• Treatment of Myasthenia Gravis
  P.Sahota, D.Khurana, S.Prabhakar
   

• Use and Misuse of Antimicrobial Agents
  Manpreet Sukhija, P.Pandhi

• Pharmacotherapy for Aspergillosis of Nose and Para Pasal Sinuses
  A.K.Gupta, Rijuneeta, Gupta Anish S.B.S.Mann

DRUGS BULLETIN is an independent journal having articles from various well-known authors. The opinion expressed in these articles is not necessarily those of the Committee of Management or their Advisory Committee.

Committee of Managment

Chairman & Editor
Prof. P.Pandhi

Members
Dr.S.Malhotra
Dr. Debasish Hota
Dr. Bikash Medhi

Advisory committee

Chairman
Prof K.K.Talwar

Members
Prof Sudha Suri
Prof  K Joshi
Prof S.K.Jindal
Prof J.D.Wig

Treatment of Myasthenia Gravis

Introduction

Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular transmission.Serum auto-antibodies against acetylcholine receptors (anti-AChR antibodies) at the motor end plate occur in 85% of MG patients. Treatment modalities used for the management of patients with MG are directed towards the improvement of neuromuscular trasmission with cholinesterase inhibitors, the reduction of anti-ACh response by use of nonspecific immunosuppressive drugs or the transient suppression or removal or AChR immunomodulatroy agents by therapeutic apheresis or intravenous immunoglobulin. There is enough of prospective, controlled clinical trails for medical or surgical management of MG. Teh various treatment options available for its management are summarized in table I.

1. Acetylcholinesterase inhibitors

• These drugs aim at retarding the enzyme hydrolysis of acetycholine at cholinergic synapses, so that acetylcholine accumulates are neuromuscular junetion and its action is prolonged.

Advantage

• Produce symptomative improvemtn in majority of patients.

Disadvantages

• Produce only temporary improvement.

• Require close medical supervision

• Prone to over and under-dosage, frequent side effect even at therapeutic levels.

• Usually produce less than complete response and become less effective with time.

• Don't change natural history of disease profression

• The need for cholinesterase inhibitors varies from day to daty, during same day and in response to various stress factors.

• Different muscles repsond differently to any dose.

• Dosage schedule shoul be titrated to produce optimum response in muscles causing greatest disability.

2. Immunosuppressive drugs

(a) Corticosteroids

• First of the immunosuppressive agents to be used in treatment of MG

• More than 75% patients show marked and complete relief of symptoms

• Acts at all levels of immune system and result in nonspecific immunosuppression

• Initially, started as definite treatment, to produce rapid, virtually complet improvemtn in kanority of patients permitting subsequent thymectomy to be performed with greater safety.

• As secondary treatment, in most patients who don't respond to thymectomy or other immunosuppressive drugs.

Advantages

• Produce rapid improvement in most patients

• Predictable time of  response. Usually begins in 2-3 weeks and maximum in 3 months

• Relatively simple dosage schedule

• Reduce morbidity and mortality of subsequent thymectomy.

Dosage

1. Generalized MG- Begins with 1.5-2 mg/kg/ day to have sustained improvement, then shifted over to alternate day (100-120 mg). Gradually, taper over many months to lowest dose necessary to maintain improvement (usually < 20 mg OD)

If recurrence of weakness on tapering, then increase dose and/ or add other immunosuppressive drugs.

Upto 1/3rd patients may become weaker temporarily after starting steroids, usually within first 7-10 days. Hence, in patients with bulbar or respiratory involvement, steroids should be started at low dosage and escalated slowly under close supervision.

1. Ocular MG- Begin with 5-10 mg/ day then escalate 5 mg/3-4 weeks till maximal improvement, over 4-6 months ot maintenance dose, which is usually 5-10 mg/OD

Side effects

Hypertension in up to 50% of cases

B) Other immunosuppressive agents

Advantages

Produce marked, sustained improvement in most patients.

Disadvantages

Long delay before the improvement and may have serious side effects.

Role

• It is used as intial and definitve treatment in patients with late onset MG or when steriods are contraindicated

• It is used as secondary treatment in patients who don't respond to steroids or thymectomy.

• In combination with steroids to increase their response or to permit more rapid reduction in steroid dose.

3. Plasma exchange
Role

• It is a short term intervention of patients with acutre worsening or mayasthenic symptorms for any reason.

• To rapidly improve strength before surgery

• As a chronic intermittent treatment for patients who are refractory to all other forms of treatment.

Protocol

Two-three litres of plasma is removed 3 times/ week until improvment plateause are achieved

Disadvantage

Expensive, requires concomitant immuno-suppressive therapy or thymectomy for long lasting benefit.

Side-effects

Transient cardiac arrhythmias, light headedness, chills, pedal edema thromobosis and thrombophlebitis, influenza-like illness in patients with low immunoglobulin levels.

4. Intravenous immunoglobulins (IVIG)

Mode of Action

• IVIGs block and neutralize pathogenic idiotypic antibodies, suppressess antibody mediated responses.

• Accelerates catabolism of pathogenic antibodies suppresses pathogenic cytokines.

Indications

Patients on Cholinesterase inhibitors and awaiting immunisuppressants, myasthenic crisis, patients refractory to tapering to steroids, and in patients not to undergo thymectomy for rapid improvement.

Side-effects

Headache, chills fever-related to rate fo infusion, aseptic meningitis, leucopenia, retinal necrosis, contraindicated in selective IgA deficiency.

Dose

2 gm/kg in divided doses over 2 to 5 days

5. Thymectomy

Thymectomy is recommended for most patients with MG. The maximal favourable response generally occurs 2-5 years after surgery.

Advantages

Thymetomy can produce lon-lasting improvement in majority of patients. It has not known chronic side effects.

Disadvantages

Operative morbidity and mortality, frequent long delay after improvement, total remission is rare.

Role

Potentially bebeficial in all patients with life expectancy of more than 10 years or those having thymomas.

Approach

• Transthoracic

• Transservical

• Video-assisted thoracoscopic (VATS)

6. Treatment of assocaited disseases

• Thyroid disorders

• Intercurrent infections

• Avoidance of drugs that may produce exacerbation such as:

• Aminoglycosiders

• Calcium channel blockers

• Beta blockers

• Muscle relaxants

• Botulinum toxin

• Quinidine

• Penicillamin

• Procainamide
   

7.  Myasthenic crisis

     It is defined as an exacerbation of myasthenic weakness that leads to respiratory failure rquiring intubation and mechanical ventilation.

     Approximately 30% of all patients of MG develop some degree of respiratory muscle weakness and 15-20% will experience at least one episodes of crisis.

Precipitating factors

• Infection

• Changes in medication

• Initiation of steroids

• Aminoglycoside adminsitration.

Management

• Assess clinically the respiratory rate and paradoxical respiration.

• Look for evidence of infection.

• Assess pulmonary fuction tests and need for intubation.

• Nasotracheal intubation is preferred since it is comfortable and poses less risk for tube displacement.

• Anticholinesterase medications should be discontinued after intubation and restarted one day before or on day of  extubation.

• Plasmapharesis is the mainstay of immunotherapy for short-term improvement of crisis symptoms. IVIg has also been used as an alternative.

Conclusion

There are few controlled clinical trails available for any medical or surgical modality used to treat myashenia gravis. Hence, treatment decisions must be based on knowledge of natural history of disease in each patient and predicted reponse to a specific form for treatement. Cholinesterase inhibitors are initial agents used and produce symptomatic improvement in majority of patients. However, they do not modify the course of the disease.

Immunosuppressants are indicated when weakness is not adequately controlled by anticholinesterases and their benifit out-weights possible side effects.

Short term immunotherapies such as plasmapheresis and IVIg administration are beneficial in tpatients with myasthenia crisis or to maximize strength beofre thymectomy. Occasionally, their intermittent or chornic use has been reported to be beneficial in patients who do not respond to medications/ thymectomy.

Thymectomy is beneficial in all patients with life expectancy of more than 10 years and with thymomas.

The future of myasthenia management is into specific immunotherapy, where B-cell and T-cell directed approaches are being studied to block the immunogenie sites or pathogenic auto-antibodies and hence preventing ultimate damage to neuro muscular junction

Table No 1: Treatment options available for MG

1. Medical

a) Acetycholinesterase inbibitors

• Phyridostigmine

• Neostigmine

• Ambenomium

b) Immunosuppressive drugs

• Corticosteroids

• Azathioprine

• Cyclosporine

• Cyclophosphamide

c) Plasmapheresis

d) IV immunoglobulins

e) Miscellaneous

• Splenectomy

• Splenic irradiation

• Total body irradiation

• Aminopyridines

• Ephedrine

2. Surgical

• Thymetomy

Table No 2: Routes of administration and dosage (mg)

Table 3: Other Immunosuppressive agents:

Alogorithm
Management approach to myasthenia gravis

Use and Misuse of Antimicrobial Agents

Clinicians have to rely on antimicrobial agents for treatment of infections. However, indiscriminate use or rather misuse of antimcrobial agents has lead to emergence of problems of treatment failure superinfection and resistance.

Clinical application of antimicrobial therapy

There are certain basic principles which need to be followed whenever an antimicrobial drug is prescribed.

1. Indication for treatment

This can be empirical, definitive or prophylactic . The isolation of micro-organisms does not necessarily indicate infection, for example, at sites like the skin and gastrointestinal tract, unless co-existent signs and symptoms of infection are present.

2.  Micro-organism causing the Infection

The specimens for identification of the micro-organism should be collected before antimicrobial treatment is started.  However, serious infections like meningitis or those conditions which are sufficiently characteristic  of infection by a particular organism mandate immediate antibiotic therapy.

3.  Spectrum of activity

The spectrum of activity i.e. the range of organism against which an antibiotic is effective determines the choice of drug to be used.  Empirical therapy requires use of a broad-spectrum agent like cephalosporins, quinolones, aminoglycosides and ampicillin.  But when the cusative organism is known, then definitive treatment with a narrow spectrum agent like penicillin should be used.

4.  Combination therapy2

Rationale

Infection severity and polymicrobial infection

For empirical coverage of acute infections and sepsis, community acquired and interstitial pneumonia, where a variety ofmpathogens ranging from gram-positive and gram-negative to atypical and fastidious organisms, also in immunocompromised patients, e.g. febrile neutropenia.

Guidelines for empirical treatment of some infections in adult patients:
 

Pharmacodynamics / synergy

Synergistic combinations are often sought where the development of resistance and/or subsequent failure with monotherapy is prevalent, e.g. penicillin + aminoglycoside in penicillin-sensitive streptococci.

Almost all classes of antimicrobials show the phenomenon of post antibiotic effect (PAE) i.e. the time (in hours) required to demonstrate viable regrowth of an organism after exposure and removal of a given antibiotic.  e.g. quinolones and aminoglycosides demonstrate consistent PAEs in the range of 2 to 4 hours for both gram-negative and gram-positive organisms.  Synergistic PAEs have been observed with combination of b-lactams and aminoglycosides.  The use of PAE lies in the higher protection against organism regrowth in situations where one/both antibotics becomes subtherapeutic during the dosage interval.

Disadvantages of combination therapy

Incorrect or inappropriate combinations can lead to problems like antagonism, increas3ed adverse effects, superinfection (especially with broad spectrum agents) and may be higher cost of treatment.

5.    Pharmacokinetic and pharmacodynamic factors affecting antimicrobial prescribing.  

• Location of infection

• Minimum drug concerntation achieved at side of infection.

• Plasma protein binding

• Dose and dosing frequency (depending on whether drug exhibits concentrtion dependent (e.g. aminoglycosides) or time-dependent (e.g.. b-lactams) activity.

• Mechanism of drug metabolism (decrease of dose in hepatic failure for drugs like erythromycin, chloramphenicol, metronidazole, clindamycin; decreased dose in renal failure for drugs like vancomycin, aminoglycosides)

• Route of administration.  Intravenous route is preferred in emerging situations.

• Host defence status (bactericidal agents required in emergency situation)

• Local factors (pus, low pH, anaerobic conditions, etc.)

• Age (e.g. premature babies are at risk of crey baby syndrome' with choloramphenicol, elderly patients are at increased risk of aminoglycoside toxicity due to decreased creatinine clearance).

• Genetic (e.g. hemolysis in glucose-6-phosphatase dehydragnase (G6PD) deficiency with sulfonamides, chlroamphenicol).

• Pregnancy and lactation.  Special care must be taken to avoid inadvertent antibioctic exposure to fetus/newborn.

• Drug allergy.

All these factors interpaly to give the final effect of an antimicrobial agent. Therefore, the prescribing physician should be aware of them to prevent misused of these agents.

Principles of dosage and administration

An antimicrobial agent will not be effective if it is not delivered to the site of infection in adequate amounts. Seriously ill patients may not absorb orally adminstered agents. For these patients i.v. route is the norm as even i.m. route may not provide adequate blood and tissue levels.

Therapy should be initiated with a loading dose to ensure effective blood and tissue levels as soon as possible. When the patients condition becomes atable and no contraindication to intramuscular injections exists,i.v. therapy can be changed to i.m. route. This reduces expense and risk of superinfection, but is not possible with some agents.

For determining dose of antimicrobials, combinations of standard doses and calculation involving body weight or body surface area are used. In general, standardized doses of drugs like penicillins and cephalosporins are used as they have wide margin between therapeutic and toxic blood levels. For agents with narrow amrgine. e.g. aminoglycosides, assays are needed for determining appropriate dose and avoiding toxicity although this affects the cost-effectiveness of the agen. serum levels are usually assayed after the forth or fifth dose of an agent.

Antimicrobial prophylaxis in surgery

Post operative wound sepsis is the most common nosocomial infection in patients undergoing surgery.  To prevent its occurrence, adequate antimicrobial prophylaxis is required.  Some important guidelines to be followed are:

Timing:  For effective antimicrobial prophylaxis, adequate concentrations of the drug must be present at the onset and throughout the operative procedure.  Therefore, the initial dose must be given immediately before the operation.  For antibiotics with short half-life or when operative procedure is prolonged, the second dose should be administered during the operation.  An exception is during caesarean section when initial dose is given immediately after cord clamping.

Route of administration:   Intravenous administration is the optimal method except for colorectal surgeries where oral administration of antibiotics appears to be sufficient.

Duration:  A single dose of antibiotic before the operation offers sufficinet prophylaxis for most surgical procedures.

Choice of antibiotic:  Importantly, the drug selected should be effective against the pathogens, most frequently responsible for would infection after the particular operation.  However, they need not be active against every microorganism in the initial bacterial inoculum, since some organisms may not contribute to would infection.  Other significant issues are the plasma t1/2 of each drug, the local hospital antimicrobial susceptibility pattern and the daily cost of each drug.

There are a number of problems associated with use of antimicrobial agents.  Some can be attributed to inherent factors, like allergy to a particular agent; others are the results of widespread misuse of these drugs, may be due to ignorance of the patient or overenthusiasm of thetreating physician.

Allergy to antimicrobial agents

Obtaining a clear and detailed history of allergy to a drug is frequently often difficult or impossible.  Patients who have allergic reactions witnessed by a physician should be given a card with the generic name of the offending drug.  Attending physicians and nurses should inquire about the type of reaction and should not list those agents.  There are certain principles that can be followed:
 

• Usually, skin testing should not be done unless immediate use of the drug is planned and alternative therapy is not feasible as a skin test is associated with some risk of reaction and can leave the patient sensitised to the drug.

• If skin tests with penicillins/cephalosporins are negative, the chance of severe immediate reactions is less likely but not eliminated.

• Most infections in patients with drug allergies can be treated with adequate substitutes.  But in certain cases like enterococcal endocarditis, the combination of penicillin and aminoglycoside is superior to vancomycin plus aminoglycoside, that skin testing and even attempts at desensitisation to penicillin are used.

• Cross-reactions between penicillins and cephalosporins remain an issue of concern.  The chances of such a response are heightened by inherent tendency of a patient to have allergic reaction.  Use of any drug in the same family after a previous reaction is inadvisable.

Sometimes, it may be possible to give the same drug to the patient who has a history of previous allergic reaction to it.  For example, a patient giving a history of red-neck syndrome after vancomycin use may tolerate slow administration of the drug.

Adverse reactions to antibiotics

All antibiotics are potecntially harmful and various benefit-to-risk factors must be considered whenever they are used.  The most important approach to decreasing antibiotics related side effects is judicious use of these drugs.  Familiarilty with antibiotic-induced adverse effects can improve drug selection and reduce reaction.  Before antibiotic therapy is started, the potential benefits and the possible adverse effects should be weighed in light of each patient's situation.  Minimising potential for drug-drug interactions also is useful step.  Some suggestions for reducing antibiotic-induced adverse events are as follows.  

Antibiotic resistance

Bacteria have developed different mechanisms to survive the attack due to large scale and indiscriminate use of antibiotics.  These include altered permeability of bacterial cell wall/membrane to these agents, presence of efflux pumps, inactivation of antibiotics, alteration of target binding site and various genetic mechanisms such as mutation transformation and transduction.

Antibiotics resistance is mainly determined by two factors.  The antibiotic, which, acting as a selective agents, helps to propagate organisms that have second factor; the resistance gene.  Dissemination of resistance due to genetic means is an important feature.  Over the counter availability of antiboitics is one of the worst scenarious leading to antibiotic resistance due to use of the drugs for too littele period or use when not even require.  Also, feeding of antibiotics to animals (to increase growth)  results in sub-therapeutic levels of these drugs in humans.  This favours the emergence of multidrug resistance strain of bacteria.  Chronic antibiotic use also has a 'societal effect' i.e. broad effect on other bacteria in the environment.  As most resistance mechanisms do not inactivate the antibiotic, excretion of active antibiotics into the environment facilitates a 'post-therapy' environmental selection phase of the antibiotic.  At the time, the drug is at less than therapeutic concentration, which is ideal for selecting resistance.  There are other antibiotic-like subsstances that have appeared in products of diverse forms ranging form floor cleaners to dishwashing detergents, which may contribute to the problem.  For example, triclosan is one such chemical used in toothpastes that targets a protein enoyl reductase, which is acts as one of the targets for isoniazid- a mutation in the enzyme, leads to resistance to both agents.  So factors driving emergence of drug resistance can be viewed as:
 

• Patient movement within and among medical institutions 

• Appropriateness of prescription and use

• Infection control measures

• Travel of people and goods

• Socio-economic factors

• Selection by non-antibiotic substances 

• Antibiotic residues in the environment

• Dose and duration of treatment 

• Linkage of resistance determinants

• Gene transfer

• Clonal spread

Antimicrobial resistance: a class effect?

Antibiotic use has led to increased resistance to certain group markers: penicillin, erythromycin and ciprofloxacin for b-lactams and quinolones, resistance to group markers results in large decreases in the antimicrobial activity of the less potent members of the group.  Empiric prescription guidlines based on the pharmacoepidemilology of resistance, recommending the use of potent drugs that are less incluenced by resistance to the marker, may help to counter the spread of resistance in the community.

Antibiotic failure

This is a consequence of misuse of  antibiotics. Failure to respond to an antibiotic may be due to 

• inadequate coverage

• inadequate antibiotic blood levels

• problems in antibiotic tissue penetration due to foreign body, abscess, protected focus (e.g. CSF)

• drug-drug interactions which may lead to antagonism or inactivation

• superinfection (bacterial/ fungal)

• non-infectious disease like pseudosepsis, drug fever

• untreatable infectious disease.e.g. viral infection unusual pathogens like rickettsia, chiamydia

Cost factor

Antimicrobial therapy involves considerable costs. There may be the obvious cost of acuquistion or other associated hidden costs besides the financial input in developing and marketing these agents. Some of the antibiotic cost factors in hospitalised patients are given below. Proper use of antibiotics will involve practicing the cost containment strategies given alongside.
 

To avoid these problems arising out of misuse of antimicrobials, several steps can be taken.

Clinical of guidelines

Development of clinical quidelines for antimicrobial use if fraught with its own probles. No clinical guideline can be sufficiently specific that it can apply to all clinical situations. Guidelines rarely address co-morbid conditions and concurrent therapy. They also fall to take account of patient preferences. Some clinicians perceive that guidelines lead to a loss of autonomy and choice, therapy  threatening their clinical freedom. There can certain stages in developing guidelines.

a)  Development: Guidelines should be graded according to the strength of evidence supporting them. They should be reviewed at periodic intervals that should be specified and updated according to latest medical advaces and outcome of guidelines evaluation.

b) Dissemination : In order to make the target clinicians aware of their existence, guidelines should be disseminated in different ways: publication in journals, newsletters, loval reports or documents, handbooks, group educational programs etc.

c) Implementation: This is the process that ensures that guidelines are introduced into clinical practice. Guidelines should facilities changes in practice, but if the changes are to be sustained, measures designed to promote implementation of guidelines must also change clinicans knowledge, attitudes and beliefs.

d) Evaluation: This is done to assess the efficacy of the guidelines with the aim of ensuring that they have produced the intended changes in both practice and outcome.

Guidelines are more likely to be adopted if users have participated in their development. Consequently, fewer resources are needed for effective dissemination and to promote implementation, compared with national guidelines for which greater emphasis must be placed on these phases of the process. A reasonable compromise would be to adopt national evidence-based guidelines (where such guidelines exist) for local use, a strategy that may be adequate to ensure clinicians compliance.

A step forward to counteract the problem of antimicrobial reistance is the establishment of surveillance systems. The Alliance for Prudent use of Antibiotics (APUA, www.apua.org) is one such organisation . APUA has instituted two global actions ROAR (Reservoirs of Antibacterial Resistance) project which examines resistance among commensals and GAARD (Global Advisory Board on antibiotic Resistance) which is an international effor dealing with global surveillance systems of clinical isolates (SENTRY Alexander Project and TSN)

Antibiotic formulary selection

This is an important step to encourage proper use of antimicrobials in the current era of rapid influx of new drugs into the market that challenge both the decision-making ability of the physcicians and the attempts to cost cutting. Some useful guidelines are:

1. Select drugs appropriate to diagnosis and local resistance patterns

2. Minimize drug acuisition cost through competitive bidding, buying alliances

3. Make strong recommendations for the therapy of common infectious disease seen at one's institution, including oral drugs, where appropriate.

4. Minimize administration costs-dosing restriction, preferable pharmacokinetics

5. Establish meaningful restriction policies for broad-spectrum, expensive drugs

6. Consider cost versus benefit, not just cost, of new agents when comparing

7. Use oral therapy whenever possible to maximise patients convenience, minimize nosocomial infections.

Newer use of oral antimicrobials

An effective way to combat the rising problem of resistance is to develop new drugs. But this involves enormous imputs. An even better alternative is to find out newer indications for the existing armament of antimicrobials. For example, metronidazole was conventionally used for hepatic amoebiasis. B. fragilis infections, pelvic infection etc. Later on, it was found to be useful in antibiotic-associated colitis, antibiotic-associated diarrhoea and even Clostridium difficile infection.

Intravenous-to -oral antibiotic switch therapy

There is a general misconception that infectious disease necessistate intravenous treatment and oral treatment is not as effective. Another common misconception is that antibiotics chosen for a switch regimen must be of the same type or class. This is not the case at all. The only requirement is that the agent should cover essentially the same spectrum and have the same charateristics of tissue penetration. Cost savings are maximized if patients can be switched to oral regimeans as soon as fever abates clinically, which as noted, is usually within 72 hours in normal hosts.

Thus proper use of an antimicrobial agent merits the following principles

• Choice of an agent should be made based on comparison between benefits and detriments associated with each drug.

• Cost effectiveness analysis can serve as a framework for such a comparison.

• The benefit associated with appropriate drug may be so great that durg costs and side effects become secondary consideration

• The development of future resistance is the major concern.

• In choosing an agent, doctors have to choose between the interests of the present and future patients.

In conclusion, antimicrobial therapy if put to appropriate use can be of great benefit. To avoid misuse of these drugs, the following strategy which may be labelled as "Good Antimicrobial Practice (GAP strategy)" mind when prescribing any antimicrobial"

• Do not use for trivial infections

• Use for prophylaxis only where indicated

• Use rational combinations

• Use of minimum duration

• Use in correct dose/ frequency

• Take appropriate specimen for diagnosis

• Justify use based on lcinicla diagnosis rather than laboratory reports

• Use drug in rotation/ cyclic pattern

• Use appropriate adjunctive measures like debridement.

References

1. Chambers HF, Antimicrobial agents, General considerations. In Hardman JG, Limbird LE, eds. The Pharmacological Basis of Therpaeatics. 10th Edn. MC Graw Hill 2001:1143-1170

2. Rybak MJ McGrath B.J Combination antimicrobial therapy for bacterial infections. Guidelines for the Clinicians, Drugs 1996:52:390-405

3. Wilkowske CJ General principles of antimicrobial therapy Mayo Clin Proc 1991:66:931-941

4. Woddell TK Rotstein OD. Clinical pratice guidelines. Antimicrobial prophylaxis in surgery Can Med Assoc J 1994:151:925-931

5. Gleckman RA, Borrego F. Adverse reactions to antibiotics. Postgrad Med 1997:101:97-108

6. Levy SB. The 2000 Grarrod Lecture. Factors impacting on the problem of antibiotic resistance. J Antimicrob Chemother 2002:49:25-30

7. Preto J Calvo A Gomez Lus ML Antimicrobial resistance a class effect ? J Antimicrob Chemother 2002:50 (Suppl S2) 7-12

8. Cunha BA Ortega AM Antibiotic failure Med Clin N Amer 1995:79:663-671

9. Cunha BA Intravenous-to-oral antibiotic switch. A cost-effective approach. Postgrad med 1997:101:111-128

10. Brown EM Guidelines for antibiotic usage in hospitals. J Antimicrob Chemother 2002:49:587-592

11. Crowe HM Quintilliani R. Antibiotic formulary selection Med Clin N Amer 1995:79:463-475

12. Cunha BA Newer uses for older antibiotics. Postgrad Med 1997:101:68-88

13. Leibovici L Shraga I Andreaseen S. How do you choose antibiotic treatment ? Br Med J 1999:318-1614-1616

Pharmacotherapy for Aspergillosis of Nose and Para nasal Sinuses

Fungi are ubiquitious in the environment and consequently , we are all exposed to their infectious elements on daily basis. The fungal spores mainly spread by inhalational route. So the upper respiratory tract especially the nose and paransal sinuses are the most exposed sites and hence more prone for fungal infections.

Sinonasal mycotic disease may be classified as

1. Allergic fungal rhinosinusitis (AFRS)

2. Noninvasive colonization (mycetoma or fungal ball)

3. Chronic invasive (profuse fungal growth with regional tissue invasion)

4. Acute fulminant (vascular invasion with thrombotic ischaemia)

Aspergillus is by far the most common cause of all forms of mycotic sinonasal disease. Aspergillus fumigatus is the major pathogen in western setup whereas in the Indian subcontinent. Aspergillus flavus accounts for most of the lesions. The moist and dusky air of summer sandstorms further disseminates the fungal spores and encourages their growth. Now a days with the result of medical advances, the immunocompromised patients live longer in general environment accounting for increased incidence of invasive fungal infections requiring treatment.

At times, the distinction between mycetoma and chronic invasive sinusitisis difficult clinicaly and only possible by means of histopathology.  The respiratory mucosa in early invasive sinusitis may show areas of recent haemorrhage without frank necrosis, and hyphae confined to vessels.  In allergic fungal sinusitis and  chronic fungal sinusitis, the hyphae are sparse and are over mucosal surfaces and hence are not indentifiable it the mucinous material is not submitted for examination.

The management options depend upon histopathological type of sinonasal mycosis.

Allergic fungal rhinosinusitis (AFRS)

Clinically, the patient presents with recurrent rhinorrhoea, nasal obstruction, sneezing and nasal surgeries with the findings of nasal polyposis.  Computerised tomography scan shows pansinusitis with nasal polyposis.  Histopathology typicaly reveals allergic mucin with Charcot-Leyden crystals and fungal hypae with no mucosal invasion.  Bent and Kuhn mentioned criteria for diagnosing AFS by the evidence of type-1 hypersensitivity, nasal polyposis, characteristic CT findings, eosinophilic mucus, positive fungal smear.

Treatment involves initial functional endoscopic sinus surgery (FESS) with 3 principles-

1. Complete surgical removal of allergic mucin and debris greatly decreasing the antigenic load

2. Provide permanent drainage with ventilation to sinuses.

3. Postoperative access to the previously diseased sinuses.

Medical treatment is thereafter initiated with oral steroids prednisone is indicated in the patients of AFRS.

1. No mucosal oedema

2. Mucosal oedema with or without allergic mucin

3. Polypoid oedema with or without allergic mucin

4. Sinus polyps with fungal debris or allergic mucin

The patient is started at a dose of 0.4mg/kg/day of oral prednisone for 4 days and then 0.3mg/kg/day followed by 0.2mg/kg/day or 20 mg/day, whichever is greater, is obtained for a period of one month.  This is maintained till patient achieves stage '0'.  It is  maintained for 4 months.  Then dose is tapered to 0.1 mg/kg/day and intranasal steroids at dose of 1 puff in each nostril three times a day are started simultaneously.  If patient stays at stage 'o' for 2 months, oral steriods are tapered to zero intranasal steroids for period of one year.  Patients need to be followed up monthly for 6 months and 6 monthly for 5 years.

2.  Topical nasal sprays (intransal)

Budesonide, fluticasone, flunisolide and memetasone, etc. are various steroids which can be sprayed intranaslly one puff in each nostril two or three times a day for 6 months minimum with a given of 1 micro gm/dose for a total dose of 3 micro gms/day and patient is to be kept on follow up every six monthly for three to five years.  The dose given does not produce features of sterioid toxicity and is entirely safe but can lead to posterior subcapsular cataract rarely if used for very long time.  These agents inhibit locfal inflammatory mechanism by decreasing the production of inflammatory mediators inhibiting both early and late phase reactions.

3.  Antifungal agents

These are not routinely recommended in management of AFRS as chances of recurrence even after antifungal therapy are very high.

4.  Immunotherapy

It produces a decreased amount of crusting and polyposis as well as it reduces the need for systemic and topical steroids.  Small graded doses of allergens against which they are reactive are injected subcutaneously.  But the concerns associated with immunotherapy are:

1. Worsening of disease due to introduction of foreign extraneous fungal antigens.

2. Lack of availability of specific fungal antigens 

3. Type III Gel and Coomb's tissue damage occasionally

B.  Fungal ball

The patient presents clinically with nasal obstruction, purulent nasal discharge, anosmia or facila pain. Histopathology reveals extramucosal fungal hypae with no allergic mucin and no granulomatous reaction.  Treatment includes endoscopic debridement of fungal debris with provision of ventilation.

Antifungal agents are to be used only in

1. Immunocompromised cases.

2. In case recurrence is more than three times when itraconazole is used in dosage of 200 mg BD for 8-12 weeks till healing is complete.

Itraconazole

It is triazole antifungal agent which acts by inhibiting lanosterol 14 alfa-demethyulase, a cytochrome p450 dependent enzyme, decreasing production of ergosterol, leading to cell lysis and death.  It has a long plasma half-life 25-50 hrs hence once a dosage is sufficient.  It is a prefeered agent than ketoconazole, fluconazole because of better safety profile and no dosage adjustment required in renal dysfunction.  It is gien in dosage of 200 mg twice a day for a period of 12-24 weeks.  Main side effects are nausea, vomiting, abdominal pain rash and alopecia.  The liver function tests monitoring is recommended.  It is to be cautiously combined with antihistamines like terfenadine, astemazole and cisapride as it can produce fatal arrythmias in form of torsades de pointes.

Chronic invasive fungal sinusitis

The patient presents with features of tissue invasion i.e. orbital involvement or the disease going intracranially as well as extensively involving the sinuses and surrounding structures.  Histopathology reveals granulomata formation with mutinucleated giant cells, fibrinoid necrosis.  Treatment involves surgical debulking of disease, to be followed by antifungal agents.  The type of antifungal agent to be used, depends upon the immune status of individual.

a) Immunocompetent individuals

Azoles in the form of itraconazole 200 mg BD for 20-24 wks, is the recommended dosage or till patient is asymptomatic and radiology is clear.

b) Immunocompromised cases

In these cases, amphotercin-B and itraconazole combination is preferred.

Amphotercin-B is a polyene antifungal agent acting by binding to cytoplasmic ergosterol making pores in the membrane leading to intracellular electrolyte disturbance and cell death finally.  It requires inital test dose of 1 mg in 50 in 50ml of 5% dextrose.  Then it is to be given at a dose of 0.5-1.20 mg/kg body wt/day intravenously in 5% dextrose to a total dose of 2000-2500 mg.  the main side effects are electrolyte imbalance in the form of hypokalemia, hypomagnesemia, nephrotoxicity, rigor, chills, vomiting, fever, nausea etc.

Acute fulminant sinusitis

The patient presents with a short history of tissue necrosis in form of nasal discharge, paraesthesia over face and facial puffiness with fever.  Histopathology reveals vascularl invasion of fungus with fibrinoid necrosis and thrombotic ischaemia.  The treatment involves surgical debridement to be followed by prolonged medical therapy in form of amphotericin-B.  Itraconazole is to be added if profile is aspergillosis but has no role in mycormycosis.

Newer/investigational antifungal

Formulations of amphotericin B

1. Amphotericin- B lipid complex

2. Amphotericin- B cholesteryl/ester

3. Liposomal amphotericin -B

Main advantage lies in the fact that these drugs are safe in cases with renal dysfunction and are given in cases not tolerating conventional amphotericin- B.  CSF sterilization is easier with these agents.  The drawback is the higher cost and higher dosage required to produce the action because of low potency of these agents.  The dose given is 3-5mg/kg/day as compared from 1 mg/kg/day for the conventional variant.

Azoles

a.  Voriconazole

It is an azole antifungal agent which is derivative of fluconazole with both intravenous and oral formulations.  It has passed phase III trials and is available for use.  The dosage recommended are-6mg/kg/12 hrs x2 doses-3mg/kg 12 hrs for 30 days and is to be given intravenously and then 4 mg/kg BDx 20 weeks (orally).  The main side effects are increase in SGOT/PT with reverswible visual dysfunction.

b)  SCH5962

It is an azole which is being studied for its role in ivasive fungal sinusitis and is under phase II trial is considered to be more potent than Voriconazole.

c)  Revuconazole

It is azole that is going through phase II trial.  It has documented activity against aspergillus sps.  It is well tolerated in the dosage of 88 mg/day with the adverse effects of headache, abdominal pain, diarrhoea, rash and pruitis.

Allylamines

Terbinafine

It is an allylamine inhibiting the synthesis of ergosterol by inhibiting the enzyme squalene epoxidase.  It is also undergoing trial for its use in invasive fungal sinusitis.  It is metabolized in liver and is excreted in the urine and hence dosage adjustment are required in hepatic and renal dysfunction.  It can lead to gastrointestinal upset, rash and occasionally dysguesia.

Other allylamines under trial are naftifine and butenafine.

Echionocandins

These work by inhibting 1,3 beta glucan synthesis which is critical component of the cell wall resulting in the cell wall weakening and cell lysis and cell death.

Capsofungin

It is an echinocandin antifungal agent.  It is now FDA approved drug for patients with invasive aspergillosis not tolerating or poor candidates for amphotercin- B therapy.  It is to be given at a dosage of 70mg/day intravenously for a period of 14 days.  The main side effects are phlebitis, rash, fever and headach.

Other agents under trial are

1. Anidulafungin

2. Micafungin

Sordarins

These are antifungal peptides inhibiting chitin synthesis.  The agent undergoing trial is nikkomicin.

Methods to overcome resistance to the antifungal agents.

Prophylactic therapy:  It is sometimes used in case of 

1. Neutropenia

2. Bone marrow/solid organ transplants

3. Post surgery in recurrent cases.

The drug used most commonly is amphoterein - B at a dosage of 0.1 mg/kg/day intravenously²⁵.

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