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, 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 [1,2]. Avibactam, vaborbactam, and relebactam inhibit chromosomally mediated AmpC beta-lactamases, and none inhibit the class B metallo-carbapenemases, such as New Delhi metallo-beta-lactamase [2,3]. Combination of these agents with ampicillin, amoxicillin, piperacillin, ceftolozane, ceftazidime, meropenem, and imipenem-cilastatin 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 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.
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 [4,5]. 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 [6], 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 [7]. 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 [8,9]. 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 [10-12].
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 [13]. 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 [14,15]. 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) [16]. This combination is generally not effective for piperacillin-resistant strains of Pseudomonas aeruginosa.
Piperacillin-tazobactam should be dosed at 4.5 g every six hours (for normal renal function) to treat susceptible P. aeruginosa infections. The increased dose allows for adequate drug concentrations to increase the time above the minimum inhibitory concentration (MIC), compared to the standard dose of 3.375 g every six hours. Prolonged-infusion dosing is discussed in detail elsewhere. (See "Prolonged infusions of beta-lactam antibiotics", section on 'Dosing'.)
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 [17-19]. 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]. Ceftolozane-tazobactam resulted in comparable clinical cure rates as meropenem for nosocomial pneumonia in mechanically ventilated patients [22]. 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 [23]. In trials, the microbiological efficacy and clinical cure rates with ceftazidime-avibactam were similar to those with meropenem for nosocomial pneumonia [24], imipenem for complicated urinary tract infection, and, when combined with metronidazole, were overall similar to those with meropenem for complicated intra-abdominal infections [25-27]. 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 [28,29]. Meropenem-vaborbactam was comparable to piperacillin-tazobactam in a trial of patients with complicated urinary tract infection [30]. In a small open-label, randomized controlled trial of patients with carbapenem-resistant Enterobacteriaceae (CRE) infections, including bacteremia, hospital-acquired pneumonia including ventilator-associated pneumonia, complicated intra-abdominal infections, and complicated urinary tract infection/pyelonephritis, meropenem-vaborbactam was associated with increased clinical cure, decreased mortality, and decreased nephrotoxicity compared to the best-available therapy [31]. The main role of this agent is for treatment of KPC-producing Enterobacteriaceae.
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 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 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) [32-34]. 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 [35,36]. 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 [37].
Relebactam does not enhance the clinical activity of imipenem 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 [38,39]:
●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.
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 [40]. 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 coadministration of cilastatin, a specific inhibitor of this dehydropeptidase. Imipenem-cilastatin (500 mg IV every six hours 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 therapy has been associated with central nervous system (CNS) toxicity, including change in mental state, myoclonus, and seizures [41]. In a meta-analysis of over 100 studies that compared imipenem to a noncarbapenem antibiotic, imipenem use was associated with an excess of 4 seizures per 1000 patients treated [42]. 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 [43]. 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, but that decrease has not been proven in direct head-to-head comparisons of small sample size [42]. Meropenem is useful for the treatment of bacterial meningitis (in pediatric patients >3 months old) and intra-abdominal infection [44,45].
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 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 [46,47]. It has a similar spectrum of activity as meropenem, although it appears to have more potent in vitro activity against P. aeruginosa than meropenem [48,49].
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 [50]. 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 [51]. (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 every eight hours with normal renal function) 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 [39,52]. 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 nonenteric 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 [53]. 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 severe allergy. Aztreonam is the only monobactam currently marketed. Dose reductions are recommended in the setting of renal dysfunction (table 1).
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Carbapenem-resistant enterobacterales (The Basics)")
SUMMARY
●Combination beta-lactamase inhibitors – 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 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 – 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 – 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.)
●Dosing – The dosing of these novel beta-lactams and dose modifications in patients with renal dysfunction (table 1) are important considerations in prescribing these drugs.
