By Vibhu Sharma, MD, MS
Associate Professor of Medicine, University of Colorado, Denver
Appropriate antibiotic therapy in the critically ill requires consideration of important patient-specific factors, such as antibiotic therapy in the preceding 30 days; culture and sensitivity data, if available, within the prior six months; and local resistance patterns.1 Guidelines to treat severe community-acquired pneumonia (CAP) have been published. Risk factors for Pseudomonas species and methicillin-resistant Staphylococcus aureus (MRSA) in this setting include prior isolation of either organism and hospitalization and intravenous antibiotics in the previous 90 days. However, the guidelines acknowledge the weak and variable association of these and other individual risk factors for MRSA and Pseudomonas infection in patients presenting with severe CAP, emphasizing the need for vigilance and caution while tailoring therapy in the critically ill.
Other patient-specific factors that are easy to overlook in the critically ill are the role of obesity, the volume of drug distribution, and the possibility of augmented creatinine clearance, all of which may reduce the concentration of the antibiotic at the site of disease. The pharmacokinetics of antibiotics in the obese critically ill patient remain understudied, with guidance based on small, retrospective analyses and expert opinion. Drug clearance and volume of distribution have consistently been shown to be altered in obese patients compared with the non-obese.2,3 Augmented renal clearance is a phenomenon characterized by a normal creatinine level but increased drug clearance.4
In addition to the obese critically ill patient, this phenomenon has been described in those critically ill with trauma, sepsis, hematologic malignancies, head injury, central nervous system infections, intracranial hemorrhage, and burns.5,6 Although there are limited outcomes data, a discussion about non-traditional dosing (higher doses, extended or continuous infusion strategies) is prudent in these populations at risk for augmented renal clearance. In addition to these patient-specific factors, it is important to be familiar with local resistance patterns as well as the epidemiologic setting. Given the length considerations for this article, this review is not meant to be an exhaustive discussion of all antibiotics used in the ICU (including daptomycin and aminoglycosides), but it will focus on specific points to consider when treating gram-positive and gram-negative organisms.
Antibiotics for Gram-Positive Organisms
Vancomycin and linezolid remain the workhorses for gram-positive coverage in the intensive care unit. MRSA, coagulase-negative staphylococcal (CoNS) species, and streptococci are the usual targets of both these drugs. The two main risk factors for MRSA infections in the critically ill are prior isolation (any time) of MRSA and antibiotic therapy in the prior 90 days.
Vancomycin works in a time-dependent fashion with respect to bactericidal activity; bacterial killing is dependent on time spent above a certain concentration. Therefore, activity depends on tissue distribution/concentration and the amount of disease activity targeted. Vancomycin typically has been dosed to a trough level of >15 mcg/mL to 20 mcg/mL for serious and deep-seated infections (e.g., CAP, hospital-acquired pneumonia [HAP], liver abscess, endocarditis, and brain or lung abscesses) and 10 mcg/mL to 15 mcg/mL for other infections (e.g., skin and skin structure infections, urinary tract infections, and peritonitis). More recent guidelines recommend the use of area under the curve (AUC) monitoring rather than trough concentrations alone.7 An initial loading dose of 20 mg/kg to 35 mg/kg is usual for critically ill patients, those patients receiving continuous renal replacement therapy (CRRT), and those receiving continuous infusion therapy.8 The loading dose typically is followed by 15 mg/kg in divided doses per day, with dosing intervals altered with changes in CRRT dose. Continuous infusion is recommended for scenarios in which target AUC is not achieved with intermittent dosing.7 Follow-up blood cultures are recommended after 24 hours of therapy to reduce the risk of missing persistent bacteremia due to lack of source control.
Rarely, a patient may present with an infection and MRSA bacteremia that fails to clear with guideline-consistent therapy and source control. In this scenario, reduced susceptibility to vancomycin needs to be considered, as seen in infections caused by vancomycin-intermediate Staphylococcus aureus (VISA) or vancomycin-resistant Staphylococcus aureus (VRSA).9 A higher minimal inhibitory concentration (> 4 mcg/mL) defines intermediate to complete resistance to vancomycin. Overwhelming MRSA infections may take weeks to clear despite adequate therapy, and combination therapy may be indicated. An infectious disease consultation is recommended in these complex scenarios.
Multiple studies have assessed the utility of a nasal MRSA polymerase chain reaction (PCR) screen and outcomes with respect to treatment for MRSA infection (hospital-acquired or community-acquired). Among the non-critically ill, a negative screen at admission predicts absence of culture-proven MRSA infection at various sites, including the lungs, within seven days of the negative PCR and, thus, has utility as a “rule out” test for both HAP and CAP, with a sensitivity of 83% and negative predictive value of 98%.10,11 Sensitivity and negative predictive values for ventilator-associated pneumonia (VAP) were lower (40% and 94%, respectively); this suggests that a negative MRSA PCR has lower utility in ruling out VAP due to MRSA, likely “related to artificial airways serving as an additional source of MRSA to the nasal passage.”11
There remains some question about the duration for which a negative nasal MRSA PCR can be relied upon to rule out a new lower respiratory tract infection due to MRSA. One retrospective analysis suggests that the sensitivity and negative predictive value of the test does not deteriorate over time analyzed out to 14 days.12 This analysis also suggests the high sensitivity and negative predictive values for CAP and HAP persist whether specimens are collected in the intensive care unit or the medical surgical unit. Recent nasal decolonization with mupirocin and MRSA-directed antibiotic therapy for > 48 hours may result in false-negative tests in the nares. Furthermore, patients with structural lung disease (e.g., bronchiectasis, cystic fibrosis, interstitial lung disease) may have discordant MRSA colonization in the upper respiratory tract compared to the lower respiratory tract.
Caution also is warranted with de-escalation strategies using nasal MRSA PCR screen among critically ill patients with shock, acute respiratory distress syndrome (ARDS), and if the source of sepsis is thought to be extra-pulmonary. There are no high-quality data to support withholding MRSA-directed therapy in critically ill patients based on a negative nasal MRSA PCR at admission. Adverse effects to consider with vancomycin therapy include, most importantly, acute kidney injury (AKI). The risk of AKI correlates most closely to the trough concentration and the AUC. Median trough concentration of 15.7 mg/L and AUC value of 625 mg·h/L were associated with AKI in one study; values of 8.7 mg/L and 423 mg·h/L were found in subjects without AKI (P = 0.02).13
Linezolid is a bacterial protein synthesis inhibitor and is bacteriostatic against MRSA and CoNS, but bactericidal against streptococci. Indications for therapy are essentially identical to vancomycin and include skin and skin structure infections, pneumonia, and bloodstream infections. Some clinicians favor linezolid as adjunctive therapy in suspected MRSA toxic shock syndrome, replacing vancomycin added to clindamycin to maximize protein synthesis inhibition until susceptibilities are known.14 Known infections due to vancomycin-resistant enterococci (VRE) are another indication for upfront treatment with linezolid. Linezolid is non-renally cleared, and dose adjustment is not typically required in patients with AKI; however, renal replacement therapy (RRT) may reduce linezolid levels to a subtherapeutic range, and therefore an alternative agent may be needed.15 Close monitoring of clinical response to therapy and therapeutic dose monitoring is recommended if continued use is indicated in this scenario.16
Long-term therapy (≥ 14 days) with linezolid is associated with numerous systemic toxicities that limit the duration of therapy. The risk of serotonin syndrome with concurrent use of selective serotonin uptake inhibitors is well-described. Lactic acidosis may occur any time during therapy (at the start of therapy to months out) and may be fatal. Thrombocytopenia and anemia relate mostly to longer duration of therapy and are reversible after discontinuation.
The most common diagnoses requiring treatment of MRSA that intensive care clinicians will need to consider are HAP and VAP. Relevant outcomes appear equivalent with linezolid or vancomycin in these settings.17 Catheter-associated bloodstream infections typically are treated empirically with vancomycin, and not linezolid.
Antibiotics for Gram-Negative Organisms
Piperacillin-tazobactam is a combination of a cell wall-inhibiting penicillin and a penicillinase inhibitor; it exhibits time-dependent killing. While piperacillin-tazobactam is active against most gram-positive cocci (except MRSA), it has a major role in empiric therapy for infections due to gram-negative organisms and anaerobes. Notably, anaerobes may be resistant to piperacillin-tazobactam, and if anaerobic infections are suspected, cultures in appropriate media should be sent. Common indications for piperacillin-tazobactam in the critically ill include treatment of severe CAP/HAP/VAP and intra-abdominal infections. Typical dosing is at 3.375 grams every six hours, with more severe infections (including bacteremia) and Pseudomonas species infections dosed at 4.5 grams every six hours.18 Dosing will need to be modified in patients with AKI and in those receiving CRRT, given renal clearance.
Adverse effects to be aware of include neurotoxicity (e.g., confusion, speech alteration, seizures; risk increases with AKI and in critically ill and elderly patients), diarrhea (up to 10%), thrombocytopenia (may occur as early as day 3 of therapy), anaphylaxis (risk increases with prior exposure or history of hypersensitivity-type reactions), and AKI. The latter has been thought to occur with standalone therapy and synergistically with vancomycin based on small retrospective studies. A recent prospective study suggested that piperacillin-tazobactam is associated with creatinine-defined AKI but not with changes in cystatin C levels.19 This study did not find any increased risk of dialysis or mortality with the combination of piperacillin-tazobactam and vancomycin.
Cefepime is a fourth-generation cephalosporin and is used to treat pneumonia (gram-negative rods and Streptococcus pneumoniae), urinary tract infections, skin and skin structure infections due to streptococci or methicillin-sensitive Staphylococcus aureus (MSSA), complicated intra-abdominal infections, and as empiric therapy in febrile neutropenia. The typical dose for severe infections is 2 grams every eight hours, with dosing altered in patients with AKI to account for reduced renal clearance. Consultations with clinical pharmacists and infectious disease experts are recommended when organisms with high minimum inhibitory concentrations (MICs) (> 8 mcg/mL for most gram-negative organisms) are isolated; strategies in these scenarios may include extended infusion with each dose administered over three hours or continuous infusion with a 6-gram dose run over 24 hours, for example.20 Cefepime is comparable to ceftazidime in the treatment of serious gram-negative infections and for febrile neutropenia.21 Adverse effects with cefepime include encephalopathy, myoclonus, and seizures, which are more common in the setting of reduced renal clearance. As a class, cephalosporins have been associated with hemolytic anemia, hepatitis, and drug fevers.
Meropenem, imipenem, and ertapenem are bacterial cell wall synthesis inhibitors. Carbapenemases are specific beta-lactamases that hydrolyze these antibiotics and are the major cause of resistance. All three have activity against most aerobic gram-positive organisms, most gram-negative organisms (including extended-spectrum beta-lactamase [ESBL]-producing species), and anaerobes. There are some important differences in the spectrum of activity to note. Ertapenem has poor activity against Pseudomonas and Acinetobacter species and should not be started empirically if infections with these organisms are suspected. Ertapenem also is inactive against both Enterococcus faecalis and Enterococcus faecium, while imipenem and meropenem have activity against E. faecalis but not E. faecium.
Indications for carbapenems include empiric therapy in suspected multidrug-resistant (MDR), gram-negative infections, skin and skin structure infections due to streptococci and methicillin-sensitive staphylococci (although narrower-spectrum antibiotics are preferred), anaerobic intra-abdominal or pulmonary infections, and meningitis. Imipenem and meropenem typically are dosed at 500 mg every six hours. Ertapenem is dosed at 1 gram every 24 hours, making this carbapenem an attractive choice as a transition agent to outpatient antibiotic therapy. All carbapenems are renally cleared, and dose alterations are indicated in patients with AKI as well as those on CRRT. Escherichia coli and Klebsiella resistant to third-generation cephalosporins (e.g., ceftriaxone) may imply beta-lactamase production.
The MERINO trial compared therapy with a carbapenem vs. piperacillin-tazobactam in bloodstream infections due to ESBL-producing organisms and found a significant difference in mortality favoring carbapenem therapy.22 The MERINO-2 trial compared these two antibiotics in bloodstream infections with AmpC beta-lactamase-producing organisms.23 Enterobacter species and Serratia/Pseudomonas/Acinetobacter are known to produce AmpC beta-lactamase, while others (E. coli and Klebsiella) acquire resistance via plasmid-mediated mechanisms. Similar to the MERINO trial, therapy with meropenem was associated with fewer microbiologic failures. These trials demonstrate the utility of carbapenems in the treatment of resistant gram-negative organisms but also may encourage overuse of carbapenems resulting in increasing resistance to these drugs.
Ceftolozane/tazobactam and ceftazidime/avibactam are novel beta-lactam/beta-lactamase combination antibiotics that are used in the treatment of infections due to MDR gram-negative organisms. Ceftolozane/tazobactam has good lung penetration and demonstrated in vitro activity against MDR Pseudomonas species and Enterobacteriaceae that produce ESBLs. However, it is not active in the presence of carbapenemases.24 High-dose (i.e., double the usual dose of 1.5 grams every eight hours approved for intra-abdominal infections) ceftolozane/tazobactam was compared to meropenem in the ASPECT-NP trial of nosocomial pneumonia and found to be non-inferior with respect to 28-day all-cause mortality and clinical cure.25
Ceftazidime/avibactam has a spectrum of activity similar to ceftolozane/tazobactam, with additional activity against serine carbapenamases. These include gram-negative organisms that produce OXA-type carbapenamases and Klebsiella pneumoniae carbapenamases (KPC). However, ceftazidime/avibactam is inactive against metallocarbapenamase-producing organisms.26 These also are known as New Delhi metallocarbapenemases (NDM), relating to the first description in an isolate in India in 2007 with subsequent isolation of these organisms worldwide. While both drugs may be of use in treating Pseudomonas species resistant to both ceftazidime and meropenem, an infectious disease consultation is mandatory to best treat these infections, given multiple mechanisms of resistance and baseline resistance rates as high as 18% among archived specimens.27 As noted previously, a careful review of prior culture data and treatment history is necessary to appropriately treat critically ill patients who may have been exposed to multiple courses of antibiotics. Importantly, one risk factor to keep in mind is geography, specifically prolonged residence in a country with relevant resistance patterns. For example, NDM-producing organisms are endemic in the Indian subcontinent, and significant regional spread and outbreaks have been described in some Eastern European countries and the Middle East.28,29
Cefiderocol is a novel siderophore cephalosporin that has activity against carbapenamase-producing organisms. Cefiderocol has demonstrated in vitro activity against MDR Acinetobacter, Stenotrophomonas, Klebsiella, and Pseudomonas species, including those resistant to ceftolozane/tazobactam, ceftazidime/avibactam, levofloxacin, and trimethoprim-sulfamethoxazole by virtue of its ability to resist all three major mechanisms of gram-negative resistance to carbapenems: efflux pump, cell wall permeability, and inactivation by lactamases.30 Cefiderocol is an important empiric antibiotic in the right clinical setting (e.g., prior isolation of MDR Pseudomonas in a traveler from the Indian subcontinent now admitted with a severe pneumonia).
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- Harris PNA, Tambyah PA, Lye DC, et al. Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: A randomized clinical trial. JAMA 2018;320:984-994.
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Appropriate antibiotic therapy in the critically ill requires consideration of important patient-specific factors, such as antibiotic therapy in the preceding 30 days; culture and sensitivity data, if available, within the prior six months; and local resistance patterns.
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