GOI Antibiotic Guideline For Optimizing Use Of Key Antimicrobials

In 2016 National Centre For Disease Control, Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India came out with National Treatment Guidelines for Antimicrobial Use in Infectious Diseases.

Antimicrobial Prescribing: Good Practice

1. Send for the appropriate investigations in all suspected infections as recommended. These are the minimum required for diagnosis, prognosis and follow up of these infections.


2. All attempts shall be made to send microbiological samples prior to initiating antimicrobial therapy. Rapid tests, such as Gram stain, can help determine therapeutic choices when decision on empiric therapy is required.


3. Differentiation between contamination, colonization and infection is important to prevent overuse of antimicrobials. Use hospital guidelines based on local antibiograms when choosing antimicrobial therapy whenever possible. If alternatives to those recommended as used, reasons in the case records should be documented.


4. Prescribing antibiotics just in case an infection is present is rarely justified. Where patients are in hospital close observation is usually a better option till the diagnosis is made.


5. Choice of antibiotics: This depends on antibiotic susceptibility of the causative organism. There are some infections, which can be treated by one of several drugs. The choice can be based on Toxicity, Efficacy, Rapidity of action, Pharmacokinetics and Cost. Use the most effective, least toxic and least expensive antibiotic for the precise duration of time needed to cure or prevent infection. Pathogens specific guidance in hospital policy is encouraged.Before prescribing consider the following:

1. Which organism is likely to cause the disease?


2. What is the clinical diagnosis and what other steps should be taken to reach diagnostic precision?


3. Which antimicrobial agents are available and active against the presumed cause of the illness? Is their range of antimicrobial activity appropriate and what information is available about the likelihood of drug resistance?


4. . Check for factors, which will affect choice of drug and dose, e.g., renal function, interactions, allergy, pregnancy and lactation.


5. Check that the appropriate dose is prescribed. If uncertain, contact Infectious Diseases Physician or clinical microbiologist. Alternatively, check in the formulary.


6. What is the duration of treatment?


7. Is treatment working?

6. Clinical Diagnosis: The antibiotic treatment chosen must be based on presumptive diagnosis made on some assumption regarding the nature of disease. The treating doctor may not have difficulty in choosing the appropriate antibiotic to treat a disease caused by a single microorganisms e.g scarlet fever, typhoid, anthrax, as microbiological diagnosis is implicit in clinical diagnosis. However, diseases such as pneumonia, meningitis and urinary tract infection can be caused by spectrum of bacterial species and doctor may be wrong if he has to guess which antimicrobial agent to use. In such instances one should seek a bacteriological diagnosis.

7. Empiric Therapy - If the causative agent is not known and where delay in initiating therapy would be life threatening or risk serious morbidity, antimicrobial therapy based on a clinically defined infection is justified and the following points should be taken into consideration :

1. Do not rush to treat.


2. Collect the necessary specimens before commencing therapy.


3. Cover all possible microbial causes.


4. Try to attain synergy.


5. Consider possible interaction with other drugs.


6. Accuracy of diagnosis should be reviewed regularly and treatment altered/stopped when microbiological results become available.


7. Use less costly drugs where possible

8. The need for antimicrobial therapy should be reviewed on a daily basis. For most infections 5 – 7 days of antimicrobial therapy is sufficient (simple UTI can be adequately treated with 3 days of antibiotic).

9. All IV antibiotics may only be given for 48 – 72 hours without review and consideration of oral alternatives. New microbiological or other information (e.g. fever defervescence for at least 24h, marked clinical improvement; low CRP) should at this stage often permit a switch to oral antibiotic(s), or switch to an IV narrow spectrum alternative, or cessation of antibiotics (no infection present).

10. Once culture reports are available, the physician should step down to the narrowest spectrum, most efficacious and most cost effective option. If there is no step down availed, the reason shall be documented and is subjected to clinical audit.

11. Some guiding principles for de-escalation /Escalation:

1. If ESBL +ve: drug choice is monotherapy with carbepenems. Preferably choose group I carbepenem. Piperacillin –Tazobactum and Cefoperazone –Sulbactam can be used if in-vitro sensitive and for mild infections.


2. Vancomycin should be used only for confirmed MRSA infections and not in MSSA infections.


3. In case of Pan drug resistant Pseudomonas /Acinetobacter spp. combination therapy using colistin along with beta-lactams (using PK/PD principles) should be discussed with microbiologist / physician.

12.Treatment with antibiotic combinations: In order to avoid antagonism between drugs and undesirable side effects of several antibiotics it is advisable to use a single drug where ever possible. There are situations however, when the use of antibiotic combination is desirable. The situations are:

1. A temporary expedient during the investigation of an obscure illness.


2. To prevent the development of bacterial resistance in long term therapy e.g treatment of tuberculosis.


3. To achieve synergistic effect, e.g. in treating infective endocarditis.


4. Mixed infection, when one drug is not effective against the pathogen.


5. To permit a reduction of the dose of potentially toxic drug.

The choice of the drug should be that they act synergistically. The following combinations are synergistic

1. Aminoglycoside and beta–lactam antibiotic.


2. Beta –lactam antibiotic and beta–lactamase inhibitor.


3. Beta –lactam antibiotic and Glycopeptide (vancomycin/teicoplanin).


4. Sulphamethoxazole and Trimethoprim.

14. Is Treatment working?: Where treatment is apparently failing, advice from an ID physician/clinical microbiologist should normally be sought rather than blindly changing to an alternative choice of antimicrobial agent. Antimicrobial drug therapy cannot be considered in isolation and other aspects of therapy must be taken into account in judging the effect of treatment. Even an appropriate antibiotic may be ineffective unless pus is drained, septic shock treated and hypoxia and anemia corrected. There are several conditions in which chemotherapy alone cannot eliminate an infection. Obstructive lesions can cause infection to recur, unless they can be dealt with surgically. Also, chemotherapy cannot obviate the necessity for draining an abscess or removing sequestra or calculi. Failure of treatment can also be due to a super-added infection, e.g. phlebitis, development of resistance during therapy or poor tissue penetration.

13. Laboratory control of the effects of treatment: Whether treatment has been successful or not is best judged by clinical criteria, but it is useful to know whether the infecting organism has been eliminated. Reapeated cultures are, therefore sometimes indicated.

Reserve Antimicrobials
These reserve antimicrobials will be made available following a recommendation from the Microbiology Department as per culture report or if included in an antimicrobial policy for a clinical specialty that has been agreed with antibiotic management team. They are held in reserve to maintain their effectiveness in treating certain difficult infections by reducing the spread of microbial resistance and to encourage cost effective prescribing. Before a reserve antibiotic is issued to the ward, the pharmacist is instructed to ascertain the indication and if this falls outside the approved policy, to request that the prescriber consult the ID Physician/clinical microbiologist.

The following criteria has been proposed to protect the Carbapenems and Linezolid from overuse -

1. Severe sepsis as defined by more than one organ failure of new onset and/or elevated serum lactate.


2. Clinical failure of other classes of antibiotics over 48 hours in terms of worsening inflammatory markers, unresolving fever and new/worsening hemodynamic instability.


3. Underlying severe immuno-suppression – Neutropeniea, immuno-suppressive therapy, Diabetic Ketoacidosis (DKA) etc.


4. The organism is susceptible to only carbapenems / linezolid, as per culture report.

The following criteria has been proposed for initiating Colistin-

1. Pan-resistant organism as per culture report with evidence of invasive disease – fever/ leucocytosis/elevated procalcitonin (PCT) or culture from a sterile site.


2. Clinical failure of all other classes of antibiotics over 72 hours.

The following criteria has been proposed for initiating Rifampicin

1. Empiric or proven TB as a part of ATT (4 drug regimen)

Rifampicin should not be prescribed in our country for any treatment other than for Mycobacteria and for chemoprophylaxis of meningoccal meningitis in clinically indicated population

Rifampicin should not be prescribed alone as an anti-bacterial.

The following criteria has been proposed for initiating Aminoglycosides-

1. The focus of infection is not lung or an anaerobic abscess.


2. Only as a part of initial empiric regimen of a combination therapy – shall step down to single drug after culture report.


3. Other safer drug options have been ruled out in a culture report.

Hypersensitivity

All patients should be asked about drug allergies. This is the responsibility of the doctor caring the patient. If a patient reports a drug allergy clarify whether this is an allergy or drug intolerance. In some cases there will be an overlap between drug allergy and drug intolerance.

• Clinical features suggestive of drug allergy:
  One or more symptoms developed during or following drug administration including difficulty breathing, swelling, itching, rash, and anaphylaxis, swelling of the lips, loss of consciousness, seizures or congestion involving mucous membranes of eyes, nose and mouth.


• Clinical features suggestive of drug intolerance:
  One or more symptoms developed during or following drug administration including gastrointestinal symptoms e.g. nausea, vomiting, diarrhoea, abdominal pain and feeling faint.

If patients are unable to give an allergy history, the doctor caring in the patient should take reasonable steps to contact someone who can provide a reliable allergy history. It is the prime responsibility of the prescribing doctor to ensure that:

1. The allergy box on the patient’s drug chart is completed, when a new prescription chart is written or transcribed. If no allergy - specify "No known allergy". The box should be signed and dated. If allergy history cannot be obtained, then specify "history not available." Under no circumstances should the allergy box be left blank. A pharmacist or nurse may complete the allergy box if the allergy status is documented in the clerking in notes.


2. The allergy box is completed before prescribing a new drug, except in exceptional circumstances. If patients have a suspected drug allergy then the drug and suspected reaction. Should be documented in the clerking-in notes and the drug chart.

Alert Antimicrobials

To Prevent and Control the Emergence and Spread of Antimicrobial-Resistant Micro-organisms in Hospitals” one major strategic goal is to “define guidelines for use of key antibiotics”, (“Alert” antibiotics) targeted in these guidelines are ciprofloxacin, ceftazidime, cefotaxime, ceftriaxone, vancomycin (or teicoplanin), imipenem, levofloxacin, meropenem, moxifloxacin,piperacillin-tazobactam, linezolid (oral/IV), voriconazole, caspofungin, valganciclovir, ertapenem and newer preparations of amphotericin.

Collectively, these are among the drugs most frequently prescribed irrationally which is largely responsible for the current escalation of antibiotic costs. They also account for a significant proportion of serious antibiotic toxicity including Clostridium difficilediarrhoea and CNS toxicity/seizures as well as the emergence of major antimicrobial resistance. Safer, cheaper and equally effective alternatives are often available which allow such agents to be kept in reserve for occasions when there are clear cut microbiological indications. It is critical, therefore, that these Alert antibiotics be prescribed only on the recommendation of senior medical staff or after discussion with the on-call Clinical Microbiologist or ID physician.

Alert Antibiotics And Their Indications

1. CIPROFLOXACIN, INTRAVENOUS

Oral ciprofloxacin is well absorbed and this is therefore the preferred route of administration. Intravenous therapy is only indicated in the following situations:

• When the patient is unable to swallow or the oral route is otherwise compromised.


• In serious sepsis (e.g. nosocomial pneumonia in ITU) when the recommended dose is 400mg 8 hourly.

Common indications for ciprofloxacin in the Antibiotic Policy, either alone or in combination, are as follows:

• second line therapy in exacerbation of chronic bronchitis.


• pyelonephritis.


• acute inflammatory infective diarrhoeas.


• serious infected diabetic ulcers infected burn wounds with coliforms or Pseudomonas infection presen.


• treatment of documented or presumed gram-ve bacilli resistant to penicillins or cephalosporins or when the patient is allergic (history of anaphylactic reaction or rash) to these agents.


• selected haematology patients requiring prophylaxis.


• severe acute pelvic inflammatory disease.

2. CEFTAZIDIME

Limited use only. Main indication is documented or suspected Pseudomonas aeruginosainfection. Other indications currently listed in the Antibiotic Policy are as follows:

• Second line agent in neutropenic patients with septicaemia or pneumonia.


• Empiric therapy of CAPD associated peritonitis (not children), 1g IV stat then 125mg/litre in each bag.


• Empiric therapy of post operative, post traumatic or shunt associated meningitis.


• Empiric therapy of infective exacerbation of cystic fibrosis.

3. PIPERACILLIN - TAZOBACTAM
Currently listed in the antibiotic policy for the following:

• Pneumonia or septicaemia in neutropenic patients (+ Gentamicin).


• As a single agent (or in combination with Gentamicin) for treatment of sepsis which has not responded to first line treatment or if it is not appropriate for gentamicin to be added to first-line therapy.

4. CEFTRIAXONE
IV Ceftriaxone is currently listed in the antibiotic policy for the following:

• Epiglottitis


• Brain abscess,


• Bacterial meningitis,


• Pyelonephritis in children


• Empiric therapy of septicaemia in children


• In ascites for treatment of sub-acute bacterial peritonitis


• Skin and soft tissue infections managed via out-patients or the home IV antibiotic programme


• Acute septic monoarthritis if penicillin allergic


• Spontaneous bacterial peritonitis

5. APPROPRIATE USE OF CARBEPENEMS

• Very high rates (60-75%) of resistance to 3rd and 4th generation cephalosporins {due to extended spectrum betalactamases (ESBL) production} observed in E. coli and Klebsiella species.


• This pattern of resistance although seen primarily among nosocomially acquired infections, is also seen isolates of E coli and Klebsiella species isolated from community acquired infections.


• These strains of bacteria are frequently resistant to other major classes of antibiotics (fluoroquinolones, β-lactam + β- lactamase inhibitor(BL + BLI) combinations and aminoglycosides).


• Carbapenems (imipenem, meropenem and ertapenem), beta-lactam antibiotics with exceptionally broad spectrum of activity, are the only class of antimicrobials which remain effective against ESBL-producing isolates of E coli and Klebsiella species.


• Imipenem is susceptible to degradation by the enzyme dehydropeptidase-1 (DHP-1) located in renal tubules and requires coadministrationwith a DHP-1 inhibitor cilastatin. Meropenem and ertapenem are administered without a DHP-1 inhibitor.

Indications for carbapenem use:

1. Infections [e.g., bacteremia, pyelonephritis, intra-abdominal infections (peritonitis, cholangitis, abscesses), nosocomial pneumonia etc.] confirmed (by appropriate culture and susceptibility studies) to be caused by Gram-negative bacteria (E coli, Klebsiella spp., Enterobacter spp., Pseudomonas aeruginosa, other non-fermenting Gram-negative bacilli) resistant to other classes of antimicrobials and susceptible only to carbapenemsin-vitro.


2. Initial empiric treatment for severe, life-threatening infections (associated with multi-organ dysfunction, septic shock) caused by Gram-negative bacteria.

• Febrile neutropenia


• Ventilator associated / nosocomial pneumonia


• Pyelonephritis / complicated urinary tract infections


• Complicated intra-abdominal infections

Once the culture and susceptibility reports are available, choose the most appropriate antibiotic based on spectrum of activity, toxicity and cost (‘de-escalation’).

Indications for Ertapenem use:
Ertapenem has excellent in-vitro and in-vivo activity against ESBL producing Enterobacteriaceae, but lacks activity against Pseudomonas aeruginosa, and is therefore not considered appropriate for the treatment of conditions like febrile neutropenia and serious nosocomial infections. Ertapenem does not select Carbapenem-resistant Pseudomonas aeruginosa (at least in the short-term). Its use should be restricted to severe Gram-negative or polymicrobial community acquired infections confirmed to be caused by susceptible bacterial pathogens. Hence, this drug may be recommended as the initial choice for ESBL producing strains of E coli and Klebsiella spp..

Indication of Meropenem and Imipenem
Meropenem and Imipenem regarded as third line agents and are reserved for:

• serious infections due to multiple resistant strains (e.g. ESBL)


• empiric use in the seriously ill patient in either ITU or Haematology


• the treatment of infective exacerbations in Cystic fibrosis (CF)


• severe acute narcotising pancreatitis


• Outside these clinical settings it should only be used after consultation with a Clinical Microbiologist or ID physician.

Unlike imipenem , meropenem has not been associated with CNS toxicity. Also, it is administered by convenient IV bolus injection. Clinicians must be aware that mechanism of resistance to meropenem and imipenem are different and hence in-vitro test for one carbapenem cannot be used to interpret the other.

Dose
Imipenem*: 500 mg i.v. Q6H
Meropenem: 1 gmi.v.Q8H
Ertapenem: 1gm i.v. /i.m.Q 24H

*Note Anti-infective sub-committeerecommends use at a more frequent dosing interval. They believe that optimum plasma concentrations are more reliably maintained with 6-hourly dosing.

6. LINEZOLID (IV AND ORAL FORMS)
Linezolid should only be prescribed after consulting an ID specialist or clinical microbiologist and a mandatory order form completed.

• Restricted indications including infections due to proven glycopeptide-insensitive Staphylococcus aureus or vancomycin-resistant enterococcus (currently uncommon).


• To enable IV/oral switch from IV vancomycin (used for MRSA or MRSE) to oral linezolid (when patient’s discharge is possible and continuation treatment using combination rifampicin /trimethoprim is inappropriate.


• May be an option in surgical site infections (e.g. large bowel surgery, vascular surgery, etc).


• Poor IV access and a glycopeptide is indicated.


• Use in out-patient home parenteral antibiotic therapy for skin and soft tissue infections as an alternative to IV teicoplanin.


• Rare cases of proven hypersensitivity/allergy to the glycopeptides.

7. VANCOMYCIN
Vancomycin is the drug of choice for in-patient treatment of the following infections.

• Serious (e.g. bacteraemia, osteomyelitis) coagulase negative staphylococcal and MRSA infections and penicillin resistant enterococcal infections.


• Empiric therapy in febrile neutropenic patients not responding to first line therapy.


• Continuous ambulatory peritoneal dialysis (CAPD) associated peritonitis.


• Prosthetic valve endocarditis.

8. TEICOPLANIN
Teicoplanin is a suitable alternative to vancomycin for all indications for Vancomycin except meningitis:

• patients receiving out-patient/home parenteral therapy with glycopeptidesafter loading dosages.


• inability to tolerate vancomycin.


• oncology/haematology patients.


• Rare cases of vancomycin resistant and teicoplanin sensitive strains.