Clavulanate, sulbactam, tazobactam, and avibactam 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, ticarcillin, 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 sulbactam component of ampicillin-sulbactam has activity against Acinetobacter.
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.
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.
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. At the high drug concentrations achieved in urine, the combination is also active against certain beta-lactamase producing Enterobacteriaceae. Amoxicillin-clavulanate (250 to 500 mg PO Q 8h or 875 mg PO Q12h) can be used as oral therapy for patients with otitis media, sinusitis, lower respiratory infections, bite wounds, and urinary tract infections, although there are no data that this combination is superior to other antibiotics．
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. This combination has also been used for prophylaxis and therapy of intraabdominal 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 intraabdominal and pelvic infections. However, increasing resistance worldwide to ampicillin-sulbactam of both Enterobacteriaceae and Bacteroides fragilis in intra-abdominal infections renders this drug combination less useful for this purpose.
Ticarcillin-clavulanate and piperacillin-tazobactam
Ticarcillin-clavulanate and piperacillin-tazobactam expand the spectrum of the respective penicillins to include beta-lactamase producing S. aureus, H. influenzae, Neisseria gonorrhoeae, some Enterobacteriaceae, and anaerobes (including B. fragilis). These combinations are generally not effective for ticarcillin- or 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 these two agents are similar to ampicillin-sulbactam, but they are preferred over ampicillin-sulbactam for intra-abdominal infection when an agent from this class is chosen.
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. Ceftolozane-tazobactam also performed favorably against infections caused by ESBL-producing isolates in these trials. Efficacy of ceftolozane-tazobactam may be attenuated in patients with renal impairment (estimated GFR <50 mL/min).
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. 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. The microbiological and clinical efficacy of ceftazidime-avibactam against isolates that were not ceftazidime susceptible also compared favorably with the carbapenem comparator.
Carbapenems are generally resistant to cleavage by most plasmid and chromosomal beta-lactamases and have a very broad spectrum of activity encompassing:
- 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 Stenotrophomonas 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. 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.
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. 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. 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 has a spectrum of activity similar to imipenem. 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 . Meropenem is useful for the treatment of bacterial meningitis (in pediatric patients >three months old) and intraabdominal infection.
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 has demonstrated clinical efficacy in the treatment of complicated urinary tract and intra-abdominal infections. It has a similar spectrum of activity as meropenem, although it appears to have more potent in vitro activity against P. aeruginosa than meropenem.
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. 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.
Further clinical trials are required to establish the efficacy and safety of doripenem in the setting of bacteremia and other severe infections.
Aztreonam (1-2 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. 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.
Data support the absence of cross-allergenicity between aztreonam and other beta-lactam antibiotics. 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.