Antibiotic Stewardship.

When a young inexperienced doctor needs to prescribe an antibiotic they use the following factors to select one:

  • They just happen to remember the name of the antibiotic.
  • They are familiar with the dosage of that particular drug.
  • They have read the prescription of a senior doctor so think the antibiotic must be good.
  • The drug happens to be available.
  • Everybody else in the medical or surgical unit uses it.
  • The medical representative left a few brochures of the drug in the common room.

Once doctors come into a general practice, specially but not exclusively, those who have had no further postgraduate training, prescribe an antibiotic for the following reasons:

  • The doctor is convinced that every fever requires an antibiotic.
  • The doctor thinks that the patient will get better quickly with an antibiotic which will enhance his reputation among the patients and the number of patients coming to him will increase.
  • The medical representative came and gave the doctor a talk about how good this particular antibiotic is and the doctor thinks he is being “modern or advanced” in his treatment.
  • The patient insists on it. This is probably the least logical reason for prescribing an antibiotic unless the patient is a trained physician.
  • The doctor cannot make a diagnosis so thinks that throwing a lot of drugs at the patient will provide a cure. This is the shot-gun therapy.
  • The doctor has made a wrong diagnosis on inadequate data and prescribes the wrong drug.

What should a doctor consider when prescribing an antibiotic?

  • Is an antibiotic required?
  • Which class of antibiotics is most suitable?
  • Will one do or should two antibiotics be prescribed?
  • What dose, by which route and for how long?
  • What adverse reactions to anticipate

In the USA Hospital Antibiotic Stewardship Programs are being used. The primary goal is to promote “smart use” of antibiotics in the face of data demonstrating substantial overuse. This overuse is seen in Pakistan and most third world countries, in a much greater degree.

I am providing information from UpToDate 24th September 2018. Most doctors do not have access to this data base.

PRINCIPLES OF OPTIMAL ANTIBIOTIC USE. 

A clinician may feel the need to initiate empirical antibiotic therapy before test results come back. When does a febrile or infective disease require immediate use of antibiotics?

  • When there is a purulent discharge from a wound, boil, abscess, skin ulcer, surgical incision, stab wound etc.
  • When the fever accompanies signs of meningitis, pneumonia, septic shock, acute appendicitis, endocarditis etc.
  • The patient is critically ill or in septic shock
  • In diabetic ketoacidosis which is often initiated by an infection.
  • Fever in an immunocompromised patient: a patient on chemotherapy, or steroids or on immunosuppressants after an organ transplant, or if the patient has leukemia or similar hematopoietic malignancy even if they are in remission.
  • In a urinary tract infection with painful symptoms or acute pyelonephritis.
  • In a sore throat if you can see pus points on the tonsils or a membrane on the tonsils and pharynx.
  • There is a definite diagnosis and confirmatory tests like cultures are awaited.

Initiating empiric therapy — Initiation of empiric antibacterial therapy consists of the following:

Choosing the optimal antibiotic regimen: first take appropriate samples like pus swabs, throat swabs, blood cultures, urine cultures, then take into consideration:

  • The severity and trajectory of illness. Are the patient’s vital signs stable? How long has the illness lasted? Is the patient’s condition declining? Is there involvement of multiple organs which are failing like renal failure, disturbed liver functions, declining serum oxygen levels, declining levels of consciousness, evidence of heart failure or shock?
  • The likely pathogens and their anatomic source (with consideration of source control), based on information from Gram stain and other rapid tests as appropriate. Do a Gram stain yourself and keep the dyes and a microscope available in your clinic if you are a private practitioner.
  • The likelihood of drug resistance (eg, known colonization with resistant pathogens, recent antibiotic use, exposure to healthcare facilities, local resistance patterns)
  • Host factors.
    • Is the patient allergic to the antibiotic you have chosen or has he/she been allergic to any other antibiotic from the same group? Penicillin allergies may extend to other drugs in the penicillin group like ampicillin or to the cephalosporin group. If it is a drug that is known to cause allergies in susceptible people then do a sensitivity test.
    • Will declining renal function or liver functions increase the risk of toxicity? Most drugs are excreted either by the kidney or the liver. In the event of renal failure an essential antibiotic like vancomycin or gentamycin may be administered but the dose needs to be reduced and the dosage interval needs to be increased,
    • Influence spectrum of coverage eg, in an immunocompromised patient you need an antibiotic with a wide spectrum i.e  it should cover Gram-positive, Gram-negative, anaerobes. If you are dealing with a situation where resistant organisms are likely to be encountered like staph aureus or Pseudomonas then chose a drug which will cover resistant organisms.
    • Determining the appropriate dosing and route of administration (eg, intravenous in the critically ill)
    • Initiating antibiotic therapy as promptly as possible.

Tailoring antibiotic therapy (“antibiotic time-out”) 

In patients receiving empiric antibiotic therapy, the regimen should be reevaluated on a continuing basis as the clinical status evolves and microbiology results become available (often after 48 to 72 hours). At this point, an “antibiotic time-out” should be performed, in which microbiology results are reviewed and antibiotic therapy is adjusted from empiric to definitive antibiotic therapy. The spectrum of coverage may be narrowed or broadened as appropriate, the dose may be adjusted as needed, and unnecessary components of the regimen should be eliminated. If it is apparent that the patient’s clinical status is not the result of bacterial infection, antibiotics may be discontinued altogether. During the antibiotic time-out, the indication and duration of antibiotic therapy should be estimated and stated in the medical record.

Converting from intravenous to oral antibiotic administration — Antibiotic regimens should be converted from intravenous to oral administration as soon as is feasible and clinically indicated. This intervention has been shown to decrease costs, facilitate discharges, and reduces complications associated with intravenous access without compromising clinical outcomes.

Using the shortest effective duration of therapy. A critical element in the safe use of antibiotics lies in restricting their administration to the minimum duration required for maximum efficacy. The appropriate durations of therapy are well-studied for a number of infectious disease syndromes, such as pneumonia, Staphylococcus aureus infection and candidemia.  

Lower respiratory tract infections (LRTIs) are among the most common reasons for antibiotic prescription. An estimated 30 to 85 percent of these prescriptions are unnecessary or inappropriate. The most often clinical problem for which antibiotics are prescribed unnecessarily in is an acute attack of asthma. For community acquired pneumonia often the wrong drug is prescribed most often a quinolone in Pakistan. For Chronic Obstructive Pulmonary disease (COPD) drugs are often prescribed unnecessarily and for too long. The predilection for antibiotic overuse for LRTIs (pnuemonia) is in part due to the difficulty in distinguishing between viral and bacterial infections. A substantial fraction of LRTIs are viral and do not require treatment with antibiotics. However, clinical signs and symptoms of bacterial and viral LRTIs are similar and often cannot be distinguished based on clinical features alone. Microbiologic testing can be helpful, but results from culture or other assays often take days to obtain and, in many cases, a pathogen is not identified.

Procalcitonin has good discriminatory value for distinguishing between viral and bacterial infections, and results can be obtained in hours or less. In patients with community-acquired pneumonia, procalcitonin is about 65 to 70 percent accurate in distinguishing bacterial from viral pathogens. When used as part of an algorithm in combination with clinical judgment in patients with LRTIs, procalcitonin has been shown to reduce unnecessary antibiotic use by about 25 to 50 percent without increasing morbidity or mortality

PROCALCITONIN BIOLOGY

Synthesis — Procalcitonin synthesis pathways vary in different inflammatory states. In the absence of systemic inflammation, procalcitonin synthesis is restricted to thyroid neuroendocrine cells, and the protein is not released into the blood until it is cleaved into its mature form, calcitonin. Thus, serum procalcitonin is typically undetectable in healthy persons when standard assays are used.

When systemic inflammation is caused by bacterial infection, procalcitonin synthesis is induced in nearly all tissues and released into the blood. Known triggers for synthesis include bacterial toxins, such as endotoxin, and cytokines including tumor necrosis factor (TNF)-alpha, interleukin-1-beta, and interleukin-6. In contrast, procalcitonin synthesis is not induced in most viral infections. The lack of induction is likely due to cytokines released in viral infections that inhibit TNF-alpha production, such as interferon-gamma.

Not all bacterial infections cause procalcitonin to rise, or rise to the same degree. Typical bacteria, such as Streptococcus pneumoniae or Haemophilus influenzae, tend to cause greater rises in procalcitonin than atypical bacteria. Certain fungi, such as Pneumocystis jirovecii and Candida species, and parasites, such as malaria, have also been reported to cause elevations in procalcitonin.

Noninfectious causes of systemic inflammation, such as shock, trauma, surgery, burn injury, and chronic kidney disease can also induce procalcitonin production but are less closely correlated with procalcitonin induction than bacterial infection. A number of other causes of elevated procalcitonin levels have been reported.

Kinetics — Serum procalcitonin levels rise within two to four hours of an inflammatory stimulus, typically peaking within 24 to 48 hours. Peak levels roughly correlate with the severity of infection, with higher levels observed in patients with septic shock and sepsis than with uncomplicated pneumonia or other localized infections.

CLINICAL USE.  Procalcitonin can serve as a helpful adjunct to clinical judgment for guiding antibiotic therapy and resolving diagnostic uncertainty in patients with known or suspected lower respiratory tract infections (LRTIs). However, the study of procalcitonin is evolving, the approach to procalcitonin use varies among experts, and the assay is not available at all institutions.

Procalcitonin’s greatest utility may be for guiding early antibiotic discontinuation in patients with community-acquired pneumonia (CAP). Discontinuation of antibiotics based on defined procalcitonin thresholds has been shown to reduce antibiotic use without adverse outcomes. In most other circumstances, however, we interpret procalcitonin levels qualitatively (eg, as high, low, rising, or falling), weighting its value similarly to other clinical findings.

Community-acquired pneumonia   Procalcitonin is measured to help determine when to discontinue antibiotic therapy in immunocompetent patients with known or suspected CAP.  Generally a procalcitonin level is obtained at the time of diagnosis and repeated  every one to two days, depending on severity of illness. The need for continued antibiotic therapy is based on the patient’s clinical course, suspected etiology, serial procalcitonin levels, and microbiologic tests results.Typically procalcitonin is used to inform antibiotic initiation in patients with known or suspected CAP. In critically ill patients, empiric antibiotic therapy should never be delayed for procalcitonin results. Procalcitonin has poor predictive value for the diagnosis of  ventilator associated pneumonia (VAP). Use of procalcitonin to help guide antibiotic therapy in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is controversial.

Although most clinically stable patients with suspected CAP should also receive empiric antibiotic therapy, some experts withhold antibiotics in selected low-risk patients with very low procalcitonin levels when a viral cause is suspected and close follow-up is arranged.

Urinary antigen — Alternative or complementary methods to detect S. pneumoniae and Legionella are urinary antigen assays. The urinary antigen tests for Legionella and S. pneumoniae are FDA cleared and provide results in minutes; the reagents are commercially available, and they require no equipment.

For undiagnosed fever of a few days duration both antimalarial and a drug covering Salmonella typhi are prescribed empirically. if you cannot make a diagnosis prescribe paracetamol for a few days, do appropriate tests and ask the patient to come back in 3 days time. The fever will have settled and even if an immunological test like Typhi dot or malaria ICT is positive no treatment is required. Many immunological tests become positive as there is a general rise in antibodies when there is an inflammatory process going on like a viral infection for which no antibiotic is required. If the fever persists re-examine the patient. Some signs may have developed like an enlarged spleen. a rash or petechiae, or signs in the chest which will give a clue to the diagnosis, then use the appropriate antibiotic. Use either an antibiotic or an antimalarial not both. Prescribe it for the correct time. if given for too short a duration there is the danger of developing drug resistance and if too long then unnecessary side effects will develop specially by altering the normal gut flora. These changes may persist for as long as a year and are the cause of persisting dyspepsia. Even when indicated, antibiotic treatment courses often exceed recommended durations.

Pharmacokinetic monitoring — Optimal antimicrobial dosing and administration necessitate adherence relevantpharmacokinetic (PK)/pharmacodynamics principles. Individual PK monitoring and adjustment programs should be implemented for patients receiving aminoglycosides or vancomycin. PK monitoring increases the likelihood of obtaining serum concentrations within the therapeutic range and reduces costs. Some studies have also observed reductions in nephrotoxicity, length of stay, and mortality.

Measuring antibiotic use and cost savings.  

Antibiotic use may be estimated in days of therapy (DOT) or defined daily dose (DDD); use of DOT is preferred.

DOT is an aggregate sum of days for which any amount of a specific antibiotic agent is administered to a particular patient (numerator) divided by a standardized denominator. DOT refers to the number of days a patient receives an antibiotic, regardless of the dose administered. Therefore, the calculation can be distorted if a patient receives more than one antibiotic agent (for example, if a patient receives 2 antibiotics for 7 days, the DOT equals 14) or if a patient receives antibiotics administered every other day. DOT can be used for both pediatric and adult populations. Cost cannot be calculated easily based on DOT because dose is not included.

DDD aggregates the total number of grams of each antibiotic administered during a period of time divided by a standard DDD designated by the World Health Organization (WHO). Because the data needed are typically available from the pharmacy, it is relatively easy to calculate. However, DDD underestimates the antibiotic exposure in patients with renal failure and does not account for weight-based dosing, making this metric inappropriate for pediatric populations.

Cost should be assessed according to drugs administered or prescribed (not just purchased) and should be normalized for census.

When using an antibiotic you should be aware of the spectrum or the types of bacteria it will kill: whether the antibiotic is bacteriostatic or bacteriocidal: which antibiotics are complementary hence can be used together: which antibiotic needs to have its serum levels checked both to ensure an adequate therapeutic level and also to avoid a toxic level: what is the appropriate dose and duration of therapy: whether a loading dose is required: whether you need to maintain a steady therapeutic level or ensure a trough and peak effect: do you need to measure renal or liver functions: is it safe in pregnancy: what adverse effects to watch out for.

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shaheenmoin

I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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