neurotoxicity, superinfection, blood dyscrasias, bleeding,

renal impairmentWith cefaclor; serum sickness-like syndrome, and reversible pseudolithiasis or biliary sludge formation with ceftriaxone

Table 7: Adverse effects of commonly used antibacterials2, 6, 7, 4, 9, 11, 22


Chloramphenicol (only available as eye/ear drops, ointment, IV injection; oral capsules discontinued)Frequent headache, nausea, vomiting, reversible bone marrow suppressionInfrequent stomatitis, glossitis, diarrhoea, colitis, confusionRare aplastic anaemia, anaphylaxis, grey baby syndrome (can occur with overuse of eye drops),

neuropathyColistinFrequent nephrotoxicity when given parenterally; occasional episodes of bronchospasm when given by

inhalationEthambutol (mostly dose-related )Frequent optic neuritis (with daily doses >15 mg/kg), usually reversible, characterised by decreased visual

acuity, scotoma or colour blindnessInfrequent headache, confusion, disorientation, hallucinations, acute gouty arthritis, malaise, GI disturbancesRare jaundice, peripheral neuritis, hyperuricaemia, neutropenia, eosinophilia, renal failure, allergic

reaction (rash, fever, joint pain), thrombocytopeniaFluoroquinolones (ciprofloxacin, gatifloxacin, moxifloxacin, ofloxacin (eyedrops only), norfloxacin)Frequent rash, itch, nausea, diarrhoea, dyspepsia, abdominal pain.Infrequent arthralgia, arthritis, myalgia, tendonitis12, 13, 14 crystalluria, interstitial nephritis, headache, dizziness,

insomnia, depression, QT interval prolongation.Rare blood dyscrasias, hypoglacaemia, psychotic reactions, convulsions, phototoxicity, anaphylaxis,

tendon rupture, elevated liver enzymes.Fusidate sodiumFrequent epigastric discomfort, nausea, thrombophlebitis (IV)Infrequent headacheRare elevated transaminases, thrombocytopenia, jaundice (IV), granulocytopenia, rash.Glycopeptides (teicoplanin, vancomycin)Frequent More frequent with rapid IV infusions: itch, fever, chills, eosinophillia, pain, erythema,

thrombophlebitis.Rare toxic epidermal necrolysis, erythema, anaphylaxis, erythema multiforme, superinfection,

thrombocytopenia, leucopenia, neutropenia, dizziness, tinnitus.Hexamine hippurate (methanamine hippurate)Infrequent nausea, upset stomach, dysuria, rash and stomatitis.IsoniazidFrequent morbilliform, urticarial or maculopapular rash, fever, peripheral neuritis (if pyridoxine is not given

concurrently, or if given with non-reversible ranscriptase inhibitors (NRTIs) such as stavudine), hepatitis, acne, tiredness, reduced alertness, raised antinuclear antibodies (without clinical symptoms of systemic lupus erythematosus)

Infrequent convulsions, toxic encephalopathy, optic neuritis and atrophy, memory impairment, toxic psychosisRare pellagra, gynaecomastia, amenorrhoea, urinary retention, hyperglycaemia, agranulocytosis,

thrombocytopenia, haemolytic anaemia, lupus-like syndrome, arthritic symptoms.Lincosamides (clindamycin, lincomycin)Frequent diarrhoea, pseudomembranous colitis, nausea, vomiting, abdominal pain, metallic taste, rash, itch,

contact dermatitis (topical forms)Rare anaphylaxis, blood dyscrasias, polyarthritis, jaundice, raised liver enzymes, hypotension, cardiac

arrest (rapid IV).LinezolidFrequent diarrhoea, headache, nausea, vomiting, abdominal pain, taste disturbanace, raised liver enzymes,

candidiasis, anaemia.Infrequent thrombocytopenia, leucopenia, neutropenia, eosinophila, hypertension, itching, rash, urticaria,

thromophlebitis, dizziness, insomnia, hypoaesthesia, paraesthesia, blurred vision, pancreatitis.Rare visual disturbances, and peripheral neuropathy when treatment extends >28 days, pseudomembarnous

colitis, allergy, lactic acidosis.

Table 7 Continued: Adverse effects of commonly used antibacterials2, 6, 7, 4, 9, 11, 22


Macrolides (azithromycin, clarithromycin, erythromycin, roxithromycin)Frequent nausea, vomiting, diarrhoea,abdominal pain, cramps, dyspnoea (all worst with erythromycin), cough,

candidiasis.Infrequent ixed-drug erruptions, rash, thrombophlebitis, QT interval prolongation, rash.Rare anaphylaxis, Stevens-Johnson syndrome, cholestatic hepatitis (erythromycin), acute respiratory

distress, psychiatric disturbances, hearing loss, pseudomembranous colitis, arrhythmias.NitrofurantoinFrequent allergic skin reactions, nausea, vomiting, anorexia, dyspepsia, headache, drowziness, vertigo, dizziness,

peripheral neuropathy.Infrequent Intracranial hypertension, diarrhoea, abdominal pain, pulmonary toxicity,15

Rare optic neuritis, acute hepatocellular or cholestatic reaction, chronic active hepatitis, erythema multiforme, exfolliative dermatitis, maculopapular eczematous or erythematous rashes, lupus-like syndrome.

Nitroimidazoles (metronidazole, tinidazole)Frequent nausea, diarrhoea, thrombophlebitis(IV) metallic tasteInfrequent rash, itch, dizziness, vomiting, glossitis, paraesthesia, stomatitis.Rare colitis, heptitis, pancreatitis, optic neuritis, anaphylaxis, peripheral neuropathy, seizuresPenicillins (amoxycillin, amoxycillin+clavulanate, ampicillin, benzathine penicillin, benzylpenicillin, dicloxacillin, flucloxacillin, phenoxymethylpenicillin, piperacillin. piperacillin+tazobactam, ticarcillin+clavulanate)Frequent nausea, diarrhoea, rash, urticaria, pain and inflammation (injection site), superinfection (only with

prolonged treatment and/or with broad spectrum penicillins).Infrequent fever, bronchospasm, vomiting, angioedema, erythema, toxic epidermal necrolysis, colitis, Stevens-

Johnson syndrome, haemorrhagic cystitis17, hepatoxicity (flucloxacillin, amoxycillin+clavulanate)16,18

Rare anaphylactic shock, interstitial nephritis, blood dyscrasias, serum sickness, electrolyte disturbances, haemolytic anaemia, bleeding, haemolytic uraemic syndrome

PyrazinamideFrequent hyperuricaemia, polyarthralgia, nauseaInfrequent urticaria, itch, dysuria, hepatotoxicity (rare with doses <25 mg/kg/day, varying from asymptomatic

elevation of liver enzymes, a syndrome of fever, anorexia, malaise, liver tenderness, hepatomegaly and splenomegaly, to serious reactions such as liver failure), rash, allergic reactions

Rare massive hepatic necrosis, pellagra, sideroblastic anaemia, thrombocytopenia, aggravation of porphyria, photosensitivity, acute gout

Quinupristin+dalfopristinFrequent erythema, local pain and irritation at injection site, arthralagia, myalgia, elevated transamainases, rash,

nausea, vomiting, headache, diarrhoea, elevated bilirubin.Infrequent anaphylaxis,fever, chest pain, pseudomembranous colitis, pancreatitis, peripheral oedema, hypotension,

gout, confusion, parasthesia, dizziness, hypertonia, insomnia, anxiety, leg cramps, dyspnoea, pleural effusion, urticaria, tachycardia, jaundice, hepatitis, pharyngitis, oral candidiasis, anaemia, stomatitis, eosinophilia, thrombocytopenia, anaemia.

Rifamycins (rifabutin, rifampicin)Frequent gastrointestinal disturbances, orange discolouration of urine, perspiration, tears and stools, uveitis

(rifabutin).Infrequent wheeze, hypersensitivity reactions, flu-like syndrome, blood dyscrasias, hepatotoxicity18.Rare thrombophlebitis, neurological symptoms, pseudomembranous colitis.Sulfonamides and trimethoprim (sulfadiazine, trimethoprim, sulfamethoxazole +trimethoprim)Frequent nausea, fever, vomiting, sore mouth (trimethoprim), diarrhoea, rash.Infrequent drowziness, headache, blood dyscrasias.Rare aseptic meningitis, megaloblastic anaemia, erythema, Stevens-Johnson syndrome, anaphylaxis, toxic

epidermal necrolysis, pulmonary infiltrates,hepatitis.The potential for adverse effects in older patients commonly precludes its use 19



CONCLUSIONAntibiotics are powerful agents with the potential for great clinical benefits in the treatment of infectious diseases, however, they are not benign substances and may cause significant adverse reactions. There are major differences between the different groups of antibacterial antibiotics and even within the groups both in their efficacies and adverse reactions. Additionally, other important factors contribute to problems of antibiotic usage, including the sheer volume of usage, the extensive use of broad-spectrum, rather than narrow-spectrum agents in situations where the latter drugs are efficacious, the use of newer, more expensive, heavily promoted drugs25 in situations where older, more cost-effective medication is equally effective, and the use of antibiotics in conditions such as acute bronchitis, where the aetiology is primarily viral.2 Like all good (rational) therapy, an antibiotic should only be prescribed when based on appropriate clinical and microbiological evidence that it is the treatment of choice. The clinician must ensure that all patient parameters have been taken into account, particularly evidence of past hypersensitivity. Pharmacists and doctors must be on the lookout for adverse reactions and when symptoms are described by a patient that has not been reported in the literature, it could just be that it hasn not been reported and that the patient may be suffering drom an adverse drug effect. As Napoleon Bonaparte said back in 1820, “I do not want two diseases - one nature made, one doctor made”.

REFERENCES1. Runciman WB, Roughead EE, Semple SJ. et al. Adverse

drug reactions and medication errors in Australia. Inter J Qual Health Care 2003; 15: 149-159.

2. Therapeutic Guidelines: Antibiotic Version 12 Therapeutic Guidelines Limited, 2003

3. Hardman JG, Limbird LE, Goodman Gilman A. Goodman & Gilman’s Pharmacological Basis of Therapeutics. 10th Edition, McGraw-Hill, New York, 2001.

4. Mandell GL, Bennet JE, Dolin R. Mandell, Douglas and Bennett’s Principles and Practice of Infectious diseases 5th Edition, Churchill Livingstone, New York, 2000.

5. Rawlins MD, Thompson JW. Mechanisms of adverse drug reactions. In Davis DM (ed). Textbook of Adverse Drug Reactions. 4th ed. Oxford Medical Publications, Oxford, 1991.

6. Koda-Kimble MA, Young LY, Kradjan WA, Guglielmo BJ. Handbook of Applied Therapeutics. 8th ed. Lippincott Williams & Wilkins, Philadelphia, 2005.

7. Mandell LA, Ball P, Tillotson G. Antimicrobial safety and tolerability: differences and dilemmas. Clin Infect Dis 2001; 32(Supp 1): S72-9.

8. Mosby’s Medical, Nursing & Allied Health Dictionary 6th edition, Mosby. St Louis, 2002

9. Rossi S Australian Medicines Handbook 2005, Adelaide, 2005.

10. Gupta R. Sheikh A, Strachon D. et al. Increasing hospital admissions for systemic allergic disorders in England: analysis of national admissions data. BMJ 2003; 327:1142

11. Strom BL, Schinnar R, Apter AJ et al. Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. N Engl J Med. 2003;349:1628-35.

12. ADRAC. Fluoroquinolones and tendon disorders. Aust Adv Drug React Bull 2002; 21 (4).

13. ADRAC. The Achilles heel of fluoroquinolones. Aust Adv Drug React Bull 1997; 16: 6.

14. ADRAC. Tendinitis and tendon rupture with fluoroquinolones. Aust Adv Drug React Bull 1999; 18 (3)

15. ADRAC. Pulmonary toxicity with long-term nitrofurantoin. Aust Adv Drug React Bull 2004; 23 (4)

16. ADRAC. A comparison of dicloxacillin with flucloxacillin. Aust Adv Drug React Bull 1999; 18 (2).

17. ADRAC. Haemorrhagic cystitis with ticarcillin in cystic fibrosis patients. Aust Adv Drug React Bull 2002; 21(4).

18. ADRAC. Drug induced liver disease. Aust Adv Drug React Bull 1990(3).

19. ADRAC. Serious reactions with co-trimoxazole. Aust Adv Drug React Bull 1989 8(3).

20. ADRAC. Minocycline and not so benign intracranial hypertension. Aust Adv Drug React Bull 2003; 22(1).

21. ADRAC. Hepatic reactions with minocycline. Aust Adv Drug React Bull 2003; 22 (3).

22. E-MIMS, April 2005. St Leonards: MultiMedia Australia Pty Ltd, 2005

23. Seaman HE. Lawrenson RA. Williams TJ et al. The risk of liver damage associated with minocycline: a compara-tive study. J Clin Pharmacology 2001; 41: 852-60.

24. Lawrenson RA, Seaman HE, Sundstrom A. et al. Liver damage associated with minocycline use in acne: a systematic review of the published literature and pharmacovigilance data. Drug Safety 2000; 23: 333-49.

25. Prosser H, Almond S, Walley T. Influences on GPs’ decisions to prescribe new drugs-the importance of who says what. Fam Pract 2003; 20: 61-8.

Tetracyclines (demeclocycline, doxycycline, minocycline, tetracycline)Frequent nausea, vomiting, epigastric burning, tooth discolouration, skin pigmentation, bone deformity,

reduced bone growth (children < 8 years).Infrequent rash, stomatitis, photosensitivity (demeclocycline, doxycycline), mycosis.Rare oesophageal ulcers, enterocolitis, hepatitis, fatty liver degeneration, benign intracranial hypertension

(minocycline20,21,23,24), allergic reactions, exacerbation of systemic lupus erythematosis



A long day’s travelling was required from my part of the world to reach Lorne on Victoria’s Surf Coast for Antimicrobials 2005, however the location made the trip worth it. Several of us thought we’d been given a complimentary apartment upgrade until we realised that the excellent facilities were standard across the resort.

I had attended a couple of previous Antimicrobials Scientific Meetings before, but had never presented, so this was the first opportunity for me to share my own practice-based activities with a multi-disciplinary audience as well as with my peers.

The meeting commenced with an excellent plenary session from Keith Klugman on the impact of HIV and the pneumococcal conjugate vaccine on antibiotic resistance in S. pneumoniae. Of particular interest was the impact of the pneumococcal conjugate vaccine on reduction of virus-associated pneumonia, especially influenza, which implied that a significant proportion of patients hospitalised with pneumonia actually have bacterial superinfection. There was also impressive data from some states in the US showing that antibiotic resistance in S. pneumoniae bacteraemia had fallen significantly since the introduction of the pneumococcal conjugate vaccine.

The symposium on passive surveillance gave an overview of the advantages and challenges facing the establishment of a national passive surveillance system and linking this with antimicrobial use. The presentation by Celia Cooper describing the antimicrobial usage data from South Australia has left us all in anticipation of being able to benchmark our antimicrobial usage data nationally through the federally funded scheme in the near future.

The Community Acquired Pneumonia symposium gave a thorough overview of an infection commonly encountered in routine clinical practice. The specificity, sensitivity and ease of use of the pneumococcal urinary antigen was discussed in comparison to traditional culture and Gram staining methods. The scoring methods for assessing pneumonia severity were also reviewed, with none of the methods currently in use (PSI, CURB-65 or ATS) being sufficiently specific for predicting the need for ICU care. Keith Klugman finished the session with a precis of treatment options in the era of increasing antibiotic resistance in S. pneumoniae.

The Community-Acquired Pneumonia Towards Improving Outcomes Nationally (CAPTION) project was of great interest to our hospital, especially as WA was one state not signed up to the programme. It was both reassuring and disturbing to see that a nationally funded and coordinated and funded project experienced similar sorts of problems in implementing the PSI-based CAP guidelines from the Therapeutic Guidelines: Antibiotic compared with our locally publicised and funded CAP guidelines implementation programme.

The Infectious Diseases Pharmacist Special Interest Group (IDPSIG) held its inaugural meeting as a satellite symposium of the main scientific meeting. An excellent cast of speakers, including ID Physicians and Clinical Microbiologists, ensured that there was a good attendance. Thanks must go to Sharmila Melvani and her organising committee for their hard work in organising such a successful meeting.

The ASA must be commended for again organising a scientific meeting that managed to successfully cater for the many professions connected with Microbiology and Infectious Diseases. I’ll definitely be attending again.

Matthew RawlinsInfectious Diseases PharmacistRoyal Perth Hospital, Perth, WA2005 ASA Travel Award Winner

Antimicrobials 2005 in Review


DECEMBER 2004In heterogenous MRSA, the mecI protein prevents transcription of the PBP2a protein required for expression of methicillin (and cefoxitin) resistance. Erythromycin inhibits protein synthesis by binding to the 50S subunit of rRNA. The reduced zone of inhibition to cefoxitin adjacent to the erythromycin disc may be the result of reduced/absent production of the mecI protein by S. aureus in the presence of erythromycin.

This organism may have an unstable mec gene. It should be tested for the mecA gene after induction using erythromycin. We expect it to be mecA positive and should have been reported methicillin resistant.

Dr Peter Ward and Shirley XieAustin Health, Melbourne, Victoria

MARCH 2005 The picture depicts

1) resistance to norfloxacin 10 ug

2) resistance to trimethoprim 5 u

3) a small window of reduced growth between norfloxacin and trimethoprim discs which is enhanced when the discs are moved closer together.

This pattern is suggestive of a synergistic effect between the two agents. Synergism might be able to be confirmed by checkerboard dilutions and/or agar dilution with varying strengths of the two agents. However, stability or clinical usefulness of the synergistic effect cannot not be determined by such tests ie it may be short-lived, particularly if further exposure to either agent selects for further mutations.

Both agents have an effect on DNA synthesis or metabolism; trimethoprim via purine precursors & norfloxacin via gyrase/topoisomerase inhibition. This may explain the apparent synergistic effect between the two agents.

Dr Maria YatesClinipath Pathology, Perth,WA.

Trimethoprim normally acts by binding and inhibiting the action of the tetrahydrofolate reductase enzyme

(THFR) which converts dihydrofolate to active folic acid (tetrahydrofolate). Point mutations in the THFR gene lead to change in conformation of the THFR enzyme and resistance. Perhaps, in this E. coli, trimethoprim at concentrations below the MIC is reducing THFR production. Folate is required for synthesis of purines and methylation of RNAs. Residual (sub-MIC) activity of trimethoprim would interfere or inhibit normal DNA synthesis potentially leading to mutation.

The fluoroquinolones act by inhibiting DNA gyrase and topoisomerase enzymes and consecutive mutations in the gyr gene leads to increasing conformational change of the enzyme at the fluoroquinolone binding site, resulting in increasing levels of resistance. In the E. coli in the picture, sub-MIC activity of fluoroquinolones together with errors in DNA construction (low folate related) could then lead to low level synergy between trimethoprim and fluoroquinolones.

Dr Peter Ward and Shirley XieAustin Health, Melbourne, Victoria

ANSWERS TO RECENT PICTURE QUIZZES

Picture Quiz December 2004

Picture Quiz March 2004


IS IT SAFE TO USE CARBAPENEMS IN PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY?

Articles reviewed:Incidence of carbapenem-associated allergic-type reactions among patients with versus patients without a reported penicillin allergy.

Prescott W, De Pestal D, Ellis J, Regal R.

Clinical Infectious Diseases 2004;38:1102-7

http: / /www.ncbi .nlm.nih.gov/entrez/query.fcgi?cmd=Retr ieve&db=pubmed&dopt=Abstract&lis t_uids=15095214&query_hl=1

Is it safe to use carbapenems in patients with a history of allergy to penicillin?

Sodhi M, Axtell S, Callahan J, Shelsor R.

Journal of Antimicrobial Chemotherapy 2004; 54:1155-57

ht tp: / /www.ncbi .nlm.nih.gov/entrez/query.fcgi?cmd=Retr ieve&db=pubmed&dopt=Abstract&lis t_uids=15486083&query_hl=4

As carbapenems and penicillins share a similar chemical structure, there is a risk of allergic cross-hypersensitivity. The level of this risk is ill defined, however, and carbapenems may be inappropriately avoided by prescribers in patients with a history of penicillin allergy and an alternative agent with lesser efficacy given. The objective of these two studies from centres in the American mid-west was to compare the rate of allergic reactions to carbapenems in patients with a history of penicillin allergy with those without such a history. As both studies had a similar methodology and came to similar conclusions, they are reviewed together.

MethodsHospital based retrospective chart review.

ResultsIn the Prescott et al study, 11% of patients with a history of penicillin allergy developed an allergic-type reaction when given a carbapenem compared with 3% of patients without a history of penicillin reaction (p=0.02). Most reactions were rash or drug fever. One patient with a history of rash to penicillin developed an anaphylactic reaction when given a carbapenem.

In the study by Sodhi et al, 9.2% of patients with a history of penicillin allergy developed an allergic-type reaction to a carbapenem, compared with 3.9% of patients without a history of penicillin reaction. This difference was not statistically significant (p=0.16).

The type of reaction to penicillin did not correlate with the type of reaction to the carbapenem in either study. There was no difference in the incidence or type of reaction between imipenem and meropenem.

CommentOnly 10-20% of patients reporting a history of penicillin allergy are truly allergic when assessed by skin testing (1). As these two studies were retrospective case reviews, there is no way of assessing the accuracy of the patient reported history of allergy. Nonetheless, this is the reality faced by clinicians who usually only have a patient’s self reported allergy history to guide antibiotic prescribing.

These two studies suggest that the incidence of cross-hypersensitivity between penicillins and carbapenems is low and that carbapenems can be prescribed to patients with a history of penicillin allergy if caution is exercised.

REFERENCE:1. Salbind A, Cuddy P, Foxworth J. Is this patient

allergic to penicillin? An evidence-based analysis of the likelihood of penicillin allergy. JAMA 2001; 285: 2498-2505.

David MitchellSenior Staff SpecialistCentre for Infectious Diseases & Microbiology, Westmead Hospital, Sydney, NSW

ASA Journal Club

Study Number of patients

Sodhi et al 263

Prescott et al 211

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15095214&query_hl=1







TREATMENT OF LATENT TUBERCULOSIS: THE LONG AND THE SHORT OF IT

Article reviewedShort-course therapy with rifampin plus isoniazid compared with standard therapy with Isoniazid, for latent tuberculosis infection: a meta-analysis.

Ena J, Valls V.

Clinical Infectious Diseases 2005; 40: 670-6.


Treatment of latent tuberculosis infection is widely recommended as a measure to prevent the development of active disease. This is especially important in the paediatric population who are at greatly increased higher risk of TB disease and dissemination of TB outside the pulmonary tree. The optimal therapy for latent tuberculosis must balance efficacy, compliance and a favourable side-effect profile. Single drug therapy with Isoniazid for 6-12 months is the standard treatment regimen, but concerns arise regarding patient’s compliance with this duration of therapy. Previous short-course regimens using rifampin plus pryazinamide for 2 months have been linked to significant hepatotoxicity and death in adult patients, causing the American Thoracic Society and US Centres for Disease Control and Prevention to caution against its usage.

MethodsIn the current study, the authors performed a meta-analysis to determine the efficacy of short-course therapy (3 months of rifampin plus isoniazid) versus the standard regimen of isoniazid (6-12 months). Endpoints evaluated in the study included the development of active tuberculosis, severe adverse drug reactions and death. Five randomised clinical trials were identified involving 1926 adult participants. The majority of patients (n=1390) were HIV-infected, the remaining participants were HIV-negative or had not been tested. Dosing was the same in all dual therapy regimens (rifampin 600mg plus isoniazid 300mg daily for 3 months) but single Isoniazid regimens varied from 300mg daily for 6 months (3 trials), 9 months (1 trial) and 12 months (1 trial). The latter two trials also included daily pyridoxine (vitamin B6 [50mg]) with the isoniazid. Mean follow-up ranged from 13-36.5 months. Statistical analysis was performed on the basis of intention-to-treat and 95% confidence intervals of the risk differences between regimens calculated.

ResultsThe frequency of participants who developed active tuberculosis was equivalent among both regimens (pooled risk difference, 0%, 95% CI –1% to 2%). There was a trend suggesting increased side effects with combination therapy but this did not reach statistical significance. Only 3 trials provided mortality data (n=1390) and again there

was no significant difference in the regimens (pooled risk difference, –1%, 95% CI –4% to 2%). Subgroup analysis was performed to assess the effects of HIV-status, duration of treatment and trial quality. When the high-quality trials were assessed (74% of sample size), there was no difference in outcomes or safety between the two regimens.

CommentFrom this meta-analysis, it appears that short course regimen of 3 months daily rifampin plus Isoniazid is equally efficacious as traditional latent tuberculosis monotherapy. Side effects, in particular hepatotoxicity, are similar between regimens, thus patients will continue to need close monitoring. No paediatric studies were included in the analysis, reflecting the paucity of data on which to base recommendations in this population. Although current recommendations for treatment of latent tuberculosis in children still focus on monotherapy with isoniazid, short course therapy (rifampicin and isoniazid) appears well tolerated and effective in children1. Greater compliance with short course regimens remains the greatest potential benefit but substantive evidence for improved compliance is lacking and further studies are warranted in both children and adults.

REFERENCE1. Ormerod LP. Rifampicin and isoniazid prophylactic

chemotherapy for tuberculosis. Arch Dis Child 1998;78:169.

Sarah Cherian Paediatric Infectious Diseases Fellow

David BurgnerPaediatric Infectious Diseases ConsultantPrincess Margaret Hospital for Children, Perth, WA

ASA Journal Club





TOBRAMYCIN IN CHILDREN WITH CYSTIC FIBROSIS (CF): ONCE OR THREE-TIMES DAILY?

Article ReviewedOnce versus three-times daily regimens of tobramycin treatment for pulmonary exacerbations of cystic fibrosis - the TOPIC study: a randomised controlled trial.

Smyth A, Tan KH, Hyman-Taylor P, Mulheran M, Lewis S, Stableforth D, Prof Knox A; TOPIC Study Group.Lancet 2005; 365: 573-8.


Once daily dosing (ODD) of aminoglycosides is well established in adult medicine, but the role in patients, especially children, with CF remains controversial. Although there have been at least 3 or 4 studies in adults and children with CF, they have suffered from the typical issues of small numbers and/or design that plague so many studies of antibacterial therapy in acute respiratory exacerbations of CF. Two large, multi-centre studies of ODD in CF were initiated some years ago. Whilst the USA study has been abandoned, the UK TOPIC study (Tobramycin Once-daily Prescribing in Cystic Fibrosis) has at last been published following presentation at the 2002 North American Cystic Fibrosis Conference.

MethodsThe goals of this large multi-centre study were to compare the safety and efficacy of once vs three times daily dosing (MDD) in adults and children with CF. 244 patients with infective exacerbation of CF from 21 UK centres were randomised to once or three-times daily tobramycin (given as 30-minute infusions) with ceftazidime for 14 days. Treatment was. Primary outcome measure was change in forced expiratory volume in 1s (FEV1), over the 14 days of treatment, and change in FEV1 compared to baseline. The study was adequately powered for equivalence.

ResultsTwo hundred and nineteen patients (125 children) were available for analysis of endpoints such as change in FEV1 after 14 days of therapy (tobramycin + ceftazidime), a clinical scoring system, C-reactive protein, indicators of nephro – and oto-toxicity and time to next course of IV antibiotics. The mean FEV1 predicted increase of the order of 10% over baseline is consistent with such studies in CF and was not different between the two treatment groups. None of the other parameters of efficacy (clinical score, CRP, time to next IV) differed between groups. Measures of nephrotoxicity (the tubular enzyme NAG and serum magnesium) suggested reduced toxicity in the ODD group.

CommentAn accompanying editorial highlights some deficiencies in the study. These include the expected criticism of clinical scoring systems, the lack of power to detect a difference in nephrotoxicity in the adult group, and the decision not to include/report a large amount of other interesting data such as sputum levels and drug pharmacokinetics. However, this study was the first to be sufficiently powered to detect a difference in the primary outcome parameter of FEV1 and no difference was found. Although the pharmacokinetic differences in patients with CF make it unwise to extrapolate from non-CF studies, the results of reduced nephrotoxicity in the non-CF studies is reassuring. The extended survival of patients with CF and thus repeated exposure to aminoglycosides put these patients at potential risk of toxicity.

The method of TDM included a trough of <1mg/L in the ODD group. This has been recommended by UK CF Trust as the preferred method. Given that serum creatinine may be a poor indicator of early loss of GFR in CF, that most tobramycin assays do not quantitate concentrations <1mg/L, and that exposure (as indexed by AUC) correlates with nephrotoxicity, this TDM methodology may not be optimal for patients exposed to repeated courses.

Although the TOPIC study, like many other such anti-infective studies in acute respiratory exacerbations of CF, has some flaws, Alan Smyth and his colleagues should be congratulated in performing such a large, multi-centre study which significantly adds to the literature on ODD of tobramycin in CF.

Kingsley CoulthardDirector of PharmacyWomen’s & Children’s Hospital, Adelaide, SA

ASA Journal Club




An oxidase-positive gram-negative bacillus was isolated on Xylose –Lysine Decarboxylase (XLD) agar from a stool specimen taken from a hospitalised patient with diarrhoea. The organism was found to be resistant to imipenem on agar dilution breakpoint testing.

Figure 1 shows susceptibility testing results obtained after inoculation with a 1:10 dilution of 0.5 McF suspension of the organism on Isosensitest agar after 24h incubation.

Key: ATM 30 = aztreonam 30µg, IMP 10 = imipenem 10µg, EDTA = plain disc with 10µl of 0.1M EDTA added after placement, IMP 10 + EDTA = imipenem + 10µl of 0.1M EDTA added after placement.

1) What does this test demonstrate?

2) What might be the identity of this organism?

3) Are there any potential infection control implications of isolating this organism with this susceptibility profi le?

Please email your responses to Dr Ronan Murray at [email protected] or [email protected]. Answers will be published in the next issue and correct responses will be acknowledged.

Picture quiz provided by Cheryll McCullough and Ronan Murray from the Department of Microbiology and Infectious Diseases, Royal Perth Hospital, Perth WA

Picture Quiz June 2005

Figure 1

ASA SUBSCRIPTIONS

Subscriptions should be sent to:

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Telephone: (08) 9224 2446Facsimile: (08) 9450 8553Email: [email protected]

NEWSLETTER CONTRIBUTIONS

Submission of articles for possible publication or letters to the editor should be sent to:

Dr Ronan MurrayASA Newsletter EditorDepartment of Microbiology and Infectious DiseasesRoyal Perth HospitalGPO Box X2213Perth WA 6847

Telephone: (08) 9224 2444Facsimile: (08) 9224 1989Email: [email protected]

mailto: [email protected]






Australian Society for Microbiology Tristate 2005 A Tropical Sensation: Mozzies, Mangoes, Mudcrabs and Microbiology

8th – 9th July 2005

Mirambeena Resort, Darwin, Northern Territory

website: http://www.tristate2005.org

3rd International AIDS Society Conference of HIV Pathogenesis and Treatment

24th – 27th July 2005

Rio De Janeiro, Brazil

website: http://www.ias-2005.org

2nd Mycology Masterclass 2005Australian Society for Microbiology

29th - 30th July 2005

Hamilton Island, Great Barrier Reef, QLD

website: http://www.2005mycologymsaterclass.org

17th Australasian Conference of the Australasian Society for HIV Medicine (ASHM)

24th – 27th August 2005

Hotel Grand ChancellorFederation Concert Hall and Convention CentreHobart, TAS

website: http://www.ashm.org.au/2005_conf/

The 45th Annual Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) 2005American Society for Microbiology

21st – 24th September 2005

New Orleans, Louisiana, USA

website: http://www.ICAAC.org

Australian Society for Microbiology 2005 National Conference

25th – 29th September, 2005

National Convention Centre, Canberra ACT

website: http://www.asm2005.org/

contact: [email protected]

43rd Annual Meeting of the Infectious Diseases Society of America (IDSA)

6th – 9th October 2005

San Francisco, California USA

website: http://www.idsociety.org

2nd International Conference on Community Acquired Pneumonia

17th – 19th September 2005

Montreal, QC, Canada

website: http://www.isc-cap.org

Appropriate use of Antimicrobials in Hospitals and the Community (International Society of Chemotherapy and Slovenian Society of Chemotherapy)

13th – 15th October 2005

Bled, Slovenia

website: http://www.albatros-bled.com/dms-2005

16th European Congress of Clinical Microbiology and Infectious DiseasesEuropean Society for Clinical Microbiology and Infectious Diseases

1st – 4th April 2006

Nice, France

website:http://www.akm.ch/eccmid2006/

Meeting Calendar

http://www.tristate2005.org

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http://www.ashm.org.au/2005_conf/

http://www.ICAAC.org

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http://www.idsociety.org

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http://www.akm.ch/eccmid2006/

Documents

Adverse Reactions to Antibacterial Agents - Australian Society for