“Early” antibiotics: absolute sine qua non or unjustified paranoia?

There is increasing emphasis by regulatory bodies and expert group guidelines to administer antibiotics expeditiously once an infection is suspected. The surviving sepsis campaign proposes a “1-h bundle” comprising of a slew of measures, including antibiotic administration. Unarguably, antibiotic therapy should not be delayed in patients who are truly septic; however, would a tight timeframe lead to injudicious administration of antibiotics in patients who may not require them, including those with non-infective illnesses? Undoubtedly, the widespread use of broad-spectrum antibiotics has resulted in the genesis of multidrug-resistant organisms in the community, almost leading to a global crisis. Besides, there is a significant risk of inducing resistant organisms, including fungi, in the individual patient due to selective pressure.

One of the early studies that caused understandable paranoia suggested that every hour of delay in antibiotic administration resulted in an increase in mortality by 7.6% in the first 6 hours after the onset of septic shock. (1) There was no documented infection in a substantial number of patients (22.1%) in this study. No information was available on the timing of source control, which clearly takes precedence in septic patients. Three patient cohorts of “approximately” 150 each were retrospectively studied, over a 15-yr period between 1989 to 2004. Other retrospective studies have also arrived at similar conclusions with a stepwise increase in mortality with delay in initiation of antibiotic therapy. (2)

However, prospective studies that address this important question of antibiotic timing have a different tale to tell. In a before-after study of patients admitted to a surgical ICU, antibiotic therapy commenced soon after suspicion of infection was compared with a conservative approach wherein antibiotics were commenced after microbiological or other objective evidence of infection was obtained. The conservative approach was more often associated with appropriate initial therapy, and resulted in a significantly lower all-cause mortality. Importantly, a significantly lower mortality was also observed in patients who required vasoactive drugs for a mean arterial pressure of less than 60 mm Hg. (3)

In 715 consecutive patients with septic shock who presented to an emergency department, there was no significant increase in 28-d mortality for up to 5 h of delay in antibiotic administration after the onset of shock. However, failure to achieve initial goals of resuscitation, the SOFA score, and lactate levels were associated with mortality on multivariate analysis. (4) Puskarich et al. observed similar findings; there was no increase in mortality for up to 6 h of delay in antibiotic administration following the diagnosis of septic shock, in patients who received a structured, early resuscitation protocol. (5)

In a randomized controlled study, patients suspected to have sepsis were administered empirical ceftriaxone by ambulance personnel or offered usual care. The median time of receiving antibiotics was 26 min before arrival to the emergency department in the intervention group compared to 70 min after arrival in the control group. The 28-d mortality was not significantly different between groups. This study included relatively few patients (3.8%) with septic shock; however, in less seriously ill patients, a delayed approach did not lead to adverse outcomes. (6)

In mechanically ventilated patients in the ICU, diagnosis of ventilator-associated pneumonia (VAP) can be difficult; radiographic infiltrates are notoriously non-specific and fever may occur due to non-infectious causes. This is a typical situation in which clinicians may feel the pressure to initiate antibiotic therapy even if there is a low index of suspicion. Besides, if there is a perceived lack of response to initial therapy, subsequent antibiotic jugglery may well ensue, with an exponential increase in superinfection with multidrug-resistant organisms. If septic shock is present, an expeditious approach is justified; however, in less severely ill patients, waiting for more objective evidence including gram stain or culture results may perhaps be more appropriate.

More recent, prospective studies suggest that initial resuscitation and attempts to identify the likely source, with treatment directed towards the most likely organisms, keeping in mind the local microbial environment may be a more appropriate approach. The importance of adequate source control cannot be overemphasized. In fact, some infections may require source control alone, such as an infected central venous catheter that leads to sepsis. Extravagant, broad-spectrum antibiotic use without adequate evaluation, in an attempt to reduce “delay”, is likely to contribute to the ever-growing list of superbugs in the community; besides, at the individual patient level, resistant pathogens are likely to freely proliferate. It may also be pointed out that in many of the studies that address delay, the time lag between the actual onset of sepsis and diagnosis is unknown; interpretation of delay when time zero is obscure may be fraught with misperceptions.

Clearly, we need to strike a balance here!  It would probably pay to apply some considered thought and get the early resuscitation going before you throw the most powerful weed killer at the presumed invasion by a bacterial army.

References:

1. Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock*: Crit Care Med. 2006 Jun;34(6):1589–96.
2. Liu VX, Fielding-Singh V, Greene JD, Baker JM, Iwashyna TJ, Bhattacharya J, et al. The Timing of Early Antibiotics and Hospital Mortality in Sepsis. Am J Respir Crit Care Med. 2017 Oct;196(7):856–63.
3. Hranjec T, Rosenberger LH, Swenson B, Metzger R, Flohr TR, Politano AD, et al. Aggressive versus conservative initiation of antimicrobial treatment in critically ill surgical patients with suspected intensive-care-unit-acquired infection: a quasi-experimental, before and after observational cohort study. Lancet Infect Dis. 2012 Oct;12(10):774–80.
4. Ryoo SM, Kim WY, Sohn CH, Seo DW, Oh BJ, Lim KS, et al. Prognostic Value of Timing of Antibiotic Administration in Patients With Septic Shock Treated With Early Quantitative Resuscitation. Am J Med Sci. 2015 Apr;349(4):328–33.
5. Puskarich MA, Trzeciak S, Shapiro NI, Arnold RC, Horton JM, Studnek JR, et al. Association between timing of antibiotic administration and mortality from septic shock in patients treated with a quantitative resuscitation protocol*: Crit Care Med. 2011 Sep;39(9):2066–71.
6. Alam N, Oskam E, Stassen PM, Exter P van, van de Ven PM, Haak HR, et al. Prehospital antibiotics in the ambulance for sepsis: a multicentre, open label, randomised trial. Lancet Respir Med. 2018 Jan;6(1):40–50.