Alexander Fleming’s discovery of penicillin in 1928 ushered in the antibiotic era with a profound impact on the treatment of infectious diseases. In his seminal paper of 1953, Harry Eagle, based on animal experiments, proposed that the therapeutic effect of penicillin depended on the duration of effective drug levels at the site of infection. High doses, leading to intermittent, excessive drug levels at the site of infection, did not exhibit an enhanced bactericidal effect. He went on to suggest that a prolonged infusion of penicillin is more likely to maintain drug levels consistently above the therapeutic threshold and hence, conceivably, more effective compared to intermittent administration (1). Several decades later, William Craig re-evaluated PK/PD principles in relation to beta-lactam antibiotics. He emphasized the crucial role of the time during which the serum beta-lactam concentration remained above the minimum inhibitory concentration (fT >MIC) as the most crucial determinant of efficacy of beta-lactams. Today, as we grapple with widespread antibiotic resistance, it is all the more important to seek techniques of optimizing therapy and diminish the emergence of resistant strains. Administration of beta-lactams as prolonged infusions has evoked considerable interest among critically ill patients with several clinical trials evaluating its efficacy.
What is the rationale behind administration of antibiotics as a prolonged infusion?
The efficacy of beta-lactam antibiotics is directly related to the duration for which the concentration of the free drug remains above the MIC of the target pathogen (%fT >MIC). Conventionally, fT >MIC of 40–70% is considered to be appropriate for optimal antibacterial effect. It has been proposed that the free plasma concentration of beta-lactams needs to remain above MIC for at least 40% of the time with carbapenems, 50–60% with penicillins, and 60–70% of the time with monobactams and cephalosporins (2). More recent studies suggest that free drug concentrations above 4 times the MIC (100%fT> 4 x MIC) for 100% of the time may be associated with a more pronounced therapeutic effect and reduce the emergence of resistant strains (3). Dosing by intermittent infusion invariably leads to peaks and troughs in antibiotic levels with unnecessarily high levels interspersed with subtherapeutic levels, that may lead to impaired efficacy. Beta-lactam levels with maximal anti-bacterial effect has been shown to be superior with prolonged compared to intermittent infusions in robust in vitro and in vivo PK/PD studies (4).
Methods of administration of antibiotics as a prolonged infusion
There are two methods of administration of antibiotics as prolonged infusions. The extended infusion is administration of the dose over a period of 3–4 hours, over approximately 40–50% of the dosing interval. A continuous infusion involves administration of the entire daily dose over 24 hours without interruption, after the initial loading dose (5).
Pharmacokinetics in critically ill patients
The volume of distribution is often higher in critically ill patients due to capillary leakage, edema, intravenous fluid resuscitation, hypoalbuminemia, presence of pleural effusions, and ascites. The higher volume of distribution may lead to dilution of antibiotic concentrations in the plasma and extracellular fluids (6). Augmented renal clearance (ARC), characterized by enhanced rate of drug elimination by the kidneys often occurs in young patients with a relatively low severity of illness. ARC is often associated with sepsis, trauma, burns, and after major surgery and may lead to suboptimal antibiotic levels and treatment failure (7). Hence, prolonged infusions may be more effective in most critically ill patients as they sustain consistent levels of beta-lactams above the MIC, thereby preventing wide fluctuation of antibiotic levels, often subtherapeutic, over prolonged durations.
Patient populations that might benefit with prolonged infusions
The clinical response varies between patients infected with susceptible compared to resistant organisms depending on the mode of beta-lactam administration. In patients with mild illness with highly susceptible organisms, intermittent administration may be equally effective compared to prolonged infusions. Critically ill and immunocompromised patients are more likely to benefit from prolonged infusions (8). Prolonged infusions are likely to be more effective in infection caused by relatively resistant organisms including carbapenemase-producing Enterobacteriaceae, carbapenem-resistant Pseudomonas aeruginosa, Acinetobacter baumanni, and Stenotrophomonas maltophilia, especially in skin and soft tissue infections and in burns (9,10). Patients on continuous renal replacement therapy may not benefit from prolonged infusion of beta-lactams because of reduced drug clearance and exposure to higher drug levels (11). Attainment of the PK/PD target of 100% fT >4 MIC was compared between prolonged and intermittent infusions of the newer antibiotic combination of ceftolozane/tazobactam in multidrug-resistant Pseudomonas aeruginosa infections. More than half of patients in this cohort were critically ill or immunocompromised. The authors observed that when the MIC was <4 mg/l, the PK/PD target was achieved by all patients in the cohort. However, in isolates with higher MICs of up to 8 mg/l, only a prolonged infusion was able to achieve the PK/PD target (12). Thus, prolonged infusions are likely to benefit among patients infected with relatively resistant organisms.
Patients with severe illness
Prolonged infusion of beta-lactam antibiotics has been clearly associated with favorable attainment of PK/PD targets. Several recent trials have evaluated the impact of prolonged infusion of beta-lactam antibiotics on clinical outcomes.
In a secondary analysis of the BICRHOME study, Bartoletti et al. evaluated the effect of prolonged compared to intermittent infusion of piperacillin-tazobactam and carbapenems on 30-day mortality of patients with cirrhosis and bloodstream infection. Piperacillin-tazobactam was administered as a loading dose of 4.5–9 g followed by a continuous infusion of 13.5–18 g over 24 hours. Meropenem was administered as a loading dose of 1 g followed by a continuous infusion of 2–6 g over 24 hours; imipenem-cilastatin was administered as a loading dose of 1 g as a loading dose, and a continuous infusion of 2–3 g over 24 hours. In the intermittent infusion arm, the drugs were administered over a 30-min duration. Continuous infusion was associated with a lower mortality (16% vs 36%, P=0.047); the effect persisted after adjustment for baseline severity of illness. Mortality reduction was observed in subgroups of patients with sepsis and those with acute on chronic liver failure with a MELD score of ≥ 25.
A retrospective observational study compared clinical outcomes before and after the implementation of a prolonged infusion protocol of piperacillin-tazobactam in patients admitted to the ICU for >72 hours. After implementation the prolonged infusion protocol, a significant reduction in the ICU and hospital length of stay was observed in this study. However, the hospital mortality remained unchanged during the entire study period (13).
Ram et al. conducted a randomized trial (RCT) that compared extended infusions administered over 4 hours compared with bolus infusions administered over 30 minutes of piperacillin-tazobactam or ceftazidime in critically ill patients with febrile neutropenia (14). A total of 105 patients were included on intention-to-treat analysis; 47 patients received an extended infusion while 58 received intermittent boluses. The overall treatment response on day 4, based on pre-specified criteria, occurred in 35 (74.4%) patients in the extended infusion arm and 32 (55.1%) patients in the intermittent bolus group (P = .044). The benefit was most profound in patients with pneumonia and those with clinically documented infection. This study revealed improved clinical outcomes with beta-lactams in immunocompromised patients with febrile neutropenia with continuous infusion of beta-lactams; the greatest benefit was observed in patients with pulmonary infections.
Beta-lactams administered as a prolonged infusion may enhance penetration into the interstitial fluid of infected lung tissue and potentiate bacterial killing (15). Ibrahim et al. compared the effect of imipenem as an extended infusion over 180 minutes compared to intermittent administration over 30-60 min in a retrospective observational study (16). The authors observed a significantly lower mortality, reduction in recurrent infections with the same organisms, and a shorter duration of mechanical ventilation and ICU stay with extended infusions compared with intermittent administration. They concluded that an extended infusion improves the PK/PD profile of imipenem and optimizes the therapeutic effect compared to intermittent administration.
Considering the relative lack of robust evidence from controlled clinical trials, several meta-analyses have evaluated prolonged compared with intermittent infusion of antibiotics on clinical outcomes in critically ill patients.
Vardakas et al. performed a meta-analysis of 1876 patients from 22 RCTs (17). The authors aimed to evaluate the efficacy of prolonged compared to short term infusion of antipseudomonal beta-lactam antibiotics in patients with sepsis. Prolonged infusion of beta-lactams was associated with a lower all-cause mortality compared with infusions administered over a shorter duration (risk ratio [RR] 0·70, 95% CI 0·56-0·87). The reduction in mortality was approximately 30% when Pseudomonas aeruginosa was the causative organism. Mortality benefit was observed with beta-lactam/beta-lactamase inhibitors; no benefit was observed with prolonged infusion of cephalosporins. No difference in clinical cure was observed between study groups. However, fewer RCTs evaluated clinical cure compared to mortality. The total dose of antibiotics administered was lower in most studies with the use of prolonged infusions compared with short term infusions.
Roberts et al. performed a meta-analysis of individual patient data in critically ill patients with severe sepsis. The authors assessed clinical outcomes in patients who received continuous compared with intermittent infusion of beta-lactam antibiotics. Three RCTs including 632 patients with severe sepsis were included in the meta-analysis. Hospital mortality was significantly lower (19.6% vs. 26.3%; relative risk, 0.74; 95% confidence interval, 0.56–1.00; P = 0.045)] and clinical cure significantly greater (55.4% vs. 46.3%; relative risk, 1.20; 95% confidence interval, 1.03–1.40; P = 0.021) in patients who received continuous compared to intermittent infusion.
The efficacy of prolonged infusions of beta-lactams may be marginal or even absent in infections with highly susceptible pathogens. However, in multidrug-resistant infections, there may be a definite advantage with the use of prolonged infusions. Antibiotic resistance is common with non-fermenting gram-negative bacilli, including Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Burkholderia pseudomallei, and Burkholderia cepacia. These organisms, commonly seen in the Asia-Pacific region, have higher MICs and may be more susceptible with prolonged compared to intermittent infusion of antibiotics (18).
Therapeutic drug monitoring
Perhaps the most effective technique of ensuring appropriate concentrations of antibiotics may be through therapeutic drug monitoring (TDM). Prolonged infusions targeting optimal PK/PD parameters combined with TDM may be particularly relevant in critically ill patients. Richter et al. evaluated therapeutic drug monitoring-guided dosing with a continuous infusion and individualized dosing of piperacillin-tazobactam (PIP) on the attainment of PK-targets in critically ill patients (19). The minimum PK-target of ≥ 33 mg/l was achieved in the large majority of patients with this method. The authors also observed that patients who attained a target of 33–64 mg/l within the initial 24 h experienced the lowest hospital mortality rates. Renal function and the initiation of renal replacement therapy may be one of the main determinants of attainment of the PK-target. This study demonstrates that prolonged infusions combined with TDM may be effective in optimizing antibiotic dosing in critically ill patients.
Areas of concern with prolonged infusions
Education of medical and nursing staff is important prior to embarking on a policy of prolonged infusions. Prescriptions need to be precise, with clear instructions on the dose, concentration, and the duration of infusion. Administration errors are likely if strict guidelines are not followed. Imprecise infusion pumps and absence of electronic medical records regarding details of administration are safety concerns. Compatibility with co-administered drugs through the same IV line needs to be ensured; this may often necessitate the use of central venous catheters with a dedicated line for prolonged antibiotic infusion. The chemical stability of antibiotics in solution also needs to be addressed; the stability of meropenem in solution, for instance, varies between 4–12 hours, with greater stability when diluted in normal saline (20). The possibility of drug loss in the dead space of infusion tubings may be substantial and flushing of lines with appropriate volumes is important.
- In an era of increasing antibiotic resistance with relatively few newer drugs, modification of administration of available drugs is an important strategy aimed to optimize therapeutic effect while minimizing the emergence of resistant strains.
- Beta-lactams demonstrate time-dependent killing; it is logical to administer them as a prolonged infusion aimed to maintain drug concentrations above the MIC for longer periods of time. This is in contrast to intermittent bolus administration that often results in highly variable levels that fail to sustain above the MIC
- There is compelling evidence that prolonged infusion of beta-lactams after an initial loading dose leads to a more favorable PK/PD profile. The advantages of a prolonged infusion may be less important in infections with susceptible strains; however, it is likely to be of benefit with resistant organisms that are common among critically ill patients
- Clinical evidence supports the use of prolonged infusion of beta-lactams in critically ill patients, especially among those infected with non-fermenting gram-negative bacilli
- Prolonged infusion of antibiotics may lead to a lower total dose. Thus, overall antibiotic consumption may potentially reduce, with a relatively lower incidence in the emergence of resistant organisms.
- Meta-analysis of RCTs suggest likely mortality benefit and improved rates of clinical cure with prolonged infusions compared to intermittent dosing
- There have been no reports of an increase in the incidence of antibiotic-associated toxicity or other adverse events following prolonged infusions. Hence, abiding by PK/PD principles appears to be logical and supports the administration of beta-lactams as prolonged infusions.
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