Safety of Newer Parenteral Antibiotics
- Reprints or correspondence: Dr. Gary E. Stein, Dept. of Medicine, Michigan State University, B 320 Life Science Bldg., East Lansing, MI 48824 (steing{at}msu.edu).
Abstract
Several parenteral antimicrobials have been introduced into clinical practice over the course of the last decade. Some of these agents (e.g., linezolid, daptomycin, and tigecycline) are prototypes of new classes of compounds. In comparative clinical trials, these newer anti-infectives have been shown to be safe and to have low rates of discontinuation by patients. However, long-term use has revealed unique toxicities associated with the use of some of these drugs. The adverse events and potential drug interactions associated with the use of these antibiotics are variable and require familiarity with the safety profile of each drug. It is especially important that clinicians be able to recognize serious adverse events associated with the use of specific drugs, because most of the adverse events can be readily reversed by cessation of therapy.
The use of antimicrobial agents has expanded dramatically during the last 30 years. Surveys of hospitals have found that approximately one-third of inpatients receive at least 1 anti-infective drug during hospitalization [1]. This high level of use of parenteral antibiotics is unlikely to decrease, because the number of multidrug-resistant and, therefore, difficult-to-treat infections is increasing in many communities [2]. In response to this growing rate of resistance to drugs, several agents have recently been marketed specifically for the treatment of certain drug-resistant bacteria [3]. These agents include new classes of compounds, such as oxazolidinones, lipopeptides, and glycylcyclines [4–6]. Safety concerns must be addressed to facilitate acceptance of this new group of antibiotics. Adverse reactions to drugs have important implications for patients, physicians, and hospitals [7].
Among hospitalized patients, antibacterials account for nearly 25% of drug-related adverse events [8]. Many adverse effects are common to a particular drug class, whereas some are limited to a particular agent. For example, the fluoroquinolones are relatively safe antimicrobials, but temafloxacin (which can cause hemolysis) and trovafloxacin (which can cause hepatotoxicity) were found to have unique toxicities and, subsequently, were withdrawn from the market [7]. Adverse effects of antibiotics are variable and can include phlebitis, hypersensitivity reactions, direct effects on tissues and organ systems, changes in microbial flora, and adverse interactions with other drugs [9]. Many of these adverse effects are not life-threatening but can have important economic implications by increasing the number of therapeutic interventions needed and the duration of the hospital stay [8]. To minimize the potential for serious adverse effects, clinicians should know the which adverse effects are associated with the antibiotics selected for their patients. Here, I review the safety profiles of newer parenteral antibiotics.
Carbapenems
The carbapenems remain unsurpassed among parenteral β-lactam antibiotics, as judged by the breadth of their antibacterial spectrum and by their stability to other bacterial β-lactamases [10]. The instability of imipenem, the first marketed carbapenem, to human renal dehydropeptidase-1 (DHP-1), necessitates that imipenem be coadministered with cilastatin. The combination of imipenem and cilastatin (Primaxin; Merck) is effective in the treatment of serious infections, but it is also a potent inducer of seizure activity [11]. Although imipenem-cilastatin is potentially neurotoxic, most of the reports of seizures associated with its use described patients who received high doses, relative to body weight or renal function, and/or who had other obvious risk factors for neurological reactions [12]. Unlike imipenem-cilastatin, meropenem (Merrem; Astra-Zeneca), a carbapenem with a high degree of stability to DHP-1, does not seem to be any more likely to induce seizures than are other β-lactam antibiotics [12]. In comparative trials among patients with bacterial meningitis, seizures have occurred in similar frequencies in patients receiving either meropenem or a third-generation cephalosporin [13, 14]. None of the seizures in patients receiving meropenem were considered to be related to use of the drug. In studies comparing meropenem with imipenem-cilastatin, seizures were reported in 0.4% of patients administered each drug [15]. In these studies, dosage recommendations for imipenem-cilastatin were carefully monitored, and patients with an increased risk of neurotoxicity were excluded.
The frequency of adverse events associated with the use of meropenem was found to be similar to the frequencies associated with other antibiotics in clinical trials [15]. The most common adverse clinical events were diarrhea (1.9%), nausea or vomiting (1%), and rash (1%). The most common laboratory abnormalities were transient increases in alanine aminotransferase levels (5.5%) and in aspartate aminotransferase levels (4%). The most common reasons for withdrawal of patients (1.4%) receiving meropenem were skin reactions (principally rash or urticaria), nausea and/or vomiting, and abnormal liver function test results. Although diarrhea occurred in 137 patients receiving meropenem, Clostridium difficile exotoxin was detected in only 2 patients. In studies comparing the use of meropenem with the use of imipenem-cilastatin in adults, nausea or vomiting was reported more frequently with imipenem-cilastatin (0.8% vs. 1.4%). In contrast to imipenem-cilastatin, the frequency of adverse events associated with the use of meropenem does not seem to escalate as the dosage is increased.
The penicillins, cephalosporins, and carbapenems each possess a bicyclic core structure, which is the molecular entity believed to be most responsible for β-lactam hypersensitivity. As with cephalosporins, a significant risk for cross-hypersensitivity has been observed between penicillins and carbapenems [16]. In a study of 100 patients with a reported or documented allergy to penicillin, 11% experienced an allergic-type reaction when treated with a carbapenem [17]. No difference in the occurrence of allergic-type reactions was observed between imipenem-cilastatin and meropenem. The majority of reactions were either rash or hives. Only 1 patient with a history of rash in reaction to penicillin experienced an anaphylactic reaction when treated with the carbapenem. A similar incidence of allergic reactions was found in a retrospective review of 163 patients with a reported penicillin allergy who received meropenem or imipenem-cilastatin [18]. Among the 15 (9.2%) patients allergic to penicillin who developed a hypersensitivity reaction, 11 manifested a maculopapular rash as the reaction to the carbapenem. Only 1 patient developed facial edema in addition to the maculopapular rash. These hypersensitivity reactions occurred, on average, 3.6 days after the start of treatment. There were no cases of anaphylaxis.
The effect of treatment with meropenem for 7 days on intestinal microflora has been studied in healthy volunteers [19]. The numbers of enterobacteria and streptococci decreased during the administration period, whereas the numbers of enterococci increased. There was a decrease in numbers of clostridia, Bacteroides species, and gram-negative cocci, but the numbers of gram-positive cocci and rods were not changed. C. difficile was not detected from any volunteer. The intestinal flora returned to normal in all volunteers within 2 weeks after the termination of meropenem treatment, and no new colonization with strains resistant to meropenem was observed.
Ertapenem (Invanz; Merck) is a carbapenem with a narrower spectrum of activity than that of imipenem and meropenem but with a long elimination half-life, which allows for once-daily dosing [20]. In phase 2 and phase 3 clinical trials, ∼2000 patients received up to 2 g of ertapenem daily [21]. The most common adverse events associated with receipt of ertapenem were diarrhea (5%), vein complications (4%), nausea (3%), and headache (2%). The incidence of C. difficile–associated diarrhea (CDAD) was 0.3% (6/1866 patients). Three patients (0.2%) had seizures during therapy with ertapenem that were considered to be related to the drug. Ertapenem therapy was discontinued for 1.2% of patients because of the occurrence of adverse events. The most common reasons for discontinuation of the drug were gastrointestinal upset and rash.
Changes in laboratory test values occurred in 14% of patients in the ertapenem study groups. The most common alterations were a transient elevation in aminotransferase levels (8%). Ertapenem therapy was discontinued for 0.2% of patients because of a change in a laboratory test value.
During clinical trials of ertapenem therapy, 8% of patients experienced moderate-to-severe symptoms at the infusion site, most commonly pain, followed by tenderness, local phlebitis, erythema, and induration. With regard to tolerability of intramuscular administration, 28% of patients receiving ertapenem intramuscularly and 33% of patients receiving ceftriaxone intramuscularly experienced ⩾1 symptom at the injection site. In a separate study comparing the tolerability of 1-g doses of ertapenem and ceftriaxone administered intramuscularly once daily (both drugs were reconstituted in lidocaine), 36% (31/87) and 43% (13/30) of patients, respectively, experienced symptoms at the injection site [22]. The most common symptom was tenderness, followed by pain. Symptoms were moderate to severe in 1 patient (1%) who received ertapenem and in 3 patients (10%) who received ceftriaxone.
In a study of the effect of the drugs on intestinal microflora in 10 healthy volunteers, 1 g of ertapenem was administered intravenously once daily for 7 days [23]. During administration of ertapenem, the number of Escherichia coli organisms decreased. There was an overgrowth of low levels of yeast on day 8. The total numbers of anaerobic bacteria decreased during ertapenem administration. The numbers of bifidobacteria and Bacteroides fragilis group strains were significantly reduced, and there were minor alterations in the number of lactobacilli and clostridia. Both the aerobic and anaerobic microflora returned to normal levels by day 35.
Cephalosporins
Cefepime (Maxipime; Elan) is a fourth-generation cephalosporin that is active in vitro against a broad range of common pathogenic bacteria [24]. Approximately 2000 patients with mild-to-severe bacterial infections were treated with cefepime in comparative studies of clinical efficacy [25]. The majority of patients studied received 2 g of cefepime every 12 h by the intravenous route, whereas patients with less-severe infections received 0.5–1 g every 12 h. The median duration of dosing was 7 days. The most common adverse events involved the digestive system (6.3%), including nausea (1.8%), diarrhea (1.7%), vomiting (1.5%), and constipation (1.2%). These adverse effects were similar in frequency to those seen with ceftazidime, the comparator drug. The most common adverse event associated with the use of cefepime use was headache (2.4%). Rash was observed in 1.8% of cefepime-treated patients. The most common laboratory test abnormalities were changes in liver function test results, such as levels of alanine aminotransferase (2%) and aspartate aminotransferase (1.5%). The incidence of discontinuation of cefepime was more common among patients receiving >2 g/day (2.9%) than among patients receiving the lower dose (1.4%). Overall, rash was the most common reason therapy was discontinued. The incidence of seizures in association with the use of cefepime was rare: 11 episodes (0.2%) occurred among all cefepime-treated patients. Only 3 episodes (0.1%) were of probable or unknown relationship to cefepime therapy. Cases of neurotoxicity (e.g., confusion and disorientation) induced by cefepime have also been reported [26]. These neurological findings are often associated with myoclonus and are most frequently encountered in elderly patients and in patients with uremia.
Neutropenia (⩽500 cells/µL) probably or possibly related to cefepime therapy occurred in only 9 (0.3%) of 3314 courses in clinical trials. In an analysis of patients receiving extended cefepime therapy for osteomyelitis, 8 of 13 courses resulted in neutropenia after an average of 25 days of therapy [27].
The influence of cefepime on the intestinal flora has been studied in healthy persons [28]. During administration, there was a decrease in the numbers of E. coli and bifidobacteria and an increase in the numbers of Clostridium and Bacteroides species. In a retrospective review of antibiotic use in a university hospital, the substitution of cefepime for third-generation cephalosporins led to a decrease in cephalosporin use and, more important, a decrease in the numbers of ceftazidime-resistant Klebsiella pneumoniae, piperacillin-resistant Pseudomonas aeruginosa, and ceftazidime-resistant P. aeruginosa [29]. In a study of enteric colonization in a pediatric intensive care unit, the numbers of antibiotic-resistant bacilli isolated from rectal swab specimens significantly diminished, compared with baseline cultures, in patients by the last 6 months of the 2 years of cefepime preference [30].
Fluoroquinolones
The newer fluoroquinolones have improved activity against gram-positive bacteria and have become widely used in the treatment of respiratory tract infections [31]. These “respiratory fluoroquinolones” include levofloxacin (Levaquin; Ortho-McNeil), moxifloxacin (Avelox; Bayer), and gatifloxacin (Tequin; Bristol-Myers Squibb). Adverse reactions to these antibiotics usually become apparent within the first week of therapy and occur with similar frequencies among young and elderly patients [32]. The occurrence of adverse events tends to increase along with increasing doses and increasing duration of therapy.
Adverse gastrointestinal effects (e.g., nausea, vomiting, and diarrhea) are the most frequently (2%–20%) reported adverse effects related to use of the fluoroquinolones [33]. Neurotoxicity is an important adverse effect and should be considered when these agents are used. Mild reactions occur in the form of headache, dizziness, or insomnia. Severe neurological reactions are rare and include psychotic reactions, hallucinations, and seizures [34]. Elderly patients and patients with other CNS impairments are more likely to manifest signs of neurotoxicity.
Dose-related prolongation of the QT interval is a potentially life-threatening adverse effect noted during clinical trials of newer fluoroquinolones [35]. In general, these agents should not be used to treat patients with known QT interval prolongation or patients taking medications that predispose to the development of torsades de pointes (e.g., antipsychotics, tricyclic antidepressants, and antiarrhythmics) [36]. All quinolone antimicrobials have been shown to produce cartilage damage in immature animals, although there is little evidence of quinolone-induced arthropathy in humans [37]. Nevertheless, fluoroquinolones are not currently recommended for routine use in children and have not yet been approved for pediatric use in the United States. In general, fluoroquinolones should not be given to nursing mothers, and their safety for use during pregnancy has yet to be established [38]. Musculoskeletal symptoms, such as arthralgia and tenosynovitis, have been occasionally reported during treatment with fluoroquinolones. Tendonitis and tendon rupture, most frequently affecting the Achilles tendon, can occur with all fluoroquinolones and are often associated with renal failure or prior corticosteroid therapy [39].
Drug interactions with these newer fluoroquinolones are uncommon, but close monitoring of patients receiving medications such as warfarin, antiarrhythmics, digoxin, and hypoglycemic agents is prudent [40, 41].
The safety of levofloxacin, the active L-isomer of the racemate ofloxacin, has been assessed among >5000 patients in clinical trials [42]. Dosage regimens ranged from 250 to 500 mg once daily for up to 14 days of therapy. The overall incidence of adverse effects associated with levofloxacin treatment was 6.2%. The most commonly encountered adverse reactions included nausea (1.2%–6.6%), diarrhea (1.2%–5.4%), headache (1.2%–5.4%), constipation (0.1%–3.1%), rash (0.7%–1.3%), dizziness (0.5%–1.6%), and pain at the injection site (1.5%–5.6%). Approximately 4% of all patients treated with levofloxacin discontinued therapy because of adverse events.
With regard to serious adverse events, the use of levofloxacin has been associated with QTc interval prolongation and rare cases of polymorphic ventricular tachycardia [43]. Patient risk factors have included prolongation of QTc interval prior to treatment, left ventricular dysfunction, hypokalemia, and concomitant use of drugs known to cause QTc interval prolongation or torsades de pointes [44]. Tendonitis and tendon rupture, most frequently affecting the Achilles tendon, are also rare complications of therapy with levofloxacin [45]. Predisposing factors may include corticosteroid therapy and, perhaps, renal disease and transplantation. Peripheral neuropathy can be a serious adverse effect associated with the use of levofloxacin, and it also necessitates prompt discontinuation of this antibiotic. Patients may experience symptoms such as numbness, tingling, and pain within 1 day after beginning therapy [46]. Hypersensitivity reactions to levofloxacin have included anaphylactoid reactions and toxic epidermal necrolysis [47, 48]. A case of fatal hypoglycemia in an elderly patient with diabetes related to administration of levofloxacin has been reported recently [49].
The effect of levofloxacin on intestinal flora has been investigated in 2 studies of healthy volunteers [50]. The numbers of enterococci and enterobacteria were significantly reduced during administration. Among the anaerobic bacteria, numbers of peptostreptococci, clostridia, and bifidobacteria were decreased. Drug-resistant Bacteroides strains were detected in 1 study. An association between CDAD and levofloxacin use has been observed in a matched case-control study [51]. Moreover, in a large clinical trial of levofloxacin for hospitalized patients with community-acquired lower respiratory tract infection, CDAD was diagnosed in 2.2% (11/490) of patients [52]. Patients who had previously received antibiotic therapy were significantly more likely to develop CDAD.
A hypothrombotic response resulting from the addition of levofloxacin to chronic warfarin therapy has been reported in patients within 2 days after starting therapy [53].
Gatifloxacin is an 8-methoxyfluoroquinolone with improved gram-positive and anaerobe coverage, compared with older quinolone compounds. In clinical trials involving >3000 patients, the dosage regimen of gatifloxacin was most often 400 mg once daily for 7–14 days [54]. The most common drug-related adverse events were nausea (8%), diarrhea (4%), headache (4%), and abdominal discomfort (2%). Vaginitis was reported in 6% of women. There was a relatively low frequency of CNS reactions, such as dizziness (3%) and insomnia (1%). The rate of discontinuation of gatifloxacin because of an adverse event was 3% in these trials.
Alterations in glucose homeostasis has been noted with all fluoroquinolones, but severe hypoglycemia and hyperglycemia episodes have been associated more frequently with the use of gatifloxacin [55]. Hypoglycemia is most often experienced in patients with diabetes who are receiving hypoglycemic agents [56]. The onset of hypoglycemia can occur within 24 h and may require prolonged treatment. Hyperglycemia has been observed in patients both with and without diabetes. Patients with hepatic impairment may be more susceptible to this adverse reaction and should be closely monitored [57]. These episodes occur typically after 3–10 days of receiving gatifloxacin therapy and persist for up to 28 days [58].
As observed with levofloxacin, the use of gatifloxacin has been associated with QTc interval prolongation and torsades de pointes [59]. All of the patients who experienced these adverse reactions had known risk factors, such as having received drugs known to prolong the QTc interval (amiodarone or tricyclic antidepressants), a history of heart disease or renal impairment, and advanced age. Other serious adverse events associated with gatifloxacin treatment include acute hepatitis and fulminant hepatic failure [60].
Gatifloxacin can cause significant changes in intestinal anaerobic microflora, and its use has been associated with CDAD [61]. In a study conducted in a long-term-care facility, an increase in the rate of CDAD coincided with a switch from levofloxacin to gatifloxacin [62]. The conversion from gatifloxacin back to levofloxacin reduced the risk of CDAD to its previous incidence.
Moxifloxacin is an 8-methoxyfluoroquinolone with a broad spectrum of activity and indications for the treatment of community-acquired respiratory tract infections [63]. In clinical trials involving almost 5000 patients treated with moxifloxacin (400 mg/day), the most frequently reported adverse events were nausea (8%), diarrhea (7%), and dizziness (3%). Approximately 4% of patients discontinued taking moxifloxacin as a result of drug-related adverse effects. The primary reasons for discontinuation of therapy were gastrointestinal and nervous system complaints and skin rash.
The use of moxifloxacin has been associated with increases in the QTc interval and should be avoided in high-risk patients [64]. Cases of torsades de pointes associated with moxifloxacin therapy have been reported in Europe.
In a study of healthy volunteers, moxifloxacin had only a modest effect on intestinal anaerobic microflora [65]. Moreover, this fluoroquinolone has infrequently been associated with CDAD [66]. In a recent analysis of hospitalized patients, the use of moxifloxacin was associated with an incidence and outcome of CDAD comparable to those associated with the use of levofloxacin.
Moxifloxacin has been associated with enhancing the effect of warfarin [67]. A significant elevation in the prothrombin time can occur shortly (range, 3–7 days) after initiation of moxifloxacin therapy.
Glycylcyclines
Tigecycline (Tygacil; Wyeth) is the first of the glycylcyclines to undergo clinical development. Tigecycline is an expanded broad-spectrum antibiotic with activity against gram-negative, gram-positive, anaerobic, and atypical pathogens [68]. In dose-escalating studies of tigecycline in healthy subjects (phase 1 trials), the most common adverse effects reported were dose-related nausea and vomiting [69]. The gastrointestinal adverse events were dose limiting at 300 mg. Prolonging the duration of infusion did not improve nausea for subjects receiving 200 mg, but gastrointestinal effects were diminished when subjects were fed, compared with effects in subjects who had fasted. Dosing schedules of 25 or 50 mg every 12 h were well tolerated in fed subjects. During these investigations, there were no clinically relevant changes in laboratory parameters, blood pressure, or intervals on electrocardiography.
In a phase 2 clinical trial of patients with complicated skin or skin-structure infections, 25 or 50 mg of tigecycline was infused over the course of 1 h at 12-h intervals for 7–14 days [70]. Patients assigned to the 25-mg group received a loading dose of 50 mg of tigecycline; patients in the 50-mg group received a loading dose of 100 mg. Nausea was the most common adverse event, occurring in 22% and 35% of patients in the 25-mg and 50-mg groups, respectively. Other common adverse effects included vomiting (13% and 19% of patients, respectively), diarrhea (11% and 9%), headache (8% and 5%), and pain (6% and 6%). In the 50-mg group, 5 patients (6%) discontinued therapy because of an adverse effect: 2 had nausea and vomiting, 1 had diarrhea, 1 had paresthesia, and 1 had an allergic reaction. Abnormal laboratory test results possibly related to tigecycline were observed in 9 patients. These included elevated serum transaminase levels in 5 patients (4 in the 50-mg group), elevated serum alkaline phosphatase levels in 2 patients (1 per group), elevated blood urea nitrogen level in 1 patient (50-mg group), and anemia in 1 patient (25-mg group). Of the 4 deaths that occurred during this study, none was considered related to treatment with tigecycline. In a phase 2 clinical trial of 111 patients with complicated intra-abdominal infections, a 100-mg loading dose, followed by 50 mg of tigecycline every 12 h, was administered for up to 2 weeks. Nausea (42%) and vomiting (27%) were again the most commonly reported adverse effects. Although no patients withdrew from the study because of an adverse event, 1 patient developed moderately severe colitis due to infection with C. difficile.
Tigecycline has been compared with vancomycin plus aztreonam in 2 phase 3 clinical trials of patients with complicated skin and skin-structure infections. Patients in the tigecycline groups received a 100-mg loading dose followed by 50 mg every 12 h for up to 14 days. A total of 566 patients received at least 1 dose of tigecycline. In the pooled analysis of these 2 studies, gastrointestinal complaints were reported most often in patients who received tigecycline. The most frequent gastrointestinal adverse events were nausea (34%), vomiting (20%), and diarrhea (8%). Headache was reported in 9% of patients. Abnormal laboratory values were reported infrequently, and no cases of CDAD were reported. Tigecycline has also been compared with imipenem-cilastatin in a phase 3 clinical trial of patients with complicated intra-abdominal infections, which made use of the same dosing regimen as was used for patients with skin infections [71]. The side effects reported in these 404 patients were similar to those in the studies of patients with skin and skin-structure infections. Once again, gastrointestinal adverse effects were reported most often and included nausea (18%), vomiting (13%), and diarrhea (6%). A similar frequency of gastrointestinal side effects was reported by patients who received the comparator antibiotic. The most frequent adverse effects in patients who received imipenem-cilastatin were nausea (13%), vomiting (9%), and diarrhea (7.5%). There was no significant difference between the treatment groups in the number of patients who required antiemetic therapy because of nausea and/or vomiting. Approximately 5% of patients discontinued therapy in both study groups because of an adverse event.
There are sparse clinical data at this time concerning the safety of long-term use of tigecycline. In compassionate use experience, patients have tolerated treatment with tigecycline for atypical mycobacteria infections for several months without experiencing major organ toxicity.
Lipopeptides
Daptomycin (Cubicin; Cubist) is a cyclic lipopetide antibiotic used in the treatment of serious gram-positive infections, including those caused by methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci [5]. In clinical trials, >1400 patients with skin or skin-structure infections were administered daptomycin at a dosage of 4–6 mg/kg once daily for 7–14 days [72]. The most common adverse effects included gastrointestinal disorders (e.g., constipation [6%], nausea [6%], and diarrhea [5%]), injection site reactions (6%), headache (5%), and rash (4%). Skeletal muscle symptoms and elevated levels of creatine phosphokinase were noted in subjects during phase 1 studies when high doses (4 mg/kg twice daily) of daptomycin were administered [73]. In phase 3 clinical trials, elevations in levels of creatine phosphokinase were reported in 3% of patients who received daptomycin at a dose of 4 mg/kg once daily. Signs and symptoms of skeletal muscle damage (e.g., myalgia and weakness) were observed in 6% of patients. However, these effects were not associated with elevations in levels of creatine phosphokinase and resolved with continued treatment. Muscle pain or weakness associated with elevations in levels of creatine phosphokinase occurred in only 0.2% of patients. Elevations in levels of creatine phosphokinase returned to normal within 10 days of stopping treatment. Overall, the use of daptomycin was discontinued for 3% of patients because of an adverse event. No deaths were attributed to daptomycin therapy.
The use of Daptomycin has also been associated with a few cases of neuropathy in phase 2 clinical studies. Doses in these studies (3 mg/kg twice daily) were higher than those used in phase 3 clinical trials. Pooled laboratory data showed no differences in hematologic parameters, blood chemistry, or hepatobiliary function between daptomycin and comparative antibiotics.
Daptomycin therapy should be discontinued in patients who develop an otherwise unexplained myopathy with elevated levels of creatine phosphokinase (>5 times the upper limit of normal) or an isolated, marked increase in levels of creatine phosphokinase (>10 times the upper limit of normal). Patients with abnormal findings who do not meet these criteria should be monitored closely, especially if they are receiving therapy with other potentially muscle-toxic agents, such as 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors (statins) [74].
Oxazolidinones
Linezolid (Zyvox; Pfizer) is the first marketed antibiotic in a new class of antimicrobial agents known as oxazolidinones [4]. Linezolid has good in vitro activity against gram-positive bacteria, including methicillin-resistant S. aureus, penicillin-resistant Streptococcus pneumoniae, and vancomycin-resistant enterococci. More than 2000 patients were treated with linezolid (400–600 mg twice daily for up to 28 days) in phase 3 clinical trials [75]. The most common adverse effects attributed to the use of linezolid included diarrhea (4%), nausea (3%), and headache (2%). Serious treatment-related adverse events occurred in 0.4% of patients. These included thrombocytopenia, abnormal liver function test results, hypertension, severe vomiting, and pancreatitis. Episodes of CDAD were rare and occurred in only 4 patients; 1 developed pseudomembranous colitis. Drug-related adverse events led to the discontinuation of linezolid for ∼3% of patients [76].
In a compassionate-use program, 796 patients (826 treatment courses) received 600 mg of linezolid every 12 h [77]. About one-third of these patients received therapy for >28 days. One hundred sixteen events (14%) resulted in discontinuation of the drug, and 75 events (9%), reported in 63 patients, were considered to be serious. The most common adverse events that resulted in discontinuation of linezolid therapy included decreased platelet counts (4% of treatment courses), gastrointestinal disturbances (2% of courses), decreased hemoglobin levels (2% of courses), and dermatologic events (2% of courses). Peripheral neuropathy was reported in 3 cases, all of which involved long durations of therapy (mean, 95 days) and underlying diseases or medications that potentially contributed to the event. The hematologic events reported were generally mild to moderate in severity, transient in nature, related to treatment duration, and reversible when therapy was discontinued. Fifteen percent of patients had a decrease in their platelet count of more than two-thirds from baseline levels. For these patients, the mean time to a 50% reduction in the platelet count was 2–3 weeks.
Linezolid has the potential for causing dose-dependent and time-dependent reversible myelosuppression [78]. The thrombocytopenia associated with linezolid therapy appears to result from an immune-mediated mechanism of platelet destruction [79]. The mechanism for the anemia is thought to be inhibition of mitochondrial respiration. In addition to clinical trial data, there have been several case reports in adults of reversible myelosuppression associated with linezolid therapy, including thrombocytopenia, anemia, and pancytopenia. Most of these cases occurred in older patients who were undergoing prolonged treatment courses and who had underlying diseases that predisposed them to developing hematologic abnormalities [80–82]. It is now evident that blood cell counts should be monitored weekly for patients who receive linezolid, especially those receiving therapy for >2 weeks. The administration of vitamin B6 (50 mg once daily) may be useful to prevent or modify the course of linezolid-associated cytopenias [83].
Sullivan et al. investigated the ecological effects of linezolid on normal intestinal microflora [50]. They observed a significant reduction in enterococci and a substantial increase in Klebsiella strains on day 8. The numbers of bifidobacteria, lactobacilli, clostridia, and Bacteroides species were markedly reduced. The MICs for B. fragilis strains increased during administration and returned to pretreatment values on day 35.
There is now a growing body of evidence that long-term (>6 months) use of linezolid is associated with peripheral and optic neuropathy [84]. In most cases, gradual improvement was noted once linezolid therapy was discontinued.
Linezolid is a weak, reversible monoamine oxidase inhibitor and has the potential to interact with adrenergic and serotonergic agents. In controlled clinical trials, only 1 episode of hypertension was related to concomitant use of a medication that could interact with a monoamine oxidase inhibitor. This patient was receiving fluoxetine, a selective serotonin reuptake inhibitor. Since these trials, there have been several case reports of the serotonin syndrome in patients who were receiving linezolid and a selective serotonin reuptake inhibitor [85]. In addition to the signs and symptoms of the serotonin syndrome (e.g., fever, agitation, mental status changes, myoclonus, and tremors), one must also be aware of the risks of lactic acidosis and liver damage when prescribing these concomitant medications [86, 87].
Streptogramins
The streptogramins are a family of compounds isolated from Streptomyces pristinaespiralis. Dalfopristin and quinupristin are streptogramins that have been combined in a 30 : 70 (wt : wt) ratio (Synercid; King). This combination produces in vitro bactericidal activity against a number of pathogens, including drug-resistant gram-positive organisms such as Enterococcus faecium, S. aureus, and S. pneumoniae [88]. Data on adverse events from phase 3 trials of >2200 patients who received quinupristin-dalfopristin have been presented elsewhere [89]. In comparative studies, patients received quinupristin-dalfopristin regimens of 7.5 mg/kg intravenously every 8 h or every 12 h for up to 27 days. In emergency-use studies, 1200 patients were treated with quinupristin-dalfopristin for a mean duration of 13 days (range, 1–98 days). Infusion site reactions (e.g., inflammation, pain, edema, and thrombophlebitis) were the most common administration-related adverse events. Venous-related adverse events were reported in 68% of patients receiving quinupristin-dalfopristin. Most events occurred with peripheral administration, so infusion through a central venous catheter is preferred. The most common nonvenous adverse events were nausea (5%), diarrhea (3%), vomiting (3%), and rash (2.5%). Laboratory abnormalities included increases in total and conjugated bilirubin levels to >5 times normal levels (4%), elevations in liver enzyme levels (2%–7%), and thrombocytopenia (2%). The discontinuation rate because of adverse reactions related to the use of quinupristin-dalfopristin was 6% for systemic reactions and 11% for local reactions.
In comparative trials, the frequency of myalgia and arthralgia associated with the use of quinupristin-dalfopristin was <2%. In noncomparative emergency-use studies, a higher percentage of patients (13%) experienced arthralgias and/or myalgias [89]. This variability is not fully understood but may be due to the severity of illness. Both disorders can be controlled with analgesics and reversed with discontinuation of therapy. A switch to a 12-hourly regimen may also be considered if the patient's infection is responding satisfactorily. In a retrospective chart review of adult and pediatric patients who developed arthralgias or myalgias while receiving quinupristin-dalfopristin therapy, 25 (50%) of the evaluable patient population had pain that may have been associated with the use of this antimicrobial agent [90]. A multivariate analysis demonstrated a strong association with chronic liver disease, receipt of a liver transplant, an elevated bilirubin level at baseline, and receipt of either cyclosporine or mycophenolate.
The effect of intravenous infusions of quinupristin-dalfopristin on fecal flora has been investigated in healthy volunteers [50]. Decreased numbers of gram-negative anaerobic microorganisms and increased numbers of enterococci and enterobacteria were observed. There was also an increase in numbers of enterococci and gram-negative anaerobic bacteria resistant to quinupristin-dalfopristin.
Quinupristin-dalfopristin is a potent inhibitor of CYP3A4 and should be used with caution in treating patients taking drugs that are substrates of 3A4 (e.g., cyclosporine, midazolam, nifedipine, protease inhibitors, and statins). Concomitant administration of cyclosporine and quinupristin-dalfopristin can cause significant increases in concentrations of cyclosporine in the blood [91]. When these drugs are used together, an empirical dosage adjustment of cyclosporine (∼50% decrease) and monitoring of serum concentrations are warranted.
Conclusion
In general, these new parenteral antimicrobials are relatively safe and have a low rate of discontinuation by patients. However, it is important that, before therapy is initiated, the patient's previous antibiotic experience, including allergies and adverse effects, be carefully reviewed [92]. Moreover, a complete review of the patient's medications may alter the antibiotic choice if a potential drug interaction exists. It is equally important to be able to recognize a drug reaction from the patient's underlying illness and comorbidities. Clinicians need to be familiar with the most common and troublesome adverse effects that occur with a given antibiotic and should also take into consideration potential toxicities (table 1). It is fortunate that most of these common adverse events are manageable and rapidly reversible after cessation of the medication. In conclusion, finding an antibiotic with a low potential for toxicity in a given patient is often not difficult, because multiple therapeutic alternatives exist for many infections [93].
Table 1
Dosing regimen and safety concerns associated with newer parenteral antibiotics.
Acknowledgments
Financial support. G.E.S.: Upside Endeavors.
Potential conflicts of interest. G.E.S.: member of tigecycline advisory board (Wyeth) and linezolid advisory board (Pfizer).
- © 2005 by the Infectious Diseases Society of America
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