Prolonged infusions of beta-lactam antibiotics

Beta-lactam antibiotics demonstrate a time-dependent effect on bacterial eradication.

Prolonged infusions attain the pharmacodynamic efficacy target defined for beta-lactam
antibiotics more effectively than short infusions. Thus, a prolonged infusion administration
strategy may improve microbiologic and clinical cure, especially when pathogens
demonstrate higher minimum inhibitory concentrations (MIC). Prolonged infusion
administration strategies for intravenous beta-lactam antibiotics may include either a
continuous infusion (over the entire dosing interval) or an extended infusion (over 3 to 4
hours).

The duration of exposure is commonly measured as the percentage of the dosing interval that
the concentration of free drug remains above the minimum inhibitory concentration (MIC) of
the pathogen (%fT >MIC). Maximizing the duration of exposure can be accomplished in
three possible ways: increasing the dose, shortening the dosing interval, or prolonging the
infusion time Prolonged infusion administration strategies for intravenous beta-lactam
antibiotics may include either a continuous infusion (over the entire dosing interval) or an
extended infusion (over 3 to 4 hours)

Clinical data suggest that prolonged (extended or continuous) infusions of beta-lactams are at
least equally effective as and, in certain circumstances, such as critical illness, more effective
than traditional intermittent infusions for gram-negative infections.

Patients with altered pharmacokinetics — Critically ill, young, or obese patients, typically
with recent surgery or trauma, may have creatinine clearance >120 mL/min and be infected
with higher-MIC, hospital-acquired pathogens. Critical illness can also lead to variable
pharmacokinetics, such as augmented drug clearance, altered volumes of distribution,
abnormal fluid balance, and/or changes in protein binding. Achieving adequate serum levels
of antibiotics in these populations can thus be extremely challenging; higher doses and
prolonged infusions may be the best pharmacologic approach in such situations.

beta-lactam drugs are well tolerated in general, and prolonged infusion strategies appear to
have no more toxicity risk than intermittent dosing

Continuous infusions are easier to administer than intermittent infusions in the ambulatory
setting with dedicated intravenous lines and portable, battery-powered infusion pumps. As an
example, patients must access their line and change the cartridge on their pump only once in
a 24-hour period, rather than every four hours with intermittent infusions. This is particularly
convenient for patients who require prolonged durations of therapy delivered in the
ambulatory setting (eg, outpatient parenteral antibiotic therapy for endocarditis or
osteomyelitis). Continuous infusions in the outpatient setting is typically used for penicillin,
nafcillin, and oxacillin. Many outpatient pumps can also be programmed to allow prolonged
infusions of piperacillin-tazobactam and cefepime.

Administration of prolonged infusions require utilization of the intravenous pump for longer
periods of time, which may be problematic for patients with limited intravenous access or
lower levels of nursing care. As an example, patients on a medical ward may need to
ambulate to the bathroom or leave the unit for procedures, which can lead to interruptions in
the infusion and impaired drug delivery. Additionally, nurses must be aware of the need to
flush intravenous line tubing at the end of the infusion to allow for complete drug
administration. Prolonged infusions also may result in higher intravenous catheter utilization
for additional venous access.. Central catheters should not be placed for the sole reason of
delivering prolonged infusions

meropenem prepared for infusion is stable for up to 4 hours at room temperature and up to 24
hours refrigerated (at concentrations up to 20 mg/mL),. Ampicillin and ampicillin/sulbactam
are often limited to intermittent infusions because of their short half-lives; however,
individual institutions may have extended stability data to allow for safe administration of
continuous ampicillin and ampicillin/sulbactam, particularly for outpatient home infusion

the greatest benefit of prolonged infusions has been primarily in critically ill patients with
higher severity of illness and in patients with P. aeruginosa infection]

situations in which prolonged infusion strategies would offer a clinical benefit over
traditional intermittent strategies are infections with organisms that have a high, but still
susceptible-range MIC to the chosen beta-lactam. patients with a high severity of illness or
with P. aeruginosa infection are more likely to benefit from prolonged infusion strategies..
These include patients with:●Structural lung disease (including cystic fibrosis)●Frequent
healthcare exposures●Prior repeated antibiotic exposures●Critical illness with severe
infection (including central nervous system infections , necrotizing fasciitis, neutropenic
fever, burns) ●Infections due to pathogens with high intrinsic resistance and predilection for
developing acquired resistance during therapy (eg, P. aeruginosa, Burkholderia cepacia,
Acinetobacter baumannii)

When piperacillin-tazobactam, meropenem, imipenem, or cefepime is chosen for treatment in

such patients, we suggest a prolonged infusion dosing strategy. In particular, we favor
prolonged infusions for critically ill patients with gram-negative rod infections and for
patients with infections due to gram-negative rods that have elevated but susceptible
minimum inhibitory concentrations (MIC) to the chosen agent.

We limit use of prolonged infusion carbapenems to three-hour infusions and to the

indications discussed above due to impaired stability of imipenem and meropenem at room
temperature. Penicillins (eg, oxacillin, nafcillin) that are stable at room temperature for
greater than 24 hours can be used in the outpatient setting with continuous infusion pumps.
These agents are dosed by summing the total daily dose and then extending the infusion over
24 hours. As an example, nafcillin dosed intermittently at 2 grams every 4 hours with 30
minute infusions would be continuously infused as 12 grams over 24 hours.

Loading doses — Loading doses are sometimes used for patients with sepsis to try to achieve
therapeutic drug levels more rapidly and are recommended in this setting by the Surviving
Sepsis Campaign Guidelines . For piperacillin-tazobactam, a 3.375 g to 4.5 g loading dose
can be given over 0.5 hours. The optimal time to start the subsequent extended infusion is 4
hours later in patients with CrCl >20 mL/min and 8 hours later in patients with CrCl <20
mL/min. Of note, administering loading doses has not been shown to decrease mortality or
time to clinical improvement compared to initiating therapy with an extended infusion

Dosing for prolonged infusions of beta-lactams[1-8]

Infusion
Creatinine clearance Dose Dosing interval
time
 3.375 or
>20 mL/minute Every 8 hours 4 hours
4.5 g
Piperacillin- ≤20 mL/minute or 3.375 or
Every 12 hours 4 hours
tazobactam* intermittent HD or PD 4.5 g
3.375 or
CRRT¶ Every 8 hours 4 hours
4.5 g
≥50 mL/minute 2g Every 8 hours 4 hours
30 to 49 mL/minute 2g Every 12 hours 4 hours
15 to 29 mL/minute 1g Every 12 hours 4 hours
CefepimeΔ
<15 mL/minute or
1g Every 24 hours 4 hours
intermittent HD
CRRT¶ 2g Every 12 hours 4 hours
500 mg or
>70 Every 6 hours 3 hours
1g
500 mg or
41 to 70 Every 8 hours 3 hours
750 mg
Imipenem◊ 250 or 500
21 to 40 Every 6 hours 3 hours
mg
6 to 20 or intermittent 250 or 500
Every 12 hours 3 hours
HD or PD mg
CRRT¶ 500 mg Every 6 hours 3 hours
≥50 mL/minute 1 or 2 g Every 8 hours 3 hours
25 to 49 mL/minute 1 or 2 g Every 12 hours 3 hours
500 mg or 1
10 to 24 mL/minute Every 12 hours 3 hours
Meropenem§ g
<10 mL/minute or 500 mg or 1 Every 24 hours,
3 hours
intermittent HD g given after HD
CRRT¶ 1 or 2 g Every 12 hours 3 hours
>50 mL/minute 2.5 g Every 8 hours 2 hours
31 to 50 mL/minute 1.25 g Every 8 hours 2 hours
16 to 30 mL/minute 0.94 g Every 12 hours 2 hours
Ceftazidime-
avibactam 6 to 15 mL/minute 0.94 g Every 24 hours 2 hours
<5 mL/minute or Every 48 hours,
0.94 g 2 hours
intermittent HD given after HD
CRRT¶ 1.25 g Every 8 hours 2 hours
1500 or
>50 mL Every 8 hours 3 hours
3000 mg
Ceftolozane- 750 or 1500
30 to 50 mL/minute Every 8 hours 3 hours
tazobactam mg
375 or 750
15 to 29 mL/minute Every 8 hours 3 hours
mg
 <15 mL/minute or 150 or 375 Every 8 hours (start
3 hours
intermittent HD mg after loading dose)
750 or 1500
CRRT¶ Every 8 hours 3 hours
mg

≥50 mL/minute 4g Every 8 hours 3 hours

30 to 49 mL/minute 2g Every 8 hours 3 hours
Meropenem- 15 to 29 mL/minute 2g Every 12 hours 3 hours
vaborbactam <15 mL/minute or
1g Every 12 hours 3 hours
intermittent HD
CRRT¶ 2g Every 8 hours 3 hours

* The higher dose of piperacillin-tazobactam (4.5 g) is used in certain situations, such as

expected augmented drug clearance (as with critical illness or cystic fibrosis) or in cases of
infections with pathogens that have high, but still susceptible, MICs to piperacillin-
tazobactam when alternative agents are not appropriate. This higher dose can also be used for
empiric treatment in communities or institutions where the P. aeruginosa MICs to
piperacillin-tazobactam range higher than 32.

◊ Imipenem is dosed by both weight and renal function. Dosing above is based on patient
weight >70 kg.
§ The higher dose of meropenem is used in patients with infections of the central nervous
system or other life-threatening infections such as necrotizing fasciitis.