Empiric Antimicrobial Therapy

Bojana Beović, Ljubljana (Slovenia)

1. Introduction

Most antibiotic are prescribed without or before knowing the pathogen and its susceptibility to antibiotics. In primary care microbiology diagnostic is usually not available and most patients get well or worse before the microbiology results would come back. At present, extensive microbiology diagnostic in primary care would increase the cost of care with little direct effect on the antibiotic therapy. In hospitals, microbiology diagnostics is encouraged in most patients, but the time to the isolation of a pathogen varies from 12 hours to several days (1), complete results including susceptibility are almost never available in less than two days. The introduction of rapid molecular diagnostics is urgently needed.

The physician has to decide on antibiotic treatment empirically. The word empirical comes from Greek empeiria which in direct translation means experience. Not that far back in the past, in the middle of last century, the physician used to practice »the art of medicine«. There was a general belief that through rigorous medical education, exposure to colleagues and individual experiences each physician always knew and did the right thing. The treatment was litteraly empirical. Later on, in the last forty years, evidence accumulated that the individual physician decisions have to be more informed and based on scientific proofs or at least opinon of colleagues with most experiences in the field. The meaning of the word »empirical« moved from individual experience to »collective« experience and scientific evidence, usually compiled together in various antibiotic treatment guidelines which started to appear in peer reviewed jurnals in the last decade of the 20th century (2).

In the 21st century empirical antibiotic treatment is challenged again. Antimicrobial resistance ruined many antibiotic treatment regimens proposed in guidelines and used in clinical practice for several decades. Antimicrobial treatment guidelines are becoming more and more tailor-made taking into account antimicrobial resistance situation in the region, in the hospital and even the patient itself. Updates of guidelines are needed to cope with »latest bacterial achievements« in terms of resistance.

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2. Determinants of the empirical choice of antibiotics (questions to be answered before prescription of an antibiotic)

2.1. The pathogen

Community-acquired infections in immunocompetent patients are caused world-wide by a few micro-organisms. Each anatomic site of infection, i.e. respiratory tract, urinary tract, skin and soft tissue, gastronitestinal tract, genital tract etc. has its typical list of micro-organisms. In respiratory tract infections empirical antibiotic treatment should cover for Streptococcus pneumoniae (3), in skin and soft tissue empirical treatment should aim to Staphylococcus aureus and Streptococcus pyogenes, in urinary tract infections the terapy should be effective against Escherichia coli (4,5). Anatomical diagnosis is therefore crucial for the choice of empiric antibiotic treatment. Age, especially its extremes, may change the spectrum of pathogens in some infections. In bacterial meningitis, Listeria monocytogenes and Enterobacteriaceae play a greater role in neonates and patients above 50 years of age (6). Broader spectrum of pathogens has to be taken into account in hospital acquired infections and infections in immunocompromised patients. Medical history should include information on travel, contact with resistant micro-organisms, contact to animals, contact with health-care or long term care facilities, previous antibiotic treatment, chronic diseases. Travel to some regions even without health-care contact is a risk factor for colonisation with ESBL positive bacteria and even carbapenem resistance (7). Health-care contact may be a risk for acquisition of resistant bacteria in some EU countries (8).

Transmission of methicillin-resistant S. aureus (MRSA) and ESBL producing bacteria in households and between humans and animals has been described several times (9,10). Colonisation with resistant bacteria is more common hospitals and in nursing homes than in the community (11). Virtually hundreds of studies have shown that previous antibiotic treatment is a risk factor for infections/colonisation with resistant micro-organisms. Previous antibiotic treatment may also change the spectrum of micro-organisms. Some chronic diseases predispone to infections with a defined pathogen. Staphyloccal infections are more common in diabetic patients (12). In patients with chronic obstructive lung disease  Haemophilus influenzae pneumonia is more common than in general population and in patients with structural lung disease community-acquired pneumonia may be caused by Pseudomonas aeruginosa, a typical nosocomial pathogen (13).

2.2. Likely Antimicrobial Susceptibility

The susceptibility my be typical for a micro-organism, but may differ from a region to a region, from hospital to hospital and even between hospital wards. Local susceptibility patterns should be provided to prescribers in a timely manner.

Broad-spectrum vs narrow spectrum: several studies have shown the relationship between the appropriate empirical antibiotic tretament and survival in patients with severe sepsis or septic shock, and not in less severely ill patients with bacteremia. Other oucome measures such as length of stay or symptoms durations may be influenced by the appropriateness of the empirical antibiotic choice (see the paragraph above). The studies in mildly ill patients are lacking. Judicious choice of empirical antibiotic should take into account the possibility of harming the patient with in-appropriate choice and deleterious effect of antimicrobial resistance favourized by broad-spectrum antibiotics for the future patients and infection episodes.

2.3. Antimicrobial dosing

Pharmacokinetical and pharmacodynamic parameters should be taken into account: oral treatment versus parenteral, loading dose is especially important in severely ill patients, the calculation should consider the distribution of antibiotics (14), the dosing shedule  should follow pharmacodynamic parameters (15). 

2.4. Antimicrobial Empirical Treatment Check-list

  • . anatomical site of infection: potential pathogens
  •   community-acquired vs hospital-acquired/health-care acquired infections
  •   immuno-competent vs immuno-compromised
  •   susceptibility patterns of potential pathogens in the community/hospital
  •   recent hospitalisation
  •   chronic diseases
  •   recent antibiotic treatment
  •   travel
  •   colonisation with resistant bacteria
  •   contact with potential resistant bacteria (human, animal source)
  •   severity of the infection/vulnerable patient
  •   the first dose of antibiotic: volume of antibiotic distribution, body mass
  •   the dosing interval, maintenance dosing: pharmacodynamic of the antibiotic, excretion problems (kidney function etc).

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3. Does appropriate empirical treatment matter?

There is a general belief that bacteria should be killed or at least stop multiplying to cure the infection. Therefore the choice of antibiotics which are not effective against the pathogen should have serious consequences for the patient. Indeed several studies have proven that appropriate treatment is related to improvement and/or survival.

First studies investigating the relevance of appropriate antibiotic treatment were published twenty years ago and focused on most severely ill patients in intensive care units (ICU) (16-19).

A large systematic review of studies looking at the relationship between appropriate antimicrobial therapy and mortality in patients with sepsis including 48 studies providing data on adjusted mortality showed that in-appropriate is related to higher mortality. In spite of heterogenicity of the studies and variable results, the relationship between appropriate antibiotic therapy and survival was visible in subgroups of patients regarding age, neutropenia, pathogen groups, presence of bacteremia, and source of infection. The impact of appropriate antibiotic treatment was greater in patients presenting with septic shock than in less severely ill patients (20).

Some more recent studies investigated the impact of appropriate empirical treatment on survival and various other outcomes. The Taiwan authors looked at the impact of appropriate emergency-room therapy on the crude 28-day mortality in 454 bacteremic patients. In-appropriate therapy was signifinatly related to mortality, the difference was again more significant in critically ill. Pseudomonas aeruginosa, MRSA, and enterococci were significantly more often isolated in patients, who received in-appropriate antibiotic therapy (21). The results of a similar Spanish study were the same, the mortality was significantly higher in patients who received in-apropriate empirical antibiotic treatment (22). Appropriate antibiotic therapy was found to be important for survival of patients with P. aeruginosa bacteremia in another Spanish study (23), but not in a similar study from Israel, in which the impact of the in-appropriate therapy was marginally significant only in patients with severe sepsis and septic shock (24). In patients with MRSA bacteremia, a retrospective study and meta-analysis of all other studies on appropriate empirical therapy for MRSA bacteremia showed that appropriate therapy matters (25). In patients with candidemia and septic shock, the mortality of patients with empirical antifungal treatment was much lower than in patients only treated with antibacterial agents (26). In patients with hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), there was no statistically difference in mortality in patients receiving appropriate vs in-appropriate antibiotic therapy, but there was a difference in secondary outcomes such as length of hospital stay, days on mechanical ventialation and clinical resolution of pneumonia (27).

Contradictory results of the studies may be explained by the heterogenicity of the patients in the studies, the impact seems to be greater in more severely ill patients and in infections with more difficult- to-treat micro-organisms (24, 27).

There are very few studies on the impact of appropriate antibiotic studies in milder community acquired infections. We may assume that there is no impact on mortality in less severely ill patients and infections with very low mortality rate, but the questions on the impact on other outcomes are still to be answered. Nevertheless, the in vitro studies suggest that early aggressive (appropriate) treatment is important for all infections with potential for the development of resistance (15).

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4. Empirical treatment: how fast?

The choice of empirical antibiotic is a complex decision which should be done as soon as possible. The definition of the time-frame for antibiotic prescribing depends upon the type of infection and is not well defined in many situations.

In acute bacterial meningitis, the studies investigating the role of pre-hospital administration of antibiotics did not show a convincing benefit. The role of pre-hospital antibiotics depends upon the individual patient course of the disease. In some patients it may take a few days untilf the typical clinical picture of acute bacterial meninigitis develops, in the others, the course is much more fulminant (28). The door-to needle time is better defined, it should not exceed 3 to 6 hours (29).

In community-acquired pneumonia two restrospective studies showed that the delay of antibiotic administration eight (30) and four (31) hours beyond the admission is related to higher mortality. More recent prospective studies did not confirm their results. Faster administration of antibiotics did not correlate with the stabilisation of the patient, but may be related to shorter length of hospital stay (13). In recent guideliness the recommendation for administration of antibiotics within a defined time-frame after admission was ommited (3, 13), and replaced by the administration of antibiotics just after the diagnosis of pneumonia thus avoiding misdiagnosis and unnecessary antibiotic treatment.

In a large retrospective study in patients with septic shock the survival was significally higher in patients who received antibiotics in the first hour of documented hypotension (32). In the international guidelines for the management of severe sepsis and septic shock (Surviving Sepsis Campaign), the recommendation of antibiotic administration within the first hour was extended from septic shock to severe sepsis (33).

There are less data on the timing of antibiotic treatment in less severe infections. In children, the Dutch approach named »wait-and-watch« was described in acute otitis media in children 2 to 12 years of age. The approach does not favor timely antibiotic treatment but a delay of three to four days in which most children get better with symptomatic treatment thus avoiding excessive use of antibiotics (34). More recent meta-analysis showed that observational strategy is not beneficial in children younger than 2 years and bilateral otitis and children with acute otitis and otorrhoea (35).

Table 1. »Door-to-needle« times in severe infections

Syndrome Interval after admission in which empirical antibiotic treatment should be administered
Acute bacterial meningitis < 3 to 6 hours
Community-acquired pneumonia Immediatelly after the diagnosis
Septic shock, severe sepsis < 1 hour

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5. Antibiotic Stewardship and Empirical Antibiotic Treatment

Antibiotic stewardship includes several activities aimed to improve empirical treatment (36).

Antibiotic resistance surveillance is one of the cornerstones of appropriate empirical antibiotic treatment (36, 37). The cummulative antibiograms should be prepared for defined time periods including the number of isolates that allows analysis (usually more than 30), and should be stratified according to the patient population (ICU, general wards, etc.).

Guidelines are one of the cornerstones of evidence-based medicine in empirical antibiotic treatment. Infectious Diseases Society of America’s and Society for Health-care Epidemiology of America’s guidelines for the development of an antibiotic stewardship program in the hospitals strongly recommend guidelines and clinical pathways as an evidence based approach to antibiotic stewardship. The recommendation is based on several studies showing that use of guidelines and/or clinical pathways led to decreased antibiotic use, more appropriate empirical antibiotic treatment, and even decrease in mortality, length of hospital stay and reversal of antibiotic resistance in some studies. Implementation of guidelines is more problematic and may be improved by education (36).

Health-care information technology in the form of computerized physician order entry and clinical decision support based on guidelines and local susceptibility data is another antibiotic stewardship support aimed at more appropriate empirical antibiotic therapy (36).

In contrast to guidelines in other topics, which may be used universally. antibiotic guidelines may differ from a region to a region, from one hospital to another and even among various hospital wards taking into account recent relevant susceptibility data. Since the development of evidence-based guidelines is a long and work-intensive process which many smaller communities and institution cannot afford, the adaptation of international guideliness to local susceptibiliy data represents a rational solution.


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6. References

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