When culture and susceptibility information are available, they should be considered in selecting and modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. The recommended dosage and administration by infection is described in Table The following formula may be used to estimate CrCl. The serum creatinine used in the formula should represent a steady state of renal function. Aseptic technique must be followed in preparation of the infusion solution.
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Carbapenems represent a class of beta-lactam antibacterial agents with a broad spectrum of activity against gram-positive, gram-negative, and anaerobic bacteria. This class is bactericidal in nature, but it does not cover species of Enterococcus faecium , methicillin-resistant Staphylococcus aureus MRSA , or Stenotrophomonas maltophilia.
Collectively, the carbapenems have been used to treat a variety of infections. As with all antibiotics, resistance within the carbapenem class is a major concern. Although carbapenems remain the drugs of choice for extended-spectrum, beta-lactamase—producing organisms, resistance may emerge via other beta-lactamases, such as metallo—beta-lactamases, alteration of porin channels, or up-regulation of efflux pumps. Therefore, carbapenems should be used judiciously, and the appropriate use of these agents must be considered carefully.
Imipenem and meropenem are veteran agents of the carbapenem class and are used primarily to treat moderate-to-severe nosocomial and polymicrobial infections, including intra-abdominal infections, nosocomial pneumonia, septicemia, and febrile neutropenia. Imipenem possesses slightly more potent in vitro activity against gram-positive pathogens, whereas meropenem possesses slightly more potent in vitro activity against gram-negative pathogens, including Pseudomonas aeruginosa.
Imipenem has a greater tendency to precipitate seizures; thus, caution must be taken, particularly among patients with impaired renal function. This carbapenem is also extremely susceptible to degradation via the enzyme dehydropeptidase-1 DHP In order to resolve this problem and ensure stability, the DHP-1 inhibitor cilastatin is used concomitantly with imipenem.
Compared with other carbapenems, ertapenem displays a decrease in activity against nosocomial infections associated with Enterococcus spp. Ertapenem is used and clinically suitable primarily for the empirical coverage of severe infections when Acinetobacter spp. It is also preferred for outpatient use as a result of its favorable pharmacokinetic profile.
However, ertapenem must be prescribed with caution because of its potential overuse, which may lead to an increase in resistance of this class of antimicrobials. In October , the FDA approved the most recent addition to the carbapenem class, doripenem Doribax.
Doripenem seems to most closely resemble the profile of meropenem, except for its increased potency of in vitro activity against P.
It is indicated for patients with complicated intra-abdominal infections and UTIs, including pyelonephritis, when the infection is caused by susceptible bacteria. Carbapenems display bactericidal activity against gram-positive, gram-negative, and anaerobic bacteria, and they are stable to most beta-lactamases. Carbapenems cause bacterial cell death by inhibiting cell wall synthesis via inactivation of penicillin-binding proteins. Doripenem displays bactericidal action against susceptible species, stability to human renal DHP and beta-lactamases including extended spectrum beta-lactamases [ESBLs], pharmacokinetic and pharmacodynamic profiles similar to meropenem including minimal risk of seizure as an adverse reaction , post-antibiotic effects in vitro against P.
In phase 1 trials, to 1, mg of doripenem, when given by intravenous IV infusion, resulted in a mean maximum plasma concentration C max of 8. The area-under-the-concentration AUC time curve was determined to be 8. In addition, plasma concentrations after 11 doses of mg were reported with no significant differences. These data represent an average half-life of one hour, with multiple dosing thus required over a hour period.
As stated earlier, doripenem is minimally protein-bound average binding, 8. At steady state, the median volume of distribution is The concentration of doripenem in the peritoneal and retroperitoneal fluid equals or exceeds concentrations required to inhibit most susceptible bacteria.
Doripenem does not undergo hepatic metabolism and is thus not expected to be affected by hepatic impairment. It is metabolized to an inactive metabolite, doripenem-M1 by the enzyme, DHP Doripenem is cleared by the kidneys at a mean clearance rate of The clearance rate is slightly higher in patients of Hispanic and Latino descent than in those of Caucasian descent.
No differences were seen among patients of other racial or ethnic backgrounds. A mg dose given one hour before hemodialysis yielded mg of doripenem and 28 mg of the inactive metabolite. Although the hemodializability of doripenem has been determined, there is no current recommendation for dosage adjustments in patients undergoing hemodialysis.
In two identical multinational multicenter, randomized, double-blind studies, a total of adults with complicated intra-abdominal infections received either IV doripenem mg every eight hours, given over one hour, or IV meropenem 1 g every eight hours, given over three to five minutes. As for clinical cure rates among microbiologically evaluable patients, doripenem was determined to be non-inferior to meropenem at 25 to 45 days at the end of treatment.
In one study, the doripenem clinical cure rate was Non-inferiority was also observed among the microbiological modified intent-to-treat patients, which included those with pathogen isolation at the baseline evaluation without regard to susceptibility.
In two multinational multicenter, randomized double-blind studies, a total of 1, adults with complicated UTIs, including pyelonephritis, were evaluated. In one study, the authors compared IV doripenem mg every eight hours, given over one hour, with IV levofloxacin Levaquin, PriCara mg once daily.
In the other study, the methodology was the same but was not comparative. In both studies, all patients were allowed to switch to an oral levofloxacin regimen of mg once daily for a total of 10 days of therapy.
Oral or IV levofloxacin mg once daily for 10 to 14 days was also given to patients with confirmed concurrent bacteremia. In terms of overall microbiological cure rates, doripenem was considered to be non-inferior to meropenem among patients who were microbiologically evaluable at five to 11 days at the end of therapy.
Eradication rates were Non-inferiority was also observed among microbiological modified intent-to-treat population, which included patients with pretreatment urine cultures. A New Drug Application NDA for doripenem is currently under review by the FDA for the additional indication of nosocomial pneumonia, based on two international multicenter, randomized, open-label, comparison phase 3 clinical trials. All patients had clinically and radiologically confirmed nosocomial pneumonia, including early-onset ventilator-associated pneumonia, reported within the first five days of ventilation onset.
Early onset was considered less than five days of mechanical ventilation. After a minimum of three days of IV therapy, all patients were allowed to switch to oral levofloxacin mg once daily for seven to 14 days of treatment. All patients had clinically and radiologically confirmed nosocomial pneumonia, including early-onset and late-onset ventilator-associated pneumonia.
Late onset was considered five days or more of mechanical ventilation. Non-inferiority was also observed in the clinical modified intent-to-treat patients. Safety and adverse reactions associated with doripenem are best summarized from pooled data from three pivotal phase 3 studies.
The studies included a total of adults who were treated with doripenem for complicated UTIs or complicated intra-abdominal infections. The most common adverse reactions observed were headache, nausea, diarrhea, rash, and phlebitis. The rate of discontinuation of doripenem because of adverse effects was extremely low: 0. Voluntarily reported, postmarketing safety data from outside the U.
However, the true frequency has not been established because of data limitations. Two additional phase 3 studies DORI-9 and DORI of nosocomial pneumonia, including ventilator-associated pneumonia, did attempt to quantify the frequency of seizures with doripenem, compared with standard therapy.
The fact that no metabolism of doripenem was detected in vitro utilizing pooled human microsomes suggests that doripenem is not a substrate for hepatic cytochrome P CYP enzymes. It is therefore unlikely that doripenem has any drug interactions via the CYP system by enzyme induction or inhibition. Doripenem is eliminated unchanged primarily via the kidneys; hence, the concurrent use of probenecid is not recommended because it interferes with active tubular secretion of doripenem, resulting in increased plasma concentrations.
Carbapenems, as documented in the literature, can lead to significantly reduced serum valproic acid concentrations, which may result in loss of seizure control. Although the mechanism of this interaction is not fully understood, in vitro and animal studies suggest that carbapenems might inhibit valproic acid glucuronide hydrolysis or the valproic acid intestinal transporter necessary for absorption. Ortho-McNeil recommends frequent monitoring of serum valproic acid levels after doripenem therapy begins or consideration of an alternative antibacterial or anticonvulsive agent if therapeutic serum valproic acid concentrations cannot be maintained or if a seizure occurs.
Doripenem is not indicated for patients with a known serious hypersensitivity to doripenem or other carbapenems. It should not be used in patients with a history of an anaphylactic reaction to beta-lactam antibiotics because of cross-reactivity; this has been clearly documented in the literature.
Appropriate precautions should be taken before doripenem therapy is initiated, because serious and occasionally fatal hypersensitivity and serious skin reactions, such as Stevens—Johnson syndrome or toxic epidermal necrolysis, may occur in patients receiving beta-lactam antibiotics.
A thorough history of the severity and type of hypersensitivity reaction to carbapenems, penicillins, cephalosporins, or other allergens should be obtained before patients start doripenem therapy, because cross-reactivity with beta-lactam antibiotics has been documented. If hypersensitivity develops, doripenem should be discontinued and an alternative therapy should be initiated. Renal function should be assessed before patients begin therapy and during the course of therapy, because the drug may accumulate, resulting in varied degrees of renal impairment.
Medication profiles of patients should also be screened for potential drug interactions. As with most antibiotics, including the carbapenems, doripenem has been linked to C. This may permit the overgrowth of C.
For this reason and because of the potential emergence of resistance to doripenem, this agent should be used judiciously for documented bacterial infections.
Pneumonitis has also been observed with inhaled doripenem; therefore, this medication should not be given via the inhalation route. In patients 18 years of age and older, the recommended dosage for doripenem is mg every eight hours, given as an IV infusion over one hour. Doripenem is available in single-use clear glass vials; it must be reconstituted and diluted with either 0. After preparation, products prepared in 0. When refrigerated, prepared doripenem is stable for 24 hours regardless of the solution in which it is prepared.
For complicated intra-abdominal infections, it is recommended for five to 14 days; for complicated UTIs including pyelonephritis , the duration of therapy is typically for 10 days, although it may be extended to 14 days for concurrent bacteremia. As the most recently approved agent in its class, doripenem Doribax is a promising agent with a spectrum of activity similar to that of meropenem against gram-negative bacteria and similar to imipenem against gram-positive bacteria.
The potential advantages of doripenem include a slightly better in vitro activity against P. Doripenem was also studied via extended infusion, which has been gaining popularity as a result of the pharmacokinetic and pharmacodynamic advantages over bolus dosing. These data are promising; extended infusion was found to be effective and well tolerated in ventilator-associated pneumonia patients. The data also suggest that doripenem, of all the carbapenems, may have the greatest ability to prevent the emergence of carbapenem-resistant mutant strains, with the potential to address the widespread problem of resistance echoed by the Infectious Disease Society of America and, most recently, by the Strategies to Address Antimicrobial Resistance Act, which was introduced in Congress in late On the basis of the current in vitro and clinical data, doripenem may prove useful for hospitalized patients with serious infections who need broad-spectrum antibacterial coverage or who have an infection with a highly resistant pathogen.
Disclosure: The authors have no financial relationships to report in regard to this article. National Center for Biotechnology Information , U. Journal List P T v. Author information Copyright and License information Disclaimer.
This article has been cited by other articles in PMC. Complicated Intra-abdominal Infections 7 , 9 In two identical multinational multicenter, randomized, double-blind studies, a total of adults with complicated intra-abdominal infections received either IV doripenem mg every eight hours, given over one hour, or IV meropenem 1 g every eight hours, given over three to five minutes.
Complicated Urinary Tract Infections 7 , 9 In two multinational multicenter, randomized double-blind studies, a total of 1, adults with complicated UTIs, including pyelonephritis, were evaluated.
Nosocomial Pneumonia 9 A New Drug Application NDA for doripenem is currently under review by the FDA for the additional indication of nosocomial pneumonia, based on two international multicenter, randomized, open-label, comparison phase 3 clinical trials. Footnotes Disclosure: The authors have no financial relationships to report in regard to this article.
Comparative review of the carbapenems.
Doripenem (Doribax), a New Carbapenem Antibacterial Agent