The modern era of antibiotics starts with the discovery of penicillin by Alexander Fleming in 1928. Since then, antibiotics have transformed the face of modern medicine and enabled major advances in the treatment of patients. So much so that antibiotics could partially be credited for the staggering increase in the general population’s life expectancy from around 60 years old in the UK in the 1920s, according to the Office for National Statistics, to 81 years old in 2015.
Critical care is a young specialty whose evolution has largely been shaped by the evolution of antimicrobial therapy. It can be argued that the only treatment we can offer our patients is antimicrobials, the rest – vasoactive medications, mechanical ventilation, diuretics and so on – are merely supportive measures.
The aim of this chapter is to present the aspects of antimicrobial therapy most pertaining to a cardiothoracic critical care context. Data are presented as valid in 2016. We do not assume to give an exhaustive representation of the myriad of issues faced by the modern intensivist, but to offer a brief update of the most important issues we are currently confronting.
There is no universal recipe for which antibiotics should be used first in a critically ill patient. As shown in Figure 12.1, the choice is individualised for the patient, unit, hospital and geographical area. Most clinicians, when faced with a patient with a severe infection or septic shock, would choose to start with a broad spectrum antibiotic or combination and narrow down as pathogens and their susceptibilities are identified.
The comparative effects of appropriate and inappropriate antibiotic therapy are well illustrated in a recent retrospective study by Neinaber et al. conducted over 6 years in a single institution in the USA. In this study, the risk of nosocomial infections, the median length of stay and the hospital mortality were significantly higher in the inappropriate antibiotic group.
Figure 12.1 Flow chart for choice of antibiotic.
An example of an algorithm for presumptive antibiotic therapy for pneumonia in a critically ill patient is presented in Figure 12.2.
Figure 12.2 Presumptive antibiotic therapy for pneumonia in the ICU. HCAP Health Care Associated Pneumonia; HAP hospital acquired pneumonia.
Critically ill patients have multiple risk factors for serious and life-threatening infections. Exposure to antibiotics and other treatments which eradicate and modify the commensal flora, compromised host defences due to nutritional deficiencies, critical illness, compromised integument (intravascular devices, percutaneous interventions and devices) and disruption of cellular and humoral immunity as in the transplant patients lead to a high susceptibility to sepsis. In the context of severe infections, Table 12.1 highlights the most prevalent microorganisms in Western world critical care patients.
|Diagnosis||Potential pathogens||Initial therapy||Alternative therapy|
|Catheter-related blood stream infections|
|Pneumonia, including VAP||Gram-negative rods, Haemophilus, S. pneumoniae||Piperacillin-tazobactam|
In the last few years there has been a focus on the most appropriate way of administering and dosing antibiotics in intensive care. This has been triggered by a better understanding of the critical illness pathophysiology, as well as the emergence of new technologies that alter the pharmacodynamics and pharmacokinetics of drugs in this patient population (Figure 12.3).
Figure 12.3 The kill characteristics of antibiotics. Modified from Tsai et al. (2015).
Time dependent antimicrobials (fT>MIC) include beta-lactams, glycopeptides, macrolides and linezolid. Their concentrations have to be well above the minimum inhibitory concentration (MIC) for the pathogen for at least 40% of the interval between doses in order to achieve their therapeutic targets. There is a growing body of research concerning the administration of beta-lactams as a continuous or prolonged infusion so that the optimum concentration is achieved for sustained periods of time.
Concentration dependent antimicrobials (fCmax/MIC) include aminoglycosides, fluoroquinolones, metronidazole, echinocandins, polyenes and daptomycin. These antibiotics need to be administered in doses which achieve target concentrations well above 8–9 times MIC of the pathogen.
The antibiotic concentrations in the target tissues are influenced by the pharmacokinetic changes in the critically ill patient.
1. Volume of distribution, Vd – increased for hydrophilic drugs due to increased total body water; unchanged for lipophilic drugs.
2. Clearance and elimination – may change according to the renal and hepatic blood flows and function; severely deranged in septic shock; drug clearance and elimination also dependent on whether renal replacement therapy is instituted.
3. Decreased albumin levels – the volume of distribution and clearance of protein-bound drugs increase, decreasing their efficacy.
4. End-organ dysfunction – cardiac dysfunction in the context of septic shock increases the elimination half-time and the risk of toxicity and drug accumulation.
The pharmacokinetics of antibiotics in patients on extracorporeal circuits is a growing area of research. The volume and distribution and clearance of drugs is altered and these are compounded by the added potential for sequestration in the circuit. The importance of understanding the pharmacology and changing the doses and intervals of administration of antimicrobials is colossal, since subtherapeutic doses are associated with worse outcomes.
An example is provided in Figure 12.4, which shows the effect of two dosing regimens of meropenem, as described by Shekar et al. (2013).
Figure 12.4 Meropenem concentration during ECMO run with two different dosing regimens.
Unfortunately, data are very limited to be able to generalise these results for all antimicrobials. What is certain, though, so far, is that ‘one size does not fit all’ when it comes to drug dosing in patients on extracorporeal circuits. If feasible, drug levels should be monitored in this category of patients in order to establish the appropriate therapeutic regime.
Infective endocarditis (IE) is a deadly disease. Despite major improvements in diagnosis and treatment, IE remains associated with high morbidity and mortality. IE patients admitted to critical care are among the sickest the intensivist will have to deal with.
1. Patients with a prosthetic valve or with prosthetic material used for valve repair; this category includes transcatheter implanted valves and homografts.
2. Patients with previous IE; they also have a higher risk of infectious complications than patients with a first episode of IE.
3. Patients with untreated cyanotic congenital heart disease (CHD) or with prosthetic baffles or conduits as part of palliative management; the European Society of Cardiology (ESC) guidelines 2015 recommend that patients with definitive repair of CHD with prosthetic material should only receive antibiotic prophylaxis for the first 6 months, while endothelialisation of the prosthetic material occurs.
Diagnosis of infective endocarditis is based on the modified Duke criteria and the ESC 2015 guidelines, as shown in Table 12.2.
|Major and minor criteria of IE (ESC, 2015)|
Successful treatment of IE involves primarily pathogen eradication. Surgical treatment and the treatment of complications are beyond the scope of this chapter. With respect to antimicrobials in IE, there are currently the following recommendations, according to the British Society of Antimicrobial Chemotherapy, 2012 guidelines.
1. Initial empirical treatment of native valve endocarditis (NVE) depends on the clinical presentation.
(i) NVE indolent presentation: amoxicillin + gentamicin.
(ii) NVE severe sepsis: vancomycin + gentamicin.
(iii) NVE severe sepsis + risk of MDR: vancomycin + meropenem.
3. Antibiotic treatment of IE due to oral streptococci and Streptococcus bovis group depends on minimum inhibitory concentration, MIC (usual course is 4 weeks for NVE and 6 weeks for PVE).
(i) Penicillin-susceptible strains, non-penicillin allergic patients:
(a) Benzylpenicillin, or
(b) Amoxicillin, or
(ii) Penicillin-susceptible strains, penicillin-allergic patients:
(iii) Strains relatively resistant to penicillin (higher MIC required), non-penicillin allergic patients:
(a) Benzylpenicillin, double the dose for penicillin-susceptible strains and gentamicin, or
(b) Amoxicillin, double the dose for penicillin-susceptible strains and gentamicin, or
(c) Ceftriaxone and gentamicin.
(iv) Strains relatively resistant to penicillin (higher MIC required), penicillin- allergic patients:
Vancomycin and gentamicin.
4. Antibiotic treatment of IE due to Staphylococcus spp., for NVE:
(i) Methicillin-susceptible Staphylococcus spp., non-penicillin-allergic patients:
(ii) Methicillin-susceptible Staphylococcus aureus, alternative strategy:
Vancomycin or daptomycin.
(iii) Penicillin-allergic patients or methicillin-resistant Staphylococcus spp.:
(a) Vancomycin for 4–6 weeks, intravenous administration,
(b) Daptomycin for 4–6 weeks, intravenous administration.
5. Antibiotic treatment of IE due to Enterococcus spp.:
(i) Beta-lactam and gentamicin-susceptible strains:
(a) Amoxicillin and gentamicin for 4 weeks for NVE or 6 weeks for PVE,
(b) Ampicillin with ceftriaxone for 4 weeks for NVE or 6 weeks for PVE, for E. faecalis,
(c) Vancomycin and gentamicin for 6 weeks if penicillin allergy known or suspected.
(ii) Gentamicin-resistant species – replace gentamicin with streptomycin, if susceptible to the latter.
(a) Daptomycin and ampicillin,
(c) Vancomycin, if beta-lactam resistance but vancomycin susceptibility detected.