Antimicrobials are considered as the greatest discovery of the twentieth century. In the pre-antibiotic era, infectious diseases accounted for significant morbidity and mortality and invasive medical procedures were fraught with the risk of infection. All this changed with the use of antimicrobial agents. But the miracle seems to be short lived. Irresponsible and erratic use of these life-saving instruments has resulted in the development of drug resistance in many organisms and deaths due to hospital-acquired infections is on the rise. It appears that our complacency is leading us into bigger problems in the millennium that has just dawned.
The first antimicrobials were discovered in the mid-20’s and many new molecules were discovered between 1960 and 1980. This ‘golden era of antibiotics’ saw a dramatic fall in the mortality from infections. Since the 80’s, not many new class of molecules have been discovered and the funding into antimicrobial research is on the decline and now deaths due to resistant infections is slowly increasing; in the U.S., mortality due to nosocomial infections is now 4 times that due to road traffic accidents.
Antibiotics are Life Saving drugs..
As all infections are potential threats to life, antibiotics are life-saving instruments, comparable to mechanical ventilation, dialysis and other advanced life-support devices. They are largely responsible for improved quality of life and increased life expectancy. Being weapons of such importance, they should be used with all the care and caution.
Why do doctors over-prescribe antibiotics?
70-80% of prescriptions for antimicrobials are probably written unnecessarily
“Antibiotics have been given for everything from headaches to ingrown toenails; they are swallowed, sucked, injected and smeared; they are painted on cuts, dumped into wounds, fed to the chickens and pigs and spread on the floors of the hospital wards.”
-Dr. Richard Novick
The following are the reasons:
- Lack of confidence: While it is very easy to scribble a prescription, it takes a fair amount of courage to avoid unnecessary prescriptions. Inability to make a fairly accurate clinical diagnosis is one of the most common causes for over-drugging. Inability to convince the patient about the nature and simplicity of the illness and about the non-requirement of antibacterials is another reason. Some doctors may harbour a notion that it is better to give “something powerful” for every patient so as to achieve “dramatic” results (Shot Gun therapy). But the fact remains that most patients do not demand any particular prescription from their doctor and many are indeed happy if they are explained about their problem and prescribed as less drugs as possible. Fear of law-suits for ‘negligence’ (‘act of omission’) and hence ‘defensive’ practice may also be another reason.
- Peer pressure: Some doctors may have a fear that if they do not prescribe, their ‘next door’ colleague may prescribe these ‘powerful’ drugs and get all the credit for ‘curing’ the patient. To avoid this ‘loss of practice’ they tend to prescribe these ‘powerful’ remedies. This is another face of ‘defensive’ practice.
- Patient pressure: Rarely, however, one may come across patients, some of them with half-knowledge, who insist on a prescription for antibacterials so as to “get better at the earliest” (because they are “very busy and have no time to lie down in bed”) or to “avoid any hassles”, particularly in cases of children and the elderly. Although in such situations it is the duty of the doctor to resist any such pressures, some doctors may yield to these pressures, often to appease the patients and to ‘save’ their practice.
- Company pressure: With hundreds of pharmaceutical companies and thousands of medical representatives, it is natural to come under some pressure for prescribing these drugs, which earn handsome profits for the drug industry. (“Volume building products, Sir”, the representative would tell us). With competition hotting up, the companies seem to mislead the doctors about the indications, suppress the facts on adverse effects and hide the facts on cost of therapy. Recently there is a dangerous trend of ‘combining’ antibacterials and marketing them for imaginary diseases. Many of the so called ‘newer’ antibiotics (which are in fact nothing more than modifications of existing molecules) are priced exorbitantly (even hundred times more than their older congeners) without offering any benefits over the older, time tested drugs. But it has become rather fashionable to prescribe these drugs, with many doctors feeling that ‘costlier must be better’.
The Three Most Common Situations For Antibiotic Abuse
It has been observed that the three commonest reasons for prescribing antibacterials are fever, sore throat and diarrhoea. In all these three situations, antibiotics are most often prescribed unnecessarily. Viruses being more abundant, these diseases are also most often due to the viral infections and antibacterials have no role to play in their management. Use of antibacterials in non-bacterial illness results only in the destruction of susceptible bacteria and selective proliferation of resistant bacteria, thus aiding the propagation of bacterial drug resistance.
Fever: It is a manifestation of hundreds of diseases, infective and non-infective. Antibacterials DO NOT have any beneficial effects in cases of fever due to non-bacterial causes. Self-limiting viral infections are the commonest infectious causes for fever and antibacterials have no role to play in their management, neither do they shorten the duration of the illness nor do they “prevent secondary infections”. Premature, presumptive and indiscriminate use of antibacterials in all cases of fever adds to the cost of therapy, adverse effects (ampicillin rash in infectious mononucleosis being a classic example!), development of drug resistance and may mask the signs of bacterial infection, making a proper diagnosis difficult. Therefore, the urge to prescribe antibacterials in all cases of fever should be curbed. All attempts should be made to localize the site and type of the infection. Empirical antibacterial therapy should be reserved only for emergencies. High grades of ‘fever’ may be managed with antipyretics like paracetamol or mefenamic acid (and not NSAIDs or their combinations, the ‘wonder pills’ for ‘pain and fever’!) and it should never be forgotten that antimicrobials are NOT antipyretics.
Sore throat: It is probably the commonest illness where antibacterials are misused the most. Although it accounts for 13% of all office visits, it has been found in various studies that only 8 to 20% of persons with a sore throat make a visit to a general practitioner (and in the other 80-90% it cures spontaneously!). Streptococcal sore throat is almost unknown in children below the age of 2 years and uncommon below 4 years. Roughly 10 to 20% of persons who present to an out-patient department will have group A Streptococci on throat culture and the other 80 to 90% with a sore throat will have a negative throat culture. But using clinical judgment alone will mean that 20 to 40% (or even more) of this large group of persons will receive antibiotics. Randomized trials designed to show the benefits of antibiotics over aspirin or acetaminophen in adults with sore throat have shown either no difference or a modest benefit. In most trials, the fever difference was one degree Celsius or less and it was not determined if patients felt this as an important difference. A survey of physicians in 17 European countries reported that fever in patients with tonsillitis resolved itself in two or three days, with or without antibiotic treatment. Therefore routine use of antibacterials in cases of sore throat is often uncalled for.
The Sore Throat Score developed by a group of American emergency room physicians for the clinical diagnosis of Group A Streptococcal (GAS) pharyngitis in adults can be useful in making a clinical diagnosis of Streptococcal infection (particularly in adults) and may help in decisions about antibacterial use. It includes the following four signs: 1. Tonsillar exudate 2. Swollen anterior cervical nodes 3. A history of a fever of more than 380 C. 4. Lack of a cough.
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The Sore Throat Score for Group A Streptococcal (GAS) infection |
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|
Score |
Chance of GAS |
% of patients |
Treatment |
|
None |
2.5% |
15% |
Only symptomatic |
|
One |
6-7% |
30% |
,, |
|
Two |
14-17% |
25% |
Throat swab; antibiotics after report |
|
Three |
30-34% |
20% |
,, |
|
Four |
56% |
10% |
Throat swab and antibiotics |
If the score is one or less (about 45% of patients and chance of GAS less than 10%), only symptomatic treatment is indicated. For scores 2 and 3 (45% of patients, and chance of GAS 14-34%), a throat swab culture should be taken and only symptomatic treatment should be prescribed until the culture report is available. Antibiotics should be prescribed only if the culture shows a bacterial infection. If the score is four (only 10% of patients and chance of GAS 56%), a throat swab culture should be obtained and antibiotics can be started if the situation demands. By following this simple method, 70-80% of antibacterial prescriptions for sore throat can be avoided, saving crores of rupees every year.
Diarrhoea: It is another condition where antibacterials are often over-prescribed. While there are many causes for diarrhoea, infective and non-infective, the fact remains that most of them are self-limiting and require only adequate rehydration. In all doubtful cases, a stool examination should be done for ova, cyst, blood and hanging drop if cholera is suspected. Stool culture can be done in the presence of severe and/or bloody diarrhoea, fever and systemic toxicity. Presence of polymorphonuclear leukocytes on Wright’s or Methylene blue staining usually suggests infection with Salmonella, Shigella, invasive E. coli, Yersinia, or E. histolytica. Indications for antimicrobial therapy in diarrhoeal diseases would include patients with high fever, bloody diarrhoea, severe dehydration, systemic toxicity, extremes of age, malignancy, immunocompromise, abnormal heart valve, vascular or cardiac prosthesis and hemolytic anemia, history of recent antibiotic use, recent travel, outbreak of food poisoning in the community and in patients suffering from Shigellosis, cholera, traveler’s diarrhoea, parasitic diarrhoeas and pseudomembranous enterocolitis.
The recent trend of the drug companies marketing combinations of quinolones and nitroimidazoles (like tinidazole) for “mixed diarrhoeas” should not only be discouraged, but also opposed.
The ‘Combined Antibacterial’ Wonder Pills From India!
|
Combination |
Number of brands available |
| Ciprofloxacin + Tinidazole | 37 brands |
| Nalidixic acid + Metronidazole | 13 brands |
| Norfloxacin + Metronidazole | 6 brands |
| Ofloxacin + Tinidazole | 2 brands |
| Furozolidone + Metronidazole | 14 brands |
“Mixed infections” with bacteria and amoeba are never known to occur and this ‘mixing’ is done by the drug industry to sell two drugs for indications where none may be needed. It is a matter of shame for all of us if the claims of the drug industry that these ‘combined, easy-for-the-doctor pills’ (now totaling more than 70 brands!) have a market share of nearly Rs.200 crore should be true.
Rational Use of Antibiotics
Antibiotics are the most important weapons in our hands. Each one of them have been invented after spending considerable amount of time, energy and money. Therefore, we cannot afford to lose them. We must exercise considerable restraint in prescribing antibacterials and restrict the use of antibacterials to only certain definite indications.
Indications for antibacterial therapy:
- Definitive therapy: This is for proven bacterial infections. Antibiotics (read antibacterials) are drugs to tackle bacteria and hence should be restricted for the treatment of bacterial infections only. This may sound silly, but most doctors seem to forget this simple fact! Attempts should be made to confirm the bacterial infection by means of staining of secretions/fluids/exudates, culture and sensitivity, serological tests and other tests. Based on the reports, a narrow spectrum, least toxic, easy-to-administer and cheap drug should be prescribed.
- Empirical therapy: Empirical antibacterial therapy should be restricted to critical cases, when time is inadequate for identification and isolation of the bacteria and reasonably strong doubt of bacterial infection exists: septicemic shock/ sepsis syndrome, immunocompromised patients with severe systemic infection, hectic temperature, neutrophilic leukocytosis, raised ESR etc. In such situations, drugs that cover the most probable infective agent/s should be used.
- Prophylactic therapy: Antimicrobial prophylaxis is administered to susceptible patients to prevent specific infections that can cause definite detrimental effect. These include antitubercular prophylaxis, anti rheumatic prophylaxis, anti endocarditis prophylaxis and prophylactic use of antimicrobials in invasive medical procedures etc. In all these situations, only narrow spectrum and specific drugs are used. It should be remembered that there is NO single prophylaxis to ‘prevent all’ possible bacterial infections.
What antibacterial?
There are more than 100 antibacterials available today, and each one has its own spectrum of activity, adverse effect profile and cost. The doctor should consider many factors before prescribing an antibacterial agent so as to make the treatment most effective with least adverse effects and cost.
The following factors should be considered while prescribing an antibacterial agent:
- Site of infection
- Type of infection
- Severity of infection
- Isolate and its sensitivity
- Source of infection
- Host factors
- Drug related factors
Site of infection:
As a Rule Of The Thumb, it can be remembered that the infections above the diaphragm are caused by Cocci and Gram positive organisms and infections below the diaphragm are caused by Bacilli and Gram negative organisms, although there are exceptions.
Examples:
Infections above the diaphragm: Upper respiratory tract infections like pharyngitis, tonsillitis, sinusitis, otitis, epiglottitis etc. are commonly caused by organisms like Streptococcus pyogenes, S. pneumoniae, Fusobacteria, Peptostreptococci (rarely Mycoplasma, H. influenzae) etc. and can be treated with drugs like Penicillins, Cephalosporins and Macrolides. Lower respiratory tract infections like bronchitis, pneumonitis, pneumonia, lung abscess etc. are generally caused by the organisms Streptococcus pyogenes, S. pneumoniae, Fusobacteria, Peptostreptococci, Staphylococcus aureus (rarely Mycoplasma, H. influenzae, Moraxella, Klebsiella) etc. and can be also managed with Penicillins, Cephalosporins, Macrolides and Tetracyclines.
Infections below the diaphragm: Examples include urinary tract infection, intra-abdominal sepsis, pelvic infections etc. and these are caused by the organisms like E. coli, Klebsiella, Proteus, Pseudomonas, Bacteroides etc. Quinolones, Aminoglycosides, 3rd generation cephalosporins and Metronidazole, alone or in combination are useful in these infections.
There are certain sites where the infection tends to be difficult for treatment: meningitis (impenetrable blood-brain barrier), chronic prostatitis (non-fenestrated capillaries), intra-ocular infections (non-fenestrated capillaries), abscesses (thick wall, acidic pH, hydrolyzing enzymes etc.), cardiac and intra-vascular vegetations (poor reach and penetration), osteomyelitis (avascular sequestrum) etc. In such cases higher dose, more frequent administration, longer duration, antibacterial combinations and lipophilic antibacterials may have to be used.
Type of infection: Infections can be localised or extensive; mild or severe; superficial or deep seated; acute, sub acute or chronic and extracellular or intracellular. For extensive, severe, deep seated, chronic and intracellular infections, higher and more frequent dose, longer duration of therapy, combinations, lipophilic drugs may have to be used.
Severe infections (bacteremia / pyemia / sepsis syndrome / septic shock; abscesses in lung/ brain/ liver/ pelvis/ intra-abdominal; meningitis/ endocarditis/ pneumonias/ pyelonephritis/ puerperal sepsis; severe soft tissue infections / gangrene and hospital acquired infections) can be life threatening and rapidly fatal. In such situations the drug absorption, distribution and excretion could be altered due to tissue hypoxia, changes in hemodynamics, renal and hepatic perfusion, GI absorption etc. The drug dynamics can also be altered due to acidosis, altered permeability, presence of hydrolysing enzymes at the site of infection etc. Also in such situations, possibility of infection with multiple organisms and of drug resistance make the choice difficult. In all such situations therefore, attempts should be made to identify and isolate the infecting organism from the site as well as blood by staining (of infected specimen and buffy coat smear) and culture (of infected specimen and two specimens of blood). In treating the severe infections, drugs should be administered by only intravenous route to ensure adequate blood levels. Only bactericidal drugs should be used to ensure faster clearance of the infection. If the site of infection is known, narrow spectrum drugs should be used. If the site is unknown, attempt should be made to cover all possible organisms, including drug resistant Staphylococcus, Pseudomonas and anaerobes. A combination of penicillins/3rd generation cephalosporins, aminoglycosides and metronidazole may be used. The dose should be higher and more frequent. Whenever possible, a switch to oral therapy should be made.
Isolate and sensitivity: Ideal management of any significant bacterial infection requires culture and sensitivity study of the specimen. If the situation permits, antibacterials can be started only after the sensitivity report is available. Narrow spectrum, least toxic, easy to administer and cheapest of the effective drugs should be chosen. If the patient is responding to the drug that has already been started, it should not be changed even if the in vitro report suggests otherwise.
Source of infection: Community acquired infections are less likely to be resistant whereas hospital acquired infections are likely to be resistant and more difficult to treat (e.g. Pseudomonas, MRSA etc.).
Host factors: Age of the patient, immune status, pregnancy and lactation, associated conditions like renal failure, hepatic failure, epilepsy etc. should be considered in choosing the antibacterial agent.
Age:
Infants: Chloramphenicol (can cause grey baby syndrome) and sulfa (can cause kernicterus) are contraindicated.
Below the age of 8 years: Tetracyclines are contraindicated because they are known to discolour the teeth.
Below the age of 18 years: All fluoroquinolones are contraindicated because they are known to cause arthropathy by damaging the growing cartilage.
Elderly: In the elderly, achlorhydria may affect absorption of antibacterial agents. Drug elimination is slower, requiring dose adjustments. Ototoxicity of aminoglycosides may be increased in the aged.
Compromised immune status:
In patients with extremes of age, HIV infection, diabetes mellitus, neutropenia, splenectomy, using corticosteroids or immunosuppressants, patients with cancers / blood dyscrasias, ONLY bactericidal drugs should be used. And it is indeed debatable whether antibacterials should be used to treat infections like aspiration pneumonia, UTI, catheter infections, infections through life support systems, pressure sores etc. in patients who are terminally ill (brain dead, patients with massive stroke, terminal cancers, advanced age, terminal AIDS etc.).
Pregnancy:
Drugs with known toxicity or un-established safety like tetracyclines, quinolones, streptomycin, erythromycin estolate and clarithromycin are contraindicated in all trimesters and sulfa, nitrofurantoin and chloramphenicol are contraindicated in the last trimester. Drugs with limited data on safety like aminoglycosides, azithromycin, clindamycin, vancomycin, metronidazole, trimethoprim, rifampicin and pyrazinamide should be used with caution when benefits overweigh the risks. Penicillins, cephalosporins, INH and ethambutol are safe in pregnancy. In lactating mothers sulfa, tetracyclines, metronidazole, nitrofurantoin and quinolones are contraindicated.
Renal failure:
Tetracyclines are absolutely contraindicated; aminoglycosides, cephalosporins, fluoroquinolones and sulfa are relatively contraindicated; and penicillins, macrolides, vancomycin, metronidazole, INH, ethambutol and rifampicin are relatively safe. It is better to avoid combinations of cephalosporins and aminoglycosides in these patients because both these classes of drugs can cause nephrotoxicity.
Hepatic failure:
No drugs are absolutely contraindicated; chloramphenicol, erythromycin estolate, fluoroquinolones, pyrazinamide, rifampicin, INH and metronidazole are relatively contraindicated and penicillins, cephalosporins, ethambutol and aminoglycosides are safe.
Drug factors:
- Hypersensitivity: If the patient has prior history of hypersensitivity the concerned antibacterial agent should be avoided. It is therefore important to elicit this history in all patients.
- Adverse reactions: Certain adverse reactions warrant discontinuation of therapy and the doctor should adequately educate the patients on these adverse effects.
- Interactions: Interactions with food and other concomitant drugs should be considered before instituting antibacterial therapy so as to maximize efficacy and minimize toxicity.
- Cost: Lastly, but not the least, the cost of therapy should be considered in choosing the antibacterial agent and in a developing country like India with limited spending on healthcare, this does assume significance. It should always be remembered that just because a particular drug is expensive, it need not be superior than the cheaper ones. For example, cheaper drugs like doxycycline or co-trimoxazole would be as effective as the costlier clarithromycin or cephalosporins in the management of LRTI.
Choice of Antibiotics
|
Site of infection |
Type of infection |
Drugs of choice |
Duration of treatment |
|
Upper respiratory tract infection |
Throat infections | Erythromycin or amoxycillin or penicillin V | 10 days for Group A Streptococcal infections, 10-14 days for mycoplasma. |
| Sinusitis | Amoxycillin or doxycycline or erythromycin | 2 weeks | |
| Otitis media | Amoxycillin or erythromycin | 7 days | |
|
Lower respiratory tract infection |
Bronchitis | Amoxycillin or co-trimoxazole or tetracycline | 7 days |
| Uncomplicated pneumonia | Amoxycillin or benzyl penicillin or erythromycin | 7 days | |
| Severe pneumonia of unknown aetiology | Erythromycin plus cefuroxime or cefotaxime | 7-10 days | |
| Suspected atypical pneumonia | Erythromycin | 10-14 days | |
| Hospital acquired pneumonia | Cefotaxime or ceftazidime or an antipseudomonal penicillin plus an aminoglycoside | 7-10 days | |
|
Urinary tract infection |
Lower urinary tract infection | Fluoroquinolone or Co-trimoxazole or amoxycillin or nitrofurantoin | 3-7 days |
| Upper urinary tract infection, pyelonephritis or prostatitis | Fluoroquinolones or co-trimoxazole or gentamicin or cephalosporins | 10-28 days | |
| Pelvic inflammatory disease | Doxycycline plus metronidazole | Metronidazole for 7-14 days and doxycycline for 14-21 days | |
|
Skin infections |
Impetigo | Topical fusidic acid or mupirocin; erythromycin if wide spread | 7-10 days |
| Cellulitis | Amoxycillin plus cloxacillin or erythromycin or co-amoxyclav | 7-10 days | |
|
Surgical |
Clean (cardiac, vascular, neurologic or orthopaedic) | Cefazolin | Before and during procedure |
| Clean-contaminated (head and neck, high-risk gastroduodenal or biliary tract surgery; caesarian section; hysterectomy) | Cefazolin | Before and during procedure | |
| Clean-contaminated (colorectal surgery or appendicectomy) | Cefoxitin or 3rd gen. Cephalosporins plus metronidazole | Before and during procedure | |
| Dirty (ruptured viscus) | Cefoxitin plus gentamicin or 3rd gen. Cephalosporins plus metronidazole | Before and 3-5 days after procedure | |
| Dirty (traumatic wound) | Cefazolin | Before and for 3-5 days after trauma | |
Antimicrobial agents for common use
|
Drug |
Route of administration |
Dose and frequency of administration |
Contra indications/ caution |
Interactions |
Adverse effects |
|
Penicillin G |
Intramuscular, Intravenous |
10-20 L Units every 2 to 6 hrs. |
Hypersensitivity |
None significant |
Hypersensitivity- rashes, anaphylaxis, fever, joint pains, angioedema, serum sickness like reaction, blood disorders, C.N.S. toxicity in high doses; colitis and diarrhoea; ampicillin rashes are more common in infectious mononucleosis, chronic lymphatic leukemia and HIV infection. |
|
Penicillin V |
Oral |
400-800 mg every 6-8 hours |
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|
Ampicillin |
Oral, intravenous |
New born (<1 wk): 25-50 mg/kg 12 hrly 1-4 wks: 100-200 mg/kg/day 8th hrly Older children: Same dose 6 hourly Adults: 1-12 g/day, 6 hourly |
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|
Amoxycillin |
Oral, intravenous |
Oral: 250 mg-1g every 8 hourly; Severe RTI: 3 g 12 hourly Intravenous: 500 mg -1 g every 6-8 hrs., Children- 50-100 mg/kg in 3-4 doses. |
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|
Cephalexin |
Oral |
250mg-1 g every 6 hours |
Hypersensitivity, renal failure, porphyria |
Hypersensitivity rashes, joint pains, rarely anaphylaxis; abdominal discomfort; colitis; erythema multiforme; reversible interstitial nephritis; transient hepatitis; blood disorders; dizziness etc. |
|
|
Cefazolin |
Intravenous |
1-1.5 g every 6 hours |
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Cefadroxil |
Oral |
1 g every 12 hours |
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Cefuroxime |
Intravenous, oral (axetil) |
Up to 3 g every 8 hours i.v. |
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|
Cefotaxime |
Intravenous |
1-2 g every 4-8 hours |
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Ceftriaxone |
Intravenous |
1-2 g every 12-24 hours |
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|
Ceftazidime |
Intravenous |
1-2 g every 8 hours |
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|
Cefoperazone |
Intravenous |
1.5 to 4 g, 6-8 hrly |
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|
Gentamicin |
Intramuscular, intravenous |
Adults: 2 mg/kg loading dose, then 3-5 mg/kg per day, every 8 hours |
Renal failure; myasthenia gravis; |
Ototoxicity may worsen with potentially ototoxic diuretics like furescemide |
Ototoxicity, nephrotoxicity, more common in the elderly and in renal failure; may impair neuromuscular transmission and may cause transient myasthenia |
|
Amikacin |
Intramuscular, intravenous |
15 mg/kg/day in 2-3 equally divided doses |
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|
Tetracycline |
Oral |
Adults: 1-2 g/day in 2-4 doses. |
Pregnancy, lactation; renal impairment; children below 8 years; SLE |
Antacids reduce absorption; anticonvulsants increase metabolism of doxycycline, calcium salts, oral iron and zinc reduce absorption; sucralfate and bismuth salts reduce absorption. |
Nausea, vomiting diarrhoea; erythema (discontinue); benign intracranial hypertension; colitis |
|
Demeclocycline |
Oral |
150 mg 6 hourly or 300 mg 12 hourly in adults |
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|
Doxycycline |
Oral |
100 mg twice daily on the first day, then 100 mg once or twice a day depending on the severity of infection |
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|
Erythromycin |
Oral |
>8 years: 250-500 mg every 6 hours or 0.5-1 g every 12 hrs 2-8 years: 250 mg every 6 hours < 2years: 125 mg every 6 hours |
Hepatic and renal impairment; prolonged QT interval; porphyria; estolate in liver disease |
Avoid use with astemizole, terfenadine, pimozide, midazolam, zopiclone, cisapride; increases theophylline levels |
Nausea, vomiting, abdominal discomfort; diarrhoea; rashes; arrhythmias; cholestatic jaundice |
|
Norfloxacin |
Oral |
400 mg twice daily for 3-7 days for UTI |
Age less than 18 years; pregnancy and lactation; epilepsy; hepatic and renal impairment |
Increased risk of convulsions with NSAIDs; antacids reduce absorption; anticoagulant effects of coumarins enhanced; iron and zinc reduce absorption; increases levels of theophylline, avoid concomitant use. |
Nausea, vomiting, diarrhoea, headache, dizziness, sleep disorders, rash, pruritus, anaphylaxis, increase in urea, creatinine and liver enzymes, arthralgia and myalgia, blood disorders, restlessness, hallucinations, depression, tendon damage |
|
Ciprofloxacin |
Oral, intravenous |
Oral: UTI: 250-500 mg twice daily Intravenous: 200-400 mg over 30-60 minutes, twice a day |
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|
Co-trimoxazole |
Oral |
Adult: 960-1.44 g twice daily; 480 mg twice daily if used for >14 days. Children:120-480 mg 12 hourly |
Hepatic and renal impairment; blood disorders; G6PD deficiency; breast feeding |
Enhanced effects of warfarin, sulfonylureas, phenytoin |
Nausea, vomiting, rash, Steven Johnson syndrome (discontinue), blood disorders (discontinue), glossitis, arthralgia, liver damage, colitis, eosinophilia, tinnitus, interstitial nephritis |
|
Metronidazole |
Oral, intravenous |
800 mg initially, then 400 mg 8 hrly; Intravenous: 500 mg 8 hrly. Children: 7.5 mg/kg 8 hourly |
Hepatic failure, pregnancy and lactation, |
Disulfiram like reaction with alcohol; enhances effect of anticoagulants, phenytoin; increases toxicity of lithium |
Nausea, unpleasant taste, furred tongue, headache, drowsiness, anaphylaxis, rashes. |
|
Nitrofurantoin |
Oral |
50-100 mg every 6 hours |
Renal impairment; G6PD deficiency; full term pregnancy and lactation; major organ failure | Magnesium trisilicate retards absorption |
Anorexia, nausea, vomiting, acute and chronic pulmonary reactions; SLE like syndrome; rashes etc. |
Methods of administration of antimicrobials
Route of administration: The route of administration depends on the site, type and severity of the infection and the availability of a suitable drug.
Oral route is the most preferred, easy and cheap, but it may not be reliable in all circumstances, particularly in patients with severe infections, non-compliant patients, in the presence of vomiting etc. Certain drugs like the aminoglycosides and most 3rd generation cephalosporins are not available for oral administration.
Intramuscular route should be generally restricted for the administration of procaine and benzathine penicillin and single shot of ceftriaxone; the absorption is not very reliable and it is painful and disliked by the patients.
Intravenous route is the best for the management of severe and deep-seated infections since it ensures adequate serum drug levels. Procaine penicillin and benzathine penicillin should never be given I.V. However, some drugs are not available for parenteral use (e.g. most macrolides, sulfa, tetracyclines).
Topical: Antibacterials are also used topically, but drugs used for systemic administration should not be used in skin ointments.
Dosage: Dose depends on the age of the patient, weight of the patient, associated conditions like pregnancy, renal and hepatic failure and site, type and severity of infection. Generally the dose should be higher in cases of severe, deep-seated infections and in pregnancy and lower in cases of renal failure. While unnecessary overdosage only adds to the cost and adverse effects, there should not be any compromise on adequate dose.
Frequency of administration: The drug should be administered 4-5 times the plasma half-life to maintain adequate therapeutic concentrations in the serum throughout the day. Frequency can be increased in cases of severe, deep seated and sequestrated infections and reduced in cases of renal and hepatic failure.
Duration: Duration of therapy depends on the site, type and severity of infection. (e.g. Tonsillitis-10 days; bronchitis-5-7 days; UTI-single shot to 21 days; lung abscess-2-8 weeks; tuberculosis-6-24 months etc.).
Combinations: Judicious and intelligent combination of different antibiotics can be very useful in treating certain difficult infections and in preventing or overpowering resistance. On the other hand irrational and unnecessary combinations can add to the cost and adverse effects and help in the development of drug resistance.
Antibacterial combinations can be useful in the following situations:
1. To sharpen the effect: Synergistic combination of two static drugs – e.g. Combination of Trimethoprim and Sulfamethoxazole – Co-Trimoxazole
2. Treatment of infections with multiple organisms: Mixed infections in lung abscess, peritonitis, soiled wounds etc., naturally require multiple antibiotics for complete clearance of the infection – Penicillins (for gram positive and certain anaerobes) + Aminoglycosides (for gram negative); metronidazole for bacteroides etc.
3. To prevent resistance: Use of combinations is a well known method of preventing drug resistance. The classic example is the antitubercular therapy.
4. To overcome resistance: Combination of specific drugs can be useful in overcoming the resistant infections. Examples include Penicillins + b lactamase inhibitors/b lactamase resistant penicillins for S. aureus; Penicillins/cephalosporins + aminoglycosides for Pseudomonas etc.
The following combinations are irrational, not useful or even harmful:
Combinations of bactericidal with bacteristatic drugs (e.g. Penicillins with tetracyclines);
Combinations of drugs with similar toxicity (e.g. chloramphenicol and sulfa)
Combining drugs for non-existing ‘mixed infections’ (e.g. tablets of ciprofloxacin + metronidazole/tinidazole).
Response to treatment: It depends on the nature and sensitivity of the agent, specificity of the drug, bio-availability and dosage. Longer the doubling time of the organism, longer the time it takes to respond. Thus a Streptococcal pneumonia can respond within 24 -48 hours, but tuberculosis may take 2-8 weeks to respond. One should have the patience to wait for the adequate period before changing the drug (e.g. S. pneumoniae infections – 24-48 hours; E. coli – 24-48 hours; S. typhi – 4-7 days; M. tuberculosis – 2-8 weeks etc.). Drugs should be changed midway only when there is absolutely no response or there is no expected response and the sensitivity report also suggests resistance.
Resistance to Antimicrobial Agents
Resistance to antimicrobial agents is one of the greatest problems faced by the medical community. These powerful weapons, developed by spending millions of dollars and years of dedicated research, have been rendered less effective or totally ineffective only because of our own negligence and complacence. This is indeed frustrating.
The following table provides on overview of some of the recent examples of resistance to antimicrobials:
|
Organism |
Resistance |
|
Gram Positive cocci |
Methicillin resistant Staph. aureus and coagulase negative Staphylocci, penicillin resistant Pneumococci, macrolide resistant Streptococci, vancomycin resistant Enterococci. |
|
Gram negative cocci |
Penicillin, quinolone resistant gonococci. |
|
Gram negative bacilli |
Enterobacteriaccae resistant to B lactams and B lactamase inhibitors, multi drug resistant pathogens include Shigella, E. Coli, Salmonella. |
|
Acid fast bacilli |
Multi drug resistant M. tuberculosis. |
Factors contributing to antimicrobial resistance: Antimicrobial resistance, initially a problem in hospitals and developing countries, today affects the world at large. The reasons for resistance are many. The WHO reports that the antimicrobial agents are used by too many people to treat the wrong kind of infection in the wrong dosage and for the wrong period of time in both industrialized and developing countries. Increase in poverty, over crowded living areas, crowded day care centers have all contributed in spreading the resistant bacterial infection. The tremendous increase in the size of the high risk populations because of immunocompromise, the increased frequency of invasive medical interventions and prolonged survival of patients with chronic debilitating disease have amplified the problem.
Resistance to antimicrobial agents can be due to various mechanisms:
- Inability of the drug to reach the organisms
- Inactivation of the drug
- Alteration in the target
Resistance may be acquired by mutation and passed onto the next generations. It may also be acquired by horizontal transfer from a donor cell by transformation, transduction or conjugation.
Control of use of antimicrobial agents: The following methods can be used to control the use of antimicrobial agents in hospitals: Education programmes like staff conferences, lectures and audiovisual programmes; availability of clinical pharmacist consultants; control of contact between pharmaceutical representatives and staff physicians and of various sponsorships from companies; restriction of hospital formulary to minimum number of agents needed for most effective therapy; availability of diagnostic microbiology laboratory sensitivity tests and appropriate selection of sensitivity tests for organism and site; automatic stop orders for specific high-cost agents and written justification for high-cost agents etc.
Further Reading:
- McIsaac WJ, White D, Tannenbaum D, Low DE. A clinical score to reduce unnecessary antibiotic use in patients with sore throat. Can Med Assoc J 1998;158(1) Full Text at http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1228750&blobtype=pdf
- Danchin MH, Curtis N, Nolan TM, Carapetis JR. Treatment of sore throat in light of the Cochrane verdict: is the jury still out? MJA 2002;177(9):512-515 Full text at http://www.mja.com.au/public/issues/177_09_041102/dan10028_fm.html
- Del Mar CB, Glasziou PP, Spinks AB. Antibiotics for sore throat. Cochrane Database of Systematic Reviews 1997, Issue 3. Art. No.: CD000023. Available at http://www.cochrane.org/reviews/en/ab000023.html
- Linder JA, Bates DW, Lee GM, Finkelstein JA. Antibiotic Treatment of Children With Sore Throat JAMA. 2005;294:2315-2322. Full Text at http://jama.ama-assn.org/cgi/content/full/294/18/2315
- Bharathiraja R, Sridharan S, Chelliah LR, Suresh S, Senguttuvan M. Factors affecting antibiotic prescribing pattern in pediatric practice. Indian J Pediatr [serial online] 2005 [cited 2008 Apr 22];72:877-9. Available from: http://www.ijppediatricsindia.org/text.asp?2005/72/10/877/17027
- De Bruyn G, Hahn S, Borwick A. Antibiotic treatment for travellers’ diarrhoea. Cochrane Database of Systematic Reviews 2000, Issue 3. Art. No.: CD002242. Available at http://www.cochrane.org/reviews/en/ab002242.html
- Study shows excessive, inappropriate antibiotic prescriptions for sore throats Antibiotics needed in only 10 percent of adult sore throats Available at http://www.massgeneral.org/pubaffairs/releases/091101sorethroats.htm
- Prasad K, Kumar A, Singhal T, Gupta PK. Third generation cephalosporins versus conventional antibiotics for treating acute bacterial meningitis. Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD001832. At http://www.cochrane.org/reviews/en/ab001832.html
- Lewis R. The Rise of Antibiotic-Resistant Infections Available at http://www.fda.gov/Fdac/features/795_antibio.html
- Antimicrobial resistance. WHO Fact sheet N°194 (Revised January 2002) Available at http://www.who.int/mediacentre/factsheets/fs194/en/
- Antibiotic / Antimicrobial Resistance. CDC Website At http://198.246.98.21/drugresistance/index.htm
