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Combination beta-lactamase inhibitors, carbapenems, and

monobactams
Author: Alyssa R Letourneau, MD
Section Editor: David C Hooper, MD
Deputy Editor: Allyson Bloom, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Sep 2019. | This topic last updated: Jul 29, 2019.

INTRODUCTION

The spectrum of activity and pharmacology of combination beta-lactamase inhibitors,

carbapenems, and monobactams will be reviewed here. The mechanisms of action and resistance
and major adverse reactions of the beta-lactam antibiotics, issues related to penicillins and
cephalosporins are discussed separately. (See "Beta-lactam antibiotics: Mechanisms of action and
resistance and adverse effects" and "Penicillin, antistaphylococcal penicillins, and broad-spectrum
penicillins" and "Cephalosporins".)

BETA-LACTAMASE INHIBITOR COMBINATIONS

Clavulanate, sulbactam, tazobactam, avibactam, and vaborbactam are beta-lactamase inhibitors

that have little intrinsic antibacterial activity but inhibit the activity of a number of plasmid-mediated
beta-lactamases [1]. Only avibactam inhibits chromosomally mediated AmpC beta-lactamases,
and none inhibit the class B metallo-carbapenemases, such as New Delhi metallo-beta-lactamase
[2]. Combination of these agents with ampicillin, amoxicillin, piperacillin, ceftolozane, ceftazidime,
and meropenem results in antibiotics with an enhanced spectrum of activity against many, but not
all, organisms containing plasmid-mediated beta-lactamases. The addition of avibactam to
ceftazidime, vaborbactam to meropenem, and relebactam to imipenem-cilastatin results in
enhanced activity against many, but not all, organisms producing carbapenemases. In addition,
sulbactam and tazobactam inhibit the chromosomal beta-lactamase of many Bacteroides species,
extending the spectrum of coverage of combinations with these compounds to include Bacteroides
as well.

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Dosing of combination beta-lactam beta-lactamase inhibitors is listed separately, and the dosing
should be modified in the setting of renal failure (table 1). For piperacillin-tazobactam, an extended
infusion (eg, 3.375 g infused over four hours every eight hours) is an alternative to standard
dosing; in particular, this strategy has been used for critically ill patients or for pathogens with
elevated but susceptible minimum inhibitory concentrations. The benefits of extended infusion
over standard dosing have been suggested by some studies but not all [3,4]. Overall, this dosing
regimen is at least equivalent and may be superior to standard dosing in appropriate patient
populations. (See "Prolonged infusions of beta-lactam antibiotics".)

Amoxicillin-clavulanate — Amoxicillin-clavulanate will inhibit most strains of oxacillin-sensitive

Staphylococcus aureus and beta-lactamase producing Haemophilus influenzae in addition to the
usual organisms inhibited by amoxicillin alone (see "Penicillin, antistaphylococcal penicillins, and
broad-spectrum penicillins"). At the high drug concentrations achieved in urine, the combination is
also active against certain beta-lactamase producing Enterobacteriaceae. Amoxicillin-clavulanate
can be used as oral therapy for patients with otitis media, sinusitis, lower respiratory infections,
bite wounds, and urinary tract infections [5], although there are no data that this combination is
superior to other antibiotics (such as trimethoprim-sulfamethoxazole or the second or third
generation oral cephalosporins). (See "Animal bites (dogs, cats, and other animals): Evaluation
and management".)

Ampicillin-sulbactam — Ampicillin-sulbactam is a parenteral formulation that expands the

spectrum of ampicillin to include most strains of S. aureus and beta-lactamase producing H.
influenzae, some Enterobacteriaceae, and anaerobes (including Bacteroides fragilis). The
sulbactam component of ampicillin-sulbactam has activity against many strains of Acinetobacter
baumannii. Ampicillin-sulbactam has been used to treat patients with diabetic foot ulcers [6]. This
combination has also been used for prophylaxis and therapy of intra-abdominal and pelvic
infections instead of cefoxitin. Randomized, double-blind trials showed ampicillin-sulbactam to be
equivalent to cefoxitin in prophylaxis for abdominal surgery and in the treatment of intra-abdominal
and pelvic infections [7,8]. However, increasing resistance worldwide to ampicillin-sulbactam of
both Enterobacteriaceae and B. fragilis in intra-abdominal infections renders this drug combination
less useful for this purpose [9-11].

In some parts of the world, an oral prodrug of ampicillin-sulbactam, sultamicillin, is available in

tablet form (sultamicillin tosylate) or powder for oral suspension [12]. Sultamicillin has a similar
spectrum of activity to ampicillin-sulbactam and has been used for infections of the ear, sinus,
throat, lower respiratory tract, urinary tract, female genital tract, skin, and soft tissues [13,14]. The
adult dose ranges from 375 to 750 mg two to three times daily and warrants reduction in the
setting of renal impairment.

Piperacillin-tazobactam — Piperacillin-tazobactam expands the spectrum of piperacillin to

include beta-lactamase producing S. aureus, H. influenzae, Neisseria gonorrhoeae, some
Enterobacteriaceae, and anaerobes (including B. fragilis) [15]. This combination is generally not
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effective for piperacillin-resistant strains of Pseudomonas aeruginosa. In addition, piperacillin-

tazobactam, dosed at 3.375 g every six hours, may not be an adequate dose for the treatment of
P. aeruginosa infections. Thus, the spectrum and clinical utility of this agent is similar to ampicillin-
sulbactam, but it is preferred over ampicillin-sulbactam for intra-abdominal infection when an
agent from this class is chosen. (See "Antimicrobial approach to intra-abdominal infections in
adults", section on 'Empiric antimicrobial therapy'.)

Ceftolozane-tazobactam — Ceftolozane is a novel cephalosporin whose gram-negative activity

is expanded by the addition of tazobactam. The combination has broad-spectrum in vitro activity
against aerobic and facultative gram-negative bacilli, including P. aeruginosa and most extended-
spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. It has limited gram-positive
activity against streptococci. Enterococcal and staphylococcal species are generally resistant. In
clinical trials, clinical cure rates with ceftolozane-tazobactam were similar to those with
levofloxacin for complicated urinary tract infection caused by levofloxacin-susceptible organisms
and, when combined with metronidazole, were similar to those with meropenem for complicated
intra-abdominal infections [16-19]. Ceftolozane-tazobactam also performed favorably against
infections caused by ESBL-producing isolates in these trials [20]. It is also effective in treating
carbapenem-resistant, ceftolozane-tazobactam susceptible P. aeruginosa pneumonia, as
illustrated in a small multicenter, retrospective study [21]. Efficacy of ceftolozane-tazobactam may
be attenuated in patients with renal impairment (estimated glomerular filtration rate [GFR] <50
mL/min).

Ceftazidime-avibactam — Avibactam is a novel broad-spectrum beta-lactamase inhibitor that has

minimal antibacterial activity on its own. The addition of avibactam to ceftazidime extends the
spectrum of activity to include most Enterobacteriaceae (including those that produce AmpC beta-
lactamase, ESBL, and some K. pneumoniae and OXA-type carbapenemases) as well as P.
aeruginosa species with high MICs to ceftazidime alone. Ceftazidime-avibactam does not have
activity against Acinetobacter species or organisms that produce metallo-beta-lactamases and is
less active against anaerobes than other beta lactam-beta-lactamase combinations [22]. In trials,
the microbiological efficacy and clinical cure rates with ceftazidime-avibactam were similar to
those with imipenem for complicated urinary tract infection and, when combined with
metronidazole, were overall similar to those with meropenem for complicated intra-abdominal
infections [23-25]. The microbiological and clinical efficacy of ceftazidime-avibactam against
isolates that were not ceftazidime susceptible also compared favorably with the carbapenem
comparator.

Meropenem-vaborbactam — Vaborbactam is a novel broad-spectrum beta-lactamase inhibitor

that potently inhibits class A carbapenemases (including K. pneumoniae carbapenemases [KPC]).
It is not active against class B or D carbapenemases (ie, metallo-beta-lactamases and OXA-type
enzymes). The addition of vaborbactam to meropenem reduces the MICs to meropenem among
class A carbapenemase-producing Enterobacteriaceae to wild-type MIC levels [26,27].

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Meropenem-vaborbactam was comparable to piperacillin-tazobactam in a trial of patients with

complicated urinary tract infection [28], and it is being evaluated in patients with bacteremia,
hospital-acquired pneumonia, and complicated intraabdominal infections [29,30]. The main role of
this agent is for treatment of KPC-producing Enterobaceriaceae. Clinical data are thus far limited;
an as yet unpublished randomized trial comparing meropenem-vaborbactam with the best
available therapy for treatment of carbapenem-resistant Enterobacteriaceae infections was
stopped early because of better outcomes in the meropenem-vaborbactam arm [29].

Vaborbactam does not enhance the clinical activity of meropenem against carbapenem-resistant
P. aeruginosa or Acinetobacter spp.

Imipenem-cilastatin-relebactam — Relebactam is a broad-spectrum beta-lactamase inhibitor

that inhibits class A carbapenemases (including K. pneumoniae carbapenemases [KPC]). It is not
active against class B or D carbapenemases (ie, metallo-beta-lactamases and OXA-type
enzymes). The addition of relebactam to imipenem-cilastatin improves the activity against most
species of Enterobacteriaceae (reduces the MIC by 2- to 128-fold) and against some imipenem-
nonsusceptible P. aeruginosa (reduces the MIC eightfold) [31-33]. In clinical trials of patients with
complicated urinary tract infection and intraabdominal infection, the efficacy and safety of
imipenem-cilastatin-relebactam were comparable with those of imipenem-cilastatin [34,35]. The
main role of this agent is for treatment of KPC-producing Enterobacteriaceae, but clinical data
evaluating imipenem-cilastatin-relebactam for such infections are limited.

Relebactam does not enhance the clinical activity of imipenem-cilastatin against Acinetobacter
species or Stenotrophomonas maltophilia.

CARBAPENEMS

Carbapenems are generally resistant to cleavage by most plasmid and chromosomal beta-
lactamases and have a very broad spectrum of activity encompassing [36,37]:

● Gram-negative organisms (including beta-lactamase producing H. influenzae and N.

gonorrhoeae, the Enterobacteriaceae, and P. aeruginosa), including those that produce
extended-spectrum beta-lactamases

● Anaerobes (including B. fragilis)

● Gram-positive organisms (including Enterococcus faecalis and Listeria)

Carbapenems are not generally active against S. maltophilia (which has a carbapenem-
hydrolyzing chromosomal beta-lactamase), Burkholderia cepacia, Enterococcus faecium, oxacillin-
resistant staphylococci, or JK diphtheroids.

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Although initial isolates of P. aeruginosa are usually susceptible to the carbapenems, resistance
may emerge on therapy when these drugs are used as a single agent. Evidence suggests that
carbapenems do not traverse the outer membrane of P. aeruginosa through the normal porin
channel used by the other beta-lactams but rather through a different channel [38]. Carbapenem-
resistant strains of P. aeruginosa arising on therapy generally have altered permeability to these
drugs and specific changes in their outer membrane proteins; such strains are generally not cross-
resistant to other beta-lactams nor do they produce increased or novel beta-lactamase activity.

Carbapenem-hydrolyzing beta-lactamases have been increasingly isolated from gram-negative

organisms and may limit therapy with these agents in these circumstances. (See "Beta-lactam
antibiotics: Mechanisms of action and resistance and adverse effects" and "Overview of
carbapenemase-producing gram-negative bacilli".)

All carbapenems should be dose-reduced in the setting of renal dysfunction (table 1).

Imipenem — Imipenem is inactivated in the proximal renal tubule by the normal human enzyme
renal dehydropeptidase I, with resultant low urinary levels of active drug and necrosis of the
proximal tubule in the rabbit model. Such cleavage of imipenem is prevented by co-administration
of cilastatin, a specific inhibitor of this dehydropeptidase. Imipenem-cilastatin (500 mg IV Q6h with
normal renal function) is available for clinical use. The dosing of imipenem should be carefully
titrated; patients with glomerular filtration rates of <5 mL/min should generally not receive
imipenem unless hemodialysis is ongoing or will start within 48 hours.

Imipenem-cilastatin therapy has been associated with central nervous system (CNS) toxicity,
including change in mental state, myoclonus, and seizures [39]. In a meta-analysis of over 100
studies that compared imipenem to a non-carbapenem antibiotic, imipenem use was associated
with an excess of 4 seizures per 1000 patients treated [40]. CNS toxicity with imipenem is
especially evident in patients with underlying CNS disease or impaired renal function. Imipenem
should not be used for the therapy of meningitis.

Meropenem — Meropenem has a spectrum of activity similar to imipenem [41]. Unlike imipenem,
meropenem is stable to human renal dehydropeptidase I, so can be administered without
cilastatin. Meropenem may have a slightly lower risk of producing seizures than imipenem-
cilastatin, but that decrease has not been proven in direct head-to head comparisons of small
sample size [40]. Meropenem is useful for the treatment of bacterial meningitis (in pediatric
patients >3 months old) and intra-abdominal infection [42,43].

Ertapenem — Ertapenem is a newer carbapenem with a narrower spectrum of activity than

imipenem or meropenem. It is active against most Enterobacteriaceae and anaerobes but less
active than the other carbapenems for P. aeruginosa, Acinetobacter, and Gram positive bacteria,
particularly enterococci and penicillin-resistant pneumococci. The major benefit of ertapenem over
other carbapenems is that it has a long half-life and can be administered once daily. Unlike

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meropenem, there are insufficient data to support the use of ertapenem for the therapy of
meningitis.

Doripenem — Doripenem has demonstrated clinical efficacy in the treatment of complicated

urinary tract and intra-abdominal infections [44,45]. It has a similar spectrum of activity as
meropenem, although it appears to have more potent in vitro activity against P. aeruginosa than
meropenem [46,47].

In 2014, the US Food and Drug Administration (FDA) approved revisions to the doripenem label
warning clinicians about increased mortality rates in patients with ventilator-associated bacterial
pneumonia who received doripenem rather than imipenem, based on results of a randomized trial
that was stopped early due to safety concerns [48]. In the trial, 28-day all-cause mortality was
higher and clinical response rates were lower with doripenem compared with imipenem, although
different dosing regimens and use of adjunctive aminoglycosides may have influenced these
results [49]. (See "Treatment of hospital-acquired and ventilator-associated pneumonia in adults",
section on 'Gram-negative pathogens'.)

Further clinical trials are required to establish the efficacy and safety of doripenem in the setting of
bacteremia and other severe infections.

MONOBACTAMS (AZTREONAM)

Aztreonam (1 to 2 g IV Q8h) is a monocyclic beta-lactam antibiotic with good in vitro activity

against the majority of gram-negative aerobic and facultative bacteria, including the
Enterobacteriaceae and P. aeruginosa [37,50]. It has virtually no activity against gram-positive
organisms or anaerobes; the majority of strains of Acinetobacter and S. maltophilia are resistant
and resistant strains of P. aeruginosa frequently emerge during therapy with aztreonam alone. The
spectrum of activity of aztreonam is similar to that of the aminoglycosides. However, it is less
reliable therapy than aminoglycosides for the non-enteric gram-negative bacilli such as
Acinetobacter, P. aeruginosa, and S. maltophilia.

Aztreonam is distinctive in that it is not degraded by the class B metallo-beta-lactamases, such as

New Delhi metallo-beta-lactamase. (See "Overview of carbapenemase-producing gram-negative
bacilli", section on 'Metallo-beta-lactamases'.)

Data support the absence of cross-allergenicity between aztreonam and other beta-lactam
antibiotics [51]. However, patients with ceftazidime allergy may be allergic to aztreonam because
of a shared side chain. The clinical situation in which aztreonam is most useful is in place of an
extended spectrum penicillin or cephalosporin when these are indicated but cannot be used
because of allergy. Aztreonam is the only monobactam currently marketed. Dose reductions are
recommended in the setting of renal dysfunction (table 1).

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SUMMARY

● Clavulanate, sulbactam, tazobactam, avibactam, vaborbactam, and relebactam are beta-

lactamase inhibitors that have little intrinsic antibacterial activity but inhibit the activity of a
number of plasmid-mediated beta-lactamases. Combination of these agents with ampicillin,
amoxicillin, piperacillin, ceftolozane, or ceftazidime results in antibiotics with an enhanced
spectrum of activity against many, but not all, organisms containing plasmid-mediated beta-
lactamases. The addition of avibactam to ceftazidime, vaborbactam to meropenem, and
relebactam to imipenem-cilastatin results in enhanced activity against many, but not all,
organisms producing carbapenemases. The sulbactam component of ampicillin-sulbactam
has activity against Acinetobacter. (See 'Beta-lactamase inhibitor combinations' above.)

● Carbapenems have a broad spectrum of activity against gram-negative organisms (including

those that produce extended spectrum beta-lactamases), anaerobes (including Bacteroides
fragilis), and gram-positive organisms (including Enterococcus faecalis and Listeria). When
carbapenems are used as a single agent against initially susceptible isolates of
Pseudomonas aeruginosa, resistance may emerge during therapy. (See 'Carbapenems'
above.)

● Aztreonam is a monocyclic beta-lactam with good in vitro activity against the majority of gram-
negative aerobic and facultative bacteria, including the Enterobacteriaceae and P.
aeruginosa, but virtually no activity against gram-positive organisms or anaerobes. However,
when used alone for therapy of P. aeruginosa infection, resistance may emerge. Aztreonam
has minimal cross-allergenicity with other beta-lactams with the exception of ceftazidime.
(See 'Monobactams (aztreonam)' above.)

● The dosing of these novel beta-lactams and dose modifications in patients with renal
dysfunction (table 1) are important considerations in prescribing these drugs.

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ssed on July 24, 2019).

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36. Norrby SR. Carbapenems. Med Clin North Am 1995; 79:745.

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37. Asbel LE, Levison ME. Cephalosporins, carbapenems, and monobactams. Infect Dis Clin
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38. Huang H, Hancock RE. Genetic definition of the substrate selectivity of outer membrane
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39. Calandra G, Lydick E, Carrigan J, et al. Factors predisposing to seizures in seriously ill
infected patients receiving antibiotics: experience with imipenem/cilastatin. Am J Med 1988;
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40. Cannon JP, Lee TA, Clark NM, et al. The risk of seizures among the carbapenems: a meta-
analysis. J Antimicrob Chemother 2014; 69:2043.

41. Cox CE, Holloway WJ, Geckler RW. A multicenter comparative study of meropenem and
imipenem/cilastatin in the treatment of complicated urinary tract infections in hospitalized
patients. Clin Infect Dis 1995; 21:86.

42. Condon RE, Walker AP, Sirinek KR, et al. Meropenem versus tobramycin plus clindamycin
for treatment of intraabdominal infections: results of a prospective, randomized, double-blind
clinical trial. Clin Infect Dis 1995; 21:544.

43. Chang DC, Wilson SE. Meta-analysis of the clinical outcome of carbapenem monotherapy in
the adjunctive treatment of intra-abdominal infections. Am J Surg 1997; 174:284.

44. Naber KG, Llorens L, Kaniga K, et al. Intravenous doripenem at 500 milligrams versus
levofloxacin at 250 milligrams, with an option to switch to oral therapy, for treatment of
complicated lower urinary tract infection and pyelonephritis. Antimicrob Agents Chemother
2009; 53:3782.

45. Lucasti C, Jasovich A, Umeh O, et al. Efficacy and tolerability of IV doripenem versus
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multicenter, randomized, double-blind, noninferiority study. Clin Ther 2008; 30:868.

46. Zhanel GG, Wiebe R, Dilay L, et al. Comparative review of the carbapenems. Drugs 2007;
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47. Paterson DL, Depestel DD. Doripenem. Clin Infect Dis 2009; 49:291.

48. US Food and Drug Administration. FDA approves label changes for antibacterial Doribax (do
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49. Kollef MH, Chastre J, Clavel M, et al. A randomized trial of 7-day doripenem versus 10-day
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50. Johnson DH, Cunha BA. Aztreonam. Med Clin North Am 1995; 79:733.

51. Kishiyama JL, Adelman DC. The cross-reactivity and immunology of beta-lactam antibiotics.
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GRAPHICS

Dosing of selected parenteral beta-lactam antibiotics for adult patients

Drug CrCl (mL/minute) Adult dose Frequency

Beta-lactamase inhibitor combinations

Ampicillin-sulbactam ≥30 1.5 g Every 6 hours

(mild to moderate
15 to 29 1.5 g Every 12 hours
infections)
5 to 14 1.5 g Every 24 hours

iHD* 1.5 g Every 12 to 24 hours

¶ [1]
CRRT 1.5 g Every 6 to 12 hours

Ampicillin-sulbactam ≥30 3g Every 6 hours

(moderate to severe
15 to 29 3g Every 12 hours
infections)
5 to 14 3g Every 24 hours

iHD* 3g Every 12 to 24 hours

¶ [1]
CRRT 3g Every 6 to 12 hours

Ceftazidime-avibactam >50 2.5 g Every 8 hours

31 to 50 1.25 g Every 8 hours

16 to 30 0.94 g Every 12 hours

6 to 15 0.94 g Every 24 hours

≤5 0.94 g Every 48 hours

iHD* 0.94 g CrCl 6 to 15 mL/minute:

Every 24 hours
CrCl ≤5 mL/minute: Every
48 hours
Administer after iHD on
dialysis days

CRRT [2] (based on 1.25 g Every 8 hours

preliminary data)

Ceftolozane-tazobactam >50 1.5 g Every 8 hours

(complicated UTI and
30 to 50 750 mg Every 8 hours
intra-abdominal
infections) 15 to 29 375 mg Every 8 hours

<15 Has not been studied

iHD* 750 mg once, followed by Every 8 hours

150 mg

CRRT [3] (based on 750 mg Every 8 hours

preliminary data)

Ceftolozane-tazobactam >50 3g Every 8 hours

(severe infections) [4,5]
30 to 50 1.5 g Every 8 hours

15 to 29 750 mg Every 8 hours

<15 Has not been studied

iHD* 750 mg once, followed by Every 8 hours

375 mg

CRRT [3] (based on 1.5 g Every 8 hours

preliminary data)

Imipenem-cilastatin- ≥90 1.25 g Every 6 hours

relebactam
60 to 89 1g Every 6 hours

30 to 59 0.75 g Every 6 hours

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15 to 29 0.5 g Every 6 hours

iHD* 0.5 g Every 6 hours; administer

after iHD on dialysis days

Meropenem- ≥50 4g Every 8 hours (infused

vaborbactam over 3 hours)
NOTE: Use MDRD 30 to 49 2g Every 8 hours (infused
equation formula to over 3 hours)
estimate renal function
15 to 29 2g Every 12 hours (infused
(eGFR)
over 3 hours)

<15 1g Every 12 hours (infused

over 3 hours)

iHD* 1g Every 12 hours (infused

over 3 hours) administered
after an iHD session

Piperacillin-tazobactam >40 3.375 g Every 6 hours

(mild to moderate
20 to 40 2.25 g Every 6 hours
infections)
<20 2.25 g Every 8 hours

iHD* 2.25 g Every 12 hours

CRRT ¶ [1] 2.25 g Every 6 to 8 hours

Piperacillin-tazobactam >40 4.5 g Every 6 hours

(severe infections,
20 to 40 3.375 g Every 6 hours
including Pseudomonas
aeruginosa) <20 2.25 g Every 6 hours

iHD* 2.25 g Every 8 hours

¶ [1]
CRRT 3.375 g Every 6 to 8 hours

Carbapenems

Doripenem >50 500 mg Every 8 hours

30 to 50 250 mg Every 8 hours

11 to 29 250 mg Every 12 hours

<10 Has not been studied

iHD* 250 to 500 mg Every 24 hours

¶
CRRT 250 mg to 1 g Every 8 to 12 hours

Ertapenem >30 1g Every 24 hours

≤30 500 mg Every 24 hours

iHD* 500 mg Every 24 hours;

administer after iHD on
dialysis days

CRRT ¶ [6] (based on 1g Every 24 hours

preliminary data)

Imipenem-cilastatin >70 to 89 500 mg Every 6 hours

(moderate infection) [7]
41 to 70 500 mg Every 8 hours

21 to 40 250 mg Every 6 hours

<21 250 mg Every 12 hours

iHD* 250 mg Every 12 hours;

administer after iHD on
dialysis days

CRRT ¶ [1] 250 to 500 mg Every 6 to 8 hours

Imipenem-cilastatin >70 to 89 1g Every 6 Δ to 8 hours

(severe infection) [7]
41 to 70 500 mg Every 6 hours

21 to 40 500 mg Every 8 hours

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<21 500 mg Every 12 hours

iHD* 500 mg Every 12 hours;

administer after iHD on
dialysis days

CRRT ¶ [1] 500 mg Every 6 to 8 hours

Meropenem (meningitis, >50 2g Every 8 hours

cystic fibrosis
26 to 50 2g Every 12 hours
pulmonary
exacerbation) 10 to 25 1g Every 12 hours

<10 1g Every 24 hours

iHD* 1g Every 24 hours;

administer after iHD on
dialysis days

CRRT ¶ [1] 500 mg or 1 g Every 8 to 12 hours

Meropenem (moderate >50 1g Every 8 hours

to severe infection) ◊
26 to 50 1g Every 12 hours

10 to 25 500 mg Every 12 hours

<10 500 mg Every 24 hours

iHD* 500 mg Every 24 hours;

administer after iHD on
dialysis days

CRRT ¶ [1] 500 mg or 1 g Every 8 to 12 hours

Monobactam

Aztreonam (moderate >30 1g Every 8 hours

infection)
10 to 30 500 mg Every 8 hours

<10 250 mg Every 8 hours

iHD* 1 g once, followed by 250 Every 8 to 12 hours

mg

CRRT ¶ [1] 2 g once, followed by 1 or 1 g every 8 hours or 1 to 2

2g g every 12 hours

Aztreonam (severe >30 2g Every 8 hours

infection)
10 to 30 1g Every 8 hours

<10 500 mg Every 8 hours

iHD* 2 g once, followed by 500 Every 8 hours

mg

CRRT ¶ [1] 2 g once, followed by 1 or 1 g every 8 hours or 1 to 2

2g g every 12 hours

This table lists doses of selected beta-lactam antibiotics, with suggested dosing adjustments for renal impairment.
The first dose listed for each agent represents the suggested dose for normal renal function. Renal function is
evaluated based on estimated CrCl using the Cockcroft-Gault equation. A calculator for estimating CrCl based on
the Cockcroft-Gault equation is available in UpToDate.
NOTE: Doses listed for the combination beta-lactam/beta-lactamase inhibitors are expressed as the total of grams
for both components.

CrCl: creatinine clearance; iHD: intermittent hemodialysis; CRRT: continuous renal replacement therapy; MDRD:
Modification of Diet in Renal Disease; eGFR: estimated glomerular filtration rate.
* Based on three times weekly dialysis sessions of 3 to 4 hours each; on dialysis days administer dose after dialysis. A
loading dose may be warranted for some antibiotics depending on clinical scenario; refer to Lexicomp monograph for
detail.
¶ General dose and interval range for different types of CRRT based on dialysate/ultrafiltration rate of 1 to 2 L/hour are
listed. Specific dosing depends on CRRT method, flow rate, and filter type. For specific recommendations; refer to
Lexicomp monograph included in UpToDate.
Δ An imipenem dose of 1 g given every 6 hours has been associated with an increased risk of seizures. [8]
◊ A lower dose is recommended for some skin/skin structure and urinary tract infections. Refer to Lexicomp monograph.

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References:
1. Heintz BH, Matzke GR, Dager WE. Antimicrobial dosing concepts and recommendations for critically ill adult
patients receiving continuous renal replacement therapy or intermittent hemodialysis. Pharmacotherapy 2009;
29:562.
2. Wenzler E, Bunnel KL, Belasdale SC, et al. Pharmacokinetics and dialytic clearance of ceftazidime-avibactam in a
critically ill patient on continuous venovenous hemofiltration. Antimicrobial Agents Chemother 2017 [Epub ahead of
print].
3. Bremmer DN, Nicolau DP, Burcham P, et al. Ceftolozane/tazobactam pharmacokinetics in a critically ill adult
receiving continuous renal replacement therapy. Pharmacotherapy 2016; 36:e30.
4. Munita JM, Aitken SL, Miller WR, et al. Multicenter evaluation of ceftolozane/tazobactam for serious infections
caused by carbapenem-resistant Pseudomonas aeruginosa. Clin Infect Dis 2017 [Epub ahead of print].
5. Caston JJ, De la Torre A, Ruiz Camps I, et al. Salvage therapy with ceftolozane-tazobactam for multidrug-resistant
Pseudomonas aeruginosa infections. Antimicrob Agents Chemother 2017; 61:e02136.
6. Eyler RF, Vilay AM, Nader AM, et al. Pharmacokinetics of ertapenem in critically ill patients receiving continuous
venovenous hemodialysis or hemodiafiltration. Antimicrob Agents Chemother 2014; 58:1320.
7. Pham PA, Bartlett JG. Imipenem/cilastatin. In: Johns Hopkins Antibiotics Guide
(https://www.hopkinsguides.com/hopkins), Unbound Medicine, 2017.
8. Zhanel GG, Wiebe R, Dilay L, et al. Comparative review of the carbapenems. Drugs 2007; 67:1027.
Courtesy of Stephen B Calderwood, MD and Alyssa R Letourneau, MD, with additional data from Lexicomp Online.
Copyright © 1978-2019 Lexicomp, Inc. All Rights Reserved.

Graphic 51241 Version 9.0

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Contributor Disclosures
Alyssa R Letourneau, MD Nothing to disclose David C Hooper, MD Consultant/Advisory Boards:
Tetraphase [Antibiotic (Eravacycline)]; Shionogi [Antibiotic (Cefidericol)]. Allyson Bloom, MD Nothing to
disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.

Conflict of interest policy

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