Responsible antibiotic therapy simplified

Establishing microbial diagnosis

Antibiotics are ideally needed when there is proven bacterial infection, which can be identified by isolating an organism from sterile body fluids, blood, or tissue from site of infection by culture along with antibiotic susceptibility test. However, in clinical practice this is not always possible because of number of limiting factors.^[8]

1. Tests for detection of organisms have been sent but results are awaited

2. Affordability and availability

3. Prior antibiotic use

4. Slow growing and fastidious organisms

5. Improper collection and transport of specimen and culture media.

In such cases, non-culture methods should be used to establish diagnosis of bacterial infections. This includes smear examination, antigen detection test, rapid tests, serological tests, and molecular tests such as PCR. Premature initiation of antimicrobial therapy without attempting microbial diagnosis can suppress bacterial growth and preclude the opportunity to establish a microbiological diagnosis, which is at times going to be so critical in the management of certain cases, who may require several weeks to months of directed antimicrobial therapy to achieve cure (e.g., endocarditis, septic arthritis, and meningitis). To optimize an accurate microbiological diagnosis, clinicians should ensure that diagnostic specimens are properly obtained and promptly submitted to the microbiology laboratory.

Initiation of antibiotic therapy pending culture and sensitivity reports

The best approach would be to rule out a life-threatening infection and if the child is stable, to wait and watch for the evolution of the illness. However, in cases, where it is reasonably certain that there is a possibility of a bacterial infection and waiting is dangerous/detrimental, initial therapy for infection is often empiric as guided by the clinical presentation, supportive lab evidences and will be modified or stopped as per the reports. Initiation of antibiotic too early, in such situation, will mask the gravity of illness, give false sense of security and results in poor outcome.

Interpretation of culture and sensitivity patterns to guide antibiotic therapy further

1. When an organism is identified, it is very crucial to start antibiotics pointed toward true pathogen. Contaminants and commensals should never be treated

   Contaminants are the organisms from skin, unsterile instrument whereas colonizers are the organisms from non- sterile body parts, catheter, endotracheal tube, etc., and do not cause infection. Some of the examples are as under

   • S. pneumonia and meningococci from nasopharynx

   • Gonococci from vaginal secretions

   • E. coli from stool or rectal swab

   • Pseudomonas in the endotracheal tube

   • Candida in urine

   • Staph from throat

   • CONS.

2. When a pathogenic microorganism is identified in clinical cultures, the next step performed is antimicrobial susceptibility testing (AST). AST measures the ability of a specific organism to grow in the presence of a particular drug in vitro and it indicates that the isolate is likely to be inhibited by the usually achievable concentration of a particular antimicrobial agent when the test is performed using guidelines established by the Clinical and Laboratory Standards Institute.^[9] Data are reported in the form of minimum inhibitory concentration (MIC), which are the lowest concentration of an antibiotic that inhibits visible growth of a microorganism after an overnight incubation, and are interpreted by the laboratory as “susceptible,” “resistant,” or “intermediate,” according to Clinical and Laboratory Standards Institute criteria. Some laboratory interprets susceptibility in terms of “zone of inhibition” and is presented as zone diameter. However, such methods are erroneous and hence MIC based reports are always recommended in clinical practice. However, one should not blindly follow the sensitivity reports and should be guided by the clinical condition of the child.

As described below, AST has some limitations that should be kept in mind.^[10]

1. In vivo and in vitro mismatch – Some organisms carry enzymes that, when expressed in vivo, can inactivate antimicrobial agents to which the organism shows in vitro susceptibility. For example, ESBLs in Enterobacteriaceae are enzymes that mediate resistance to almost all β-lactam agents except carbapenems (e.g., meropenem or imipenem). The production of ESBL should also be suspected when treatment with β-lactams fails despite apparent in vitro susceptibility

2. One should also remember that in vitro sensitivities do not always result in clinical cure (e.g., aminoglycosides cannot cure enteric fever even though the report always shows salmonella sensitivity to all of them)

3. Clinical laboratories may provide different AST interpretations for different sites of infection (e.g., meningitis and non-meningitis AST results for S. pneumonia).

Clinically certain bacterial infection

In certain clear-cut clinical situations, specific microbiological tests are not typically performed, and one is justified to start antibiotics at a first stretch. Here, single antimicrobial agents with a narrowest spectrum should be directed at the most likely pathogens for the duration of therapy for clinically certain bacterial infections such as community-acquired pneumonia, otitis media, diphtheria, bacillary dysentery, acute lymphadenitis, or cellulitis in the ambulatory setting.

High probability of bacterial infection while waiting for lab results

In stable clinical circumstances, antimicrobial therapy should be deliberately withheld until appropriate specimens have been collected and submitted to the microbiology laboratory. Important examples of this principle are suspected of enteric fever, urinary tract infection, infective endocarditis, osteoarticular infections, etc. Patients with these infections are frequently ill for a period of several days to weeks, and in such situations, antibiotic therapy should be delayed until multiple sets of blood cultures have been obtained.

High probability of bacterial infection and waiting is dangerous

In critically ill patients, such as those in septic shock, febrile neutropenic patients, and patients with suspected bacterial meningitis, sick looking neonate empiric therapy, often with a broad coverage, should be initiated as soon as possible, once appropriate diagnostic specimens have been collected. In these situations timing of first dose is very vital and it often decides the overall outcome. It has been shown that delayed and/or inadequate therapy for infections in critically ill, hospitalized patients are associated with poor outcomes, including greater morbidity and mortality, as well as increased length of stay.^[11] Therefore, a common approach is to use broad-spectrum antimicrobial agents as initial empiric therapy (sometimes with a combination of antimicrobial agents) to cover multiple possible pathogens commonly associated with a given clinical situation. This is true for both community- and hospital-acquired infections. Once microbiology results have helped us to detect the etiologic agent with or without antimicrobial susceptibility reports, every attempt should be made to narrow the antibiotic spectrum (de-escalation). This is very crucial component of antibiotic stewardship because it can reduce the cost and toxicity and prevent the emergence of AMR in the community.

Atypical course of a viral infection

The atypical course of a viral disease may indicate the likelihood of post-viral bacterial complications, and it is justified to start antibiotic empirically after drawing appropriate samples, for example, post-measles pneumonia, H1N1, and COVID 19.

Viral infection

High grade at the onset, fair response to paracetamol, a normal inter-febrile period and a rhythmic fever (comes up as soon as the antipyretic action of the drug wanes), the appearance of cold, cough on days 2–3, and decreasing fever by days 3–4. However, atypical progress in a suspected viral infection may a complicating bacterial infection, and antibiotics may be justified in such cases, for example, post- measles pneumonia, and pneumonia complicating flu.

Bacterial infection

Fever moderate to high at onset, poor response to paracetamol, sick inter-febrile period, and fever not abating or worsening by days 3–4. This suggests a localized bacterial infection. We should look for the focus of infection such as tonsillitis, urinary tract infection, adenoiditis, or bacillary dysentery. Once focus is identified that empirical antibiotic is justified.

Mild-to-moderate fever at the onset, child getting sicker in the inter-febrile period as the days progress, poor response to antipyretics, and trend of fever worsening by days 3–4. This suggests a bacteremic bacterial infection. It may localize to the lungs (pneumonia) or meninges (meningitis) by days 3–4 or may not localize (typhoid fever). In such situation, an empiric antibiotic is started after appropriate samples for culture, and other investigations are obtained.

At the same time, it is very important to remember non- infectious causes of fever such as Kawasaki disease, rhreumatological disorders, malignancy, dehydration fever, heat fever, and drug fever. Fever may also be absent in the presence of bacterial infection in certain situations such as sick neonate, immune-compromised child, whooping cough, chronic sinusitis, and tuberculosis.

Once it is reasonably certain that one is really dealing with a possible bacterial infection, an attempt should be made to select the most appropriate antibiotic, while making such decision following factors are considered, [Table 2].

2. Which is the likely organism? Which antibiotic is appropriate for the given situation?

We need to know the likely pathogens generally causing a particular illness in a particular age group. Age and site of infection are very crucial to predict the offending bug, for example, pneumonia in a school going child; acute otitis media in a toddler; and sepsis in a neonate. Having considered the possible pathogenic organisms, think about the antibiotics to which each of these organisms is sensitive.

One may not undergo this exercise every time. It will be very easy and practical to follow protocols and guidelines suggested by various organizations such as WHO, CDC, IDSA, and IAP [Tables 3 and 4]. Remember that it should be evidence based and as per your local epidemiology and drug susceptibility pattern.

Hospital-acquired infections or nosocomial infections are also a global health issue and have different epidemiology and varied dynamics. The rate of nosocomial infections is higher in developing countries than in developed world. They are associated with cause prolonged stay, disability, and financial burden. Most prevalent hospital associated infections include central line-associated bloodstream infections, catheter- associated urinary tract infections, surgical site infections, and ventilator-associated pneumonia. They are commonly caused by drug-resistant organisms, both Gram-positive (e.g., methicillin-resistant Staphylococcus aureus [MRSA]) and Gram-negative (e.g., Pseudomonas aeruginosa) bacteria, which are often endemic in hospitals [Table 5].

In selecting empiric antimicrobial therapy for such infections, one should consider the following factors: (1) The site of infection; (2) the organisms most likely to be colonizing that site. It is well-known that, intravascular catheter-related bacteremia is frequently a result of colonization and infection caused by staphylococci present on the skin; (3) colonization with a known organism (e.g., a screening nasal swab for MRSA) before admitting patients to the intensive care unit in situation where MRSA is highly prevalent or an outbreak situation; and (4) the local bacterial resistance patterns or antibiograms when available.

Ensure chosen antibiotic has adequate tissue penetration at the site of infection. Antibiotic penetration at the site of infection is very crucial especially in severe life-threatening infections. An antibiotic that penetrates well into the meninges is a pre-requisite for treating meningitis or sepsis in a neonate. BL-BLI and to some extent Vancomycin has poor penetration in the brain and lungs, respectively, therefore may not be a good choice for meningitis or pneumonia.^[12] Excretion of the antibiotic through the biliary tract is an advantage for treating cholangitis or enteric fever where the bacteria sequestrate in that tract. Furthermore, aminoglycosides have poor penetration into the cells and therefore are unsuitable for treating infections where the organisms are primarily intracellular, for example, Salmonella. Antimicrobial concentrations attained at some sites (e.g., ocular fluid, CSF, abscess cavity, and bone) are often much lower than serum levels. For example, first- and second-generation cephalosporins and macrolides do not cross the blood–brain barrier and are not recommended for the central nervous system infections. Daptomycin, an excellent bactericidal agent against gram-positive bacteria, is not useful for the treatment of pneumonia (e.g., pneumococcal pneumonia) because it is inactivated by lung surfactant.^[13] Sometimes antibiotics belonging to the same class have different clinical implications, for example, quinolone group of antibiotics. Moxifloxacin does not achieve significant urinary concentrations, making it unsuitable for the treatment of UTIs. Levofloxacin and ciprofloxacin are excellent choices for UTIs caused by susceptible bacteria. Some quinolones such as levofloxacin and moxifloxacin are also used as respiratory quinolones while others are not. In addition, route, dose, and duration of therapy will also be decided by site of infection, for example, meningitis, septic shock, and febrile neutropenia where parenteral antibiotics for relatively longer duration is needed.

1. What is the route, frequency, and duration?

For synergistic activity against a microorganism

Synergistic action implies that in vitro the combined effect of the antimicrobial agents is greater than the sum of their independent activities measured separately.^[14] For example, the combination of certain β-lactams and aminoglycosides exhibits synergistic activity against a variety of Gram-positive and Gram-negative bacteria and is used in the treatment of serious infections, for which rapid killing is essential (e.g., treatment of endocarditis caused by Enterococcus species with a combination of penicillin and gentamicin). Here, penicillin alone is only bacteriostatic, and gentamicin alone has no significant activity but when gentamicin is used with penicillin, the combination imparts much desires bactericidal action. Similarly for endocarditis due to S. viridans, a combination of penicillin or ceftriaxone with gentamicin results in a more rapid clearance of microorganisms. With this synergistic combination 2-week duration of therapy can be as effective as penicillin or ceftriaxone used alone for 4 weeks.

In a critically ill patients empiric therapy before microbiological etiology and/or antimicrobial susceptibility can be determined

Combination therapy is used in this setting to ensure that at least one of the administered antimicrobial agents will be active against the suspected organism(s). For example, when a patient has been hospitalized for serious septic shock, it would be appropriate to provide initial therapy with two agents that have activity against both Gram-positive and Gram-negative organisms.

For treatment of polymicrobial infections

Certain infections are caused by more than one organism. In such instances a combination regimen may be preferred for a comprehensive broader spectrum to target possible polymicrobial agents, intra-abdominal infections brain abscess, necrotizing fasciitis, etc., are poly microbial infections. Antimicrobial combinations, such as a third- generation cephalosporin or a fluoroquinolone plus metronidazole, can be used as a potential treatment option in intra-abdominal infections and can be more cost-effective than use of single molecule like carabapenem.

To prevent emergence of resistance

The emergence of AMR is generally the result of selective pressure from antimicrobial therapy probability of emergence of resistance against two drugs is lower as compared with a single drug. While using combination therapy we are reassured that at least one drug will be effective, and this in turn prevents the resistant mutant population from emerging as the dominant strain. The classic examples for such combination drug therapy include use of more than 3 or 4 drugs in the treatment of infections requiring long duration therapy such as tuberculosis and the human immunodeficiency virus (HIV). Prolonged treatment duration is likely to provide more chances of emergence of resistance especially when the therapeutic agents are limited.^[10]