Antibiotics for treatment of resistant gram-positive coccal infections
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《美国医学杂志》
Division of Infectious Diseases, Children's Hospital of Michigan; Carman and Ann Adams, Department of Pediatrics, Wayne State University School of Medicine, USA
Abstract
Vancomycin is considered the workhorse for the treatment of most drug-resistant gram-positive bacterial infections. However, concerns have been raised regarding the increasing rates of vancomycin-resistant enterococci and the clinical shortcomings of vancomycin in the treatment of invasive Staphylococcus aureus infections. Resources have been committed to the development of antimicrobial agents with activity against these organisms. This review will focus on the newer antibacterial agents that have been developed for the treatment of resistant gram-positive pathogens. Included in this review are the agents: quinupristin-dalfopristin, linezolid, daptomycin, telithromycin, and tigecycline.
Keywords: Vancomycin,Gram-positive; Bacterial infections; Antibacterial agents
Antimicrobial resistance among gram-positive organisms has been increasing steadily during the past several decades. The total usage of vancomycin, which has always been considered the last resort for treatment of resistant gram-positive infections, in the United States and Western Europe, is estimated to have increased from very small quantities in 1975 to over 14,000 kilograms in 1995.[1]
However, vancomycin is facing some major challenges. Among these challenges are the increasing rates of vancomycin resistance in enterococci,[2] vancomycin tolerance in Streptococcus pneumoniae,[3] and most recently, the identification of Staphylococcus aureus isolates with reduced susceptibility[4] or full resistance to vancomycin.[5] In addition, more and more physicians and infectious diseases specialists are regarding vancomycin as an inferior antistaphylococcal antibiotic. Treatment of S. aureus infections with vancomycin has been at times associated with high clinical failure rates, prolonged duration of bacteremia,[6] higher rates of relapsing infections,[7] and worse clinical outcomes.[8]
The recent increase in the number of patients managed on an outpatient basis resulted in an increase in the use of indwelling prosthetic devices. Unfortunately, this increase in usage of these devices has been associated with increasing number of infections caused by resistant gram-positive pathogens.
For all the above reasons, the number and complexity of infections due to resistant gram-positive infections will most likely continue to rise. Therefore, much of the focus has been recently given to producing new antimicrobial agents for the treatment and prevention of resistant gram-positive pathogens. In this article, we will cover some of these newly approved agents' period.
Quinupristin-dalfopristin (Synercid)
Quinupristin-dalfopristin is a combination of streptogramins that was first approved by the U.S. Food and Drug Administration in September 1999 for use in the treatment of serious or life- threatening infections associated with vancomycin-resistant Enterococcus faecium bacteremia and complicated skin and skin structure infections caused by methicillin susceptible Staphylococcus aureus and Streptococcus pyogenes (group A streptococcus).
Chemistry
The streptogramins belong to the macrolide-lincosamide-streptogramin group of antibiotics. They are macromolecular antibiotics produced by Streptomyces pristinaepiralis.[9] Quinupristin-dalfopristin is made up of chemically modified, water-soluble, injectable derivatives of type B streptogramin (quinupristin) and type A streptogramin (dalfopristin) in a 30:70 ratio.
Mechanism of Action and Resistance
This combination of quinupristin-dalfopristin is synergistic, and is bactericidal. The main target is the bacterial 50S ribosome that results in inhibition of protein synthesis.[10] Resistance to quinupristin-dalfopristin is not common; however, it may develop through one of several mechanisms such as modification of the target- binding site, enzymatic inactivation, or active efflux.[10]
Spectrum of Activity
The antimicrobial activity of quinupristin-dalfopristin was evaluated against more than 28,000 clinical bacterial isolates from 200 centers across the United States and Canada.[10] Quinupristin-dalfopristin demonstrated in vitroactivity (MIC < 1 mg/mL) against 90% of strains of a wide variety of multidrug-resistant gram-positive organisms, including E. faecium , methicillin-susceptible S. aureus , methicllin-resistant S. aureus , and Staphylococcus epidermidis . However, strains of Enterococcus faecalis were generally resistant to quinupristin-dalfopristin. Similarly, aerobic gram-negative enteric bacilli were not susceptible to quinupristin-dalfopristin.
Of the more than 4,000 isolates of S. pneumoniae tested, 98% were susceptible to quinupristin-dalfopristin, irrespective of resistance to beta-lactam or macrolide antibiotics. Similarly, 97 % of streptococcal species other than S. pneumoniae were susceptible to quinupristin-dalfopristin.[10] Quinupristin-dalfopristin has also demonstrated in vitro activity against Haemophilus influenzae, Legionella species, Mycoplasma species, Clostridium speciesand Chlamydia pneumoniae.
Pharmocokinetics
Quinupristin and dalfopristin are the active components circulating in plasma. Both are converted to active metabolites that contribute to the antimicrobial activity of the formulation.[9] The half-life of quinupristin and its metabolites is approximately three hours, whereas the half-life of dalfopristin and its metabolites is approximately one hour. Approximately, 75 percent of the given dose is eliminated by the gastrointestinal tract, while urinary excretion accounts for 15 percent of the quinupristin dose and 19 percent of the dalfopristin dose.
The peak plasma level of quinupristin-dalfopristin after a single 7.5 mg/kg dose given intravenously is 2.3 mg/L for quinupristin and 6.5 mg/L for dalfopristin. Both components penetrate well into interstitial fluid. Quinupristin-dalfopristin has also demonstrated prolonged post-antibiotic effect.[11] The duration of this effect is about 10 hours for S. aureus and nine hours for S. pneumoniae.
Clinical Studies and Use
Moellering RC et al assessed the clinical efficacy and safety of quinupristin-dalfopristin in the treatment of 396 patients with vancomycin-resistant E. faecium infection.[12] Quinupristin-dalfopristin in a dosage of 7.5 mg/kg was administered intravenously every eight hours for a duration judged appropriate by the investigator. The most frequent indications for treatment were bacteremia with unknown focus, bone and joint infection, catheter-related bacteremia, intra-abdominal infection, skin structure infection, and urinary tract infection. The mean duration of treatment was 14.5 + 10.7 days (range:1-108 days). The clinical success rate was 74 % (95 % confidence interval [CI]: 67 to 80 %). The bacteriologic success rate was 71 % (95 % CI: 65 to 78 %). The overall clinical and bacteriologic success rate was 66 %. The worst outcomes occurred in patients who had vancomycin-resistant E. faecium bacteremia at entry into the study, in patients who were on mechanical ventilation, or in patients who had undergone laparotomy. Superinfection by gram-positive organisms was documented in 22% of patients, and resistance to quinupristin-dalfopristin developed in six (4%) of 156 patients who could be evaluated facteriologically.
Nichols RL et al compared quinupristin-dalfopristin with cefazolin, oxacillin, and vancomycin in two randomized, open-label clinical trials involving hospitalized patients with complicated gram-positive skin and skin structure infections.[14] A total of 893 patients were enrolled, 450 patients randomized to the quinupristin-dalfopristin, and 443 randomized to the comparison drug. The majority of patients had erysipelas, traumatic wound infection, or clean surgical wound infection. S. aureus was the most frequently isolated pathogen. The two trials showed comparable clinical success rates in the quinupristin-dalfopristin group (68.2 %) and the comparison group (70.7%).
Raad I et alfound quinupristin-dalfopristin to be effective in the treatment of catheter-related bacteremia caused by S. aureus or coagulase-negative staphylococci.[15] In this small study (39 patients), quinupristin-dalfopristin was compared with vancomycin. The outcomes for the two treatment groups were the same (50 % clinical and bacteriologic responses), and the safety profiles were comparable.
Drug Interactions
Quinupristin-dalfopristin inhibits the cytochrome P450-3A4 enzyme system.[13] Some of the drugs whose plasma concentrations are predicted to increase following quinupristin-dalfopristin administration are listed in table1.[13]
Adverse Reactions
The safety profile of quinupristin-dalfopristin has been evaluated in more than 2,000 patients. The most common adverse effects were pain and inflammation at the infusion site. However, treatment discontinuation was reported in fewer than 10% of patients.[13] Other side effects include arthralgias (9%) and myalgias (6%), which have led to the discontinuation of quinupristin-dalfopristin in one third to one half of affected patients. Other common systemic adverse events have been nausea (4.6%), diarrhea (2.7%), vomiting (2.7%), rash (2.5%), headache (1.6%), pruritus (1.5%) and pain (1.5%).[12]
Liver function abnormalities have occurred in approximately 1% of patients who received quinupristin-dalfopristin. However, these effects have generally been mild and transient. No significant effects on renal function have been reported. And bone marrow toxicity has been rare.[12]
Dosage
The recommended dosage of quinupristin-dalfopristin for the treatment of vancomycin-resistant E. faecium infections in adults is 7.5 mg per kg administered intravenously every eight hours. The recommended dosage for complicated skin and skin structure infections is 7.5 mg per kg given intravenously every 12 hours. For vancomycin-resistant E. faecium infections, the duration of treatment should be based on the site and severity of the infection. The recommended minimum duration of treatment for complicated skin and skin structure infections is seven days.[13] The dosage of quinupristin-dalfopristin does not have to be adjusted in patients with renal impairment. Limited clinical data are available on the use of quinupristin-dalfopristin in patients with hepatic disease, but a dosage reduction may be required in patients with cirrhosis. Pediatric dosing is currently not available.
Linezolid (0 Zyvox)
Linezolid is the first of a new class of antimicrobial agents, the oxazolidinones. It was approved by the U.S. Food and Drug Administration (FDA) in 2000 for the treatment of skin and soft tissue infections, lower respiratory tract infections due to susceptible organisms, and vancomycin-resistant Enterococcus faecium infections including cases with concurrent bacteremia.
Chemistry
The oxazolidinones are unique because they are totally synthetic. Therefore, there are no preexisting specific resistance genes among gram-positive bacteria against this group of drugs. Their mechanism of action is also unique, which decreases the possibility of cross-resistance with currently available agents.
They were originally developed as monoamine oxidase inhibitors for treatment of depression, but subsequently discovered to have antimicrobial activity. The first oxazolidinone antimicrobial agents were developed in the late 1970s for the control of bacterial and fungal foliage diseases of various plants.[16] A series of chemical modifications of the oxazolidinone nucleus led to the discovery of two agents, eperezolid and linezolid. Although both agents showed excellent in vitro activity against gram-positive bacteria, linezolid was chosen for further clinical development.[17]
Mechanism of Action and Resistance
The oxazolidinones are considered bacteriostatic. They have a unique mechanism of action that interferes with the first step of bacterial ribosomes assembly. They bind to a site on the 50S ribosomal subunit near its interface with the 30S unit, thus preventing the formation of a 70S initiation complex.[18],[19],[20] No other known antimicrobial agent inhibits this process; therefore, there is no cross-resistance.
Being a synthetic compound, naturally occurring resistance is unlikely and in vitro induced resistance to linezolid is difficult. However, mutants of linezolid-resistant Staphylococcus aureus and Enterococcus faecalis have been produced by using serial passage on spiral gradient plates. It appears to be more difficult to generate mutants of Enterococcus faecium resistant to linezolid than for quinupristin-dalfopristin.[20]
However, cases of in vivoresistance have been reported. Tsiodras et al reported linezolid resistance in a clinical isolate of Staphylococcus aureus.[21] Linezolid resistance in clinical isolates of Enterococcus faecium[22], [23] has also been reported. Resistance is most likely to occur in seriously ill patients with indwelling prosthetic devices who are receiving prolonged courses of the antibiotic.[21],[22],[23]
Spectrum of Activity
The oxazolidinones have excellent in vitro activity against the major gram-positive bacteria and some gram-negative bacteria that are pathogenic in humans. More than 90% of the following gram-positive bacteria are inhibited by < 4 μg/ml of linezolid: Staphylococcus aureus, Listeria monocytogenes, Corynebacterium species, and Bacillus species . About 90% of the following gram-positive bacteria are inhibited by < 2 μg/ml of linezolid: Staphylococcus epidermidis, Streptococcus pneumoniae,beta hemolytic streptococci and viridans group streptococci. For enterococci, < 2 μg/mL indicates susceptibility, 4 μg/mL indicates intermediate susceptibility, and 8 μg/mL or greater indicates resistance.[17], [24]
Linezolid has good activity against many gram-positive anaerobes; however, its activity against Bacteroides fragilis is borderline (MIC of 4 μg/mL).[25]
Although linezolid has demonstrated in vitro activity against Neisseria More Details gonorrhoeae and Neisseria meningitides , it only has borderline activity (MIC= 4-16 μg/mL) against Haemophilus influenzae . It is inactive against enterobacteriace and Pseudomonas species.[25], [26] There are not enough data on linezolid effectiveness in vivo against atypical organisms including Legionella pneumophila , Mycoplasma pneumoniae , and Chlamydia pneumoniae.[25] Linezolid also has excellent in vitro activity against Nocardia .[27]
Pharmacokinetics
Linezolid is 100% bioavailable, both when given orally or intravenously. Maximum plasma concentrations are achieved 1 to 2 hours after an oral dose. Taking the drug with food may slightly delay its uptake, but the total amount of drug absorbed is unchanged. Linezolid has low serum plasma protein binding (31%) and is freely distributed to well-perfused tissues.[24]
The drug does not induce or inhibit cytochrome P450 enzymes in humans.[24]
About 35% of the parent compound is recovered in the urine, and none in feces. Therefore, the pharmacokinetic characteristics of linezolid are not markedly altered in patients with renal insufficiency, and no dosage requirement is officially recommended for patients with renal or hepatic insufficiency. Both linezolid and its two metabolites are eliminated by dialysis.[24] There is no information on the effect of peritoneal dialysis on the pharmacokinetic characteristics of linezolid, but current data suggest that in patients receiving hemodialysis, supplemental or post-dialysis doses should be administered.[28]
Clinical Studies and Use
The U.S. FDA has approved linezolid for the treatment of vancomycin-resistant Enterococcus faecium infections; pneumonia caused byStreptococcus pneumoniae (penicillin-susceptible strains only) or Staphylococcus aureus (methicillin-susceptible and methicillin-resistant strains),complicated skin and soft tissue infections caused by S. aureus (methicillin-resistant and methicillin-susceptible strains), Streptococcus pyogenes, or Streptococcus agalactiae; and uncomplicated skin and soft tissue infections caused by S. aureus (methicillin-susceptible strains only) or Streptococcus pyogenes.[24] These indications are based on the results of phase III trials presented to the FDA. In all of the studies completed so far, linezolid has been shown to be equivalent to its comparator.[29],30],[31] Linezolid is indicated for community-acquired pneumonia on the basis of comparative trials with cefpodoxime and ceftriaxone both of which possess no activity against atypical pathogens like Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella species.[32] For this reason and because linezolid also lacks good activity against Haemophilus influenzae, it should not be considered a first-line choice for community-acquired pneumonia at the present time.
No comparative trials of linezolid in patients with endocarditis, osteomyelitis, or meningitis have been performed. Although linezolid was shown to be initially efficacious in the eradication of the nasal carriage of Staphylococcus aureus, the eradication was transient and most patients were recolonized after 30 days.[33]
Drug Interaction
Adrenergic agents, phenylpropanolamine and pseudoephedrine should be reduced in patients receiving linezolid because of enhanced pressor response.[24] There is no evidence of interaction of linezolid with oral or inhaled albuterol (Data on file. Pharmacia Corp.).
Adverse Effects
Although dose-dependent and time-dependent myelosuppression was noted in dogs and rats receiving prolonged, high-dose therapy with linezolid in preclinical trials, only a few cases of reversible thrombocytopenia were noted in the phase III human trials. Therefore, it is recommended that complete blood counts be monitored weekly in patients who receive linezolid, especially those receiving the drug for more than 2 weeks, those with preexisting myelosuppression, those receiving concomitant drugs that produce bone marrow suppression, and those with chronic infection who have received previous or concomitant antibiotic therapy.[24]
Dosage
In adults, a standard dosage of 600 mg every 12 hours is recommended for treatment of most serious infections except uncomplicated skin and skin structure infections, for which an oral dosage of 400 mg every 12 hours is recommended.[24] Pediatric dosing regimens are detailed in table2.
Daptomycin (Cubicin)
Daptomycin is the first agent of a new class of antibiotics called cyclic lipopetides drug. Daptomycin was approved by the U.S. FDA in 2003 for use in adults in the treatment of skin and soft tissue infections and lower respiratory tract infections due to susceptible organisms.
Mechanism of Action and Resistance
Daptomycin has a unique but not fully understood mechanism of action. It binds to bacterial membranes and causes rapid depolarization of membrane potential. This results in inhibition of protein, DNA, and RNA synthesis resulting in bacterial cell death. Daptomycin exhibits concentration-dependent and rapid bactericidal
activity. [34],[35],[36],[37],[38],[39],[40]
So far, no significant resistance has been reported against daptomycin. In one study, S. aureus(n=4), S. epidermidis(n=4), E. faecalis(n=4), E. faecium (n=2), and S. pneumoniae(n=2) strains were tested with daptomycin at concentration 8 x MIC for spontaneous resistance. None was detected.[41] However, in phase 2 & 3 clinical studies, two cases of emerging resistance have been reported. The first was a resistant S. aureus that emerged during a phase 2 endocarditis treatment study. It was noted later that the patient was given a treatment dose lower than the protocol-defined dose. The second case involved a resistant E. faecalis in a patient with a chronic infected decubitus ulcer enrolled in a salvage trial.[41]
Spectrum of Activity
Daptomycin has shown excellent in vitro activity against S. aureus(methicillin susceptible and methicillin resistant), Streptococcus pyogenes, Streptococcus agalactiae . All of these organisms were considered susceptible to daptomycin at MIC < 1mcg/mL.However, vancomycin-susceptible Enterococcus faecalis is considered susceptible at MIC < 4 mcg/mL. ([40], [42],[43],[44],[45],[46],[47],[48]) A study in vancomycin resistant enterococcus was stopped due to slow enrollment. Therefore, it is not recommended at this time for the treatment of VRE.[49]
Daptomycin was also active against all tested strains of Clostridium difficile, Clostridium perfringens, and Corynebacterium jeikeium . It had variable susceptibilities against organisms, Actinomyces group, Eubacterium group, Lactobacillus spp, Propionibacterium spp, Corynebacterium spp, had variable susceptibilities.[50]
Susceptibility studies for daptomycin against vancomycin-intermediate S. aureus (VISA) and, more recently, vancomycin-resistant S. aureus revealed variable results with MIC range of 0.5-16.[40], [45], [51],[52],[53],[54]
Sun HK et al reported linezolid and quinupristin-dalfopristin (Q-D) resistant organisms (including S. aureus, E. faecalis and E. faecium)that were susceptible to daptomycin.[55]
Pharmacokinetics
Daptomycin exhibited linear pharmacokinetics at the 4 mg/kg and 6 mg/kg dosages. The 8mg/kg dose, however, exhibited slightly less linearity, as Cmax was 2.2 times higher than that of the 4 mg/kg dose.[56] Daptomycin was also shown to penetrate well into cantharidin-induced inflammatory blisters.[57]
Clinical Studies and Use
Clinical efficacy data are available from two randomized, investigator-blinded clinical studies comparing daptomycin 4 mg/kg once daily to vancomycin 1gm q 12 hours or semisynthetic penicillin 4-12 g/day (oxacillin, nafcillin, cloxacillin, flucloxacillin) in patients with SSTI. Study outcomes were based on the post-therapy (test-of-cure visit) conducted 7-12 days post-treatment.
Daptomycin was not inferior to the comparator agents. Actually, the daptomycin group showed greater improvement in clinical signs and symptoms by the third or fourth day than the comparator group, and the median duration of therapy was 1 day shorter, with daptomycin vs comparator in one of the studies.
There is an ongoing clinical study of treatment of right-sided endocarditis/bacteremia due to S. aureus,using a once daily dose of 6 mg/kg for 14-28 days. The comparator agents are nafcillin or vancomycin + gentamicin.
Since daptomycin has shown encouraging results in the treatment of experimental osteomyelitis, the manufacturer plans to propose an osteomyelitis study to the FDA using daptomycin 6 mg/kg.[49]
Drug Interactions
Synergy studies with several antibiotics (penicillins, cephalosporins, carbapenems, quinolones, and aminoglycosides) against susceptible organisms revealed variable effects that ranged between additive, indifferent or none antagonistic.[58]
Daptomycin does not affect the activity of the CYP450 enzymes; therefore, drug interactions via this system are not expected.[41]
Adverse Reactions
The most commonly reported side effect of daptomycin is elevation of CPK which was reported in 2-2.9% (phase I studies), 5.4-5.6% (phase II studies) and 2.8% (phase III study) of patients. In addition, during the phase III study, symptoms consistent with myopathy (pain in limb, arthralgia, back pain, myalgia, muscle cramps) were reported in 7 (1.3%) of 534 patients treated with daptomycin. Therefore, it is recommended that patients be monitored for muscle pain or weakness and weekly CPK levels while on therapy. Patients developing unexplained CPK elevations should be monitored more frequently; however, those with substantially elevated CPKs (> 10 x normal values) should discontinue daptomycin. Daptomycin should also be discontinued in those who have unexplained symptoms of myopathy and elevated CPK.[41]
Another rare but serious side effect is neuropathy. Bell's palsy was reported in two patients during phase I study and in two more cases during phase II studies. In addition, during phase II studies, there was one case of neuropathy and one case of decreased nerve conduction velocity. Interestingly, none of these side effects was appreciated during phase III studies.[41]
In general, during phase III studies, adverse events were reported in 51.3% and 52.5% of patients receiving daptomycin and comparator respectively. Serious adverse events (SAE) occurred in 10.9% of those receiving daptomycin and in 8.8% receiving comparator. The SAEs were due to cellulitis, urosepsis, hypersensitivity reaction, and diarrhea. The most commonly reported adverse events were gastrointestinal, injection site reactions, and headache.[41]
Dosage
The dose of daptomycin is 4mg/kg IV once daily for 7-14 days. Patients with creatinine clearance < 30mL/min, including those receiving hemodialysis or continuous ambulatory peritoneal dialysis, should receive 4mg/kg IV every 48 hours. Pediatric dosing is currently not available.[41]
Telithromycin (Ketek)
Telithromycin belongs to a new class of 14-membered ring macrolides called ketolides. It was approved by the U.S. FDA in April of 2004 for use in the treatment of acute exacerbation of chronic bronchitis (AECB); acute bacterial sinusitis (ABS); and mild to moderate community-acquired pneumonia (CAP).[58]
Chemistry
Ketolides are semisynthetic compounds characterized by replacement of the L-cladinose fixed on the macrolactone (erythronolide A) ring with a 3-keto group. Telithromycin is also characterized by a C11-C12 carbamate side chain that increases the affinity of the drug for ribosomes including MLSB - resistant ribosomes. This side chain also reduces resistance through the efflux pump.[58]
Mechanism of Action and Resistance
Macrolides bind to domain V of the 23S rRNA within the 50S ribosomal subunit. Telithromycin blocks protein synthesis by binding to domains II and V of 23S rRNA of the 50S ribosomal subunit, causing inhibition of bacterial replication.[59] MLSB resistance caused by erm gene affects the antimicrobial binding site of domain V on the 23S rRNA. However, the binding affinity of telithromycin to domain II is 10 folds stronger than that of erythromycin. This explains the enhanced activity of telithromycin against MLSB resistant gram-positive cocci.[60] Telithromycin does not appear to induce MLSB resistance.[60]
Spectrum of Activity
Telithromycin is highly effective against many common respiratory pathogens as well as atypical and intracellular bacteria. In addition, telithromycin is active against Moraxella More Details catarrhalis , Haemophilus influenzae , Streptococcus pyogenes .[61],[62] Telithromycin has more in vitro activity against gram-positive aerobes than macrolides and azalides.[63] Telithromycin is active against atypical organisms involved in respiratory tract infections such as Mycoplasma pneumoniae , Chlamydia pneumoniae , Legionellaspp. and Bordetella pertussis. [64],[65],[66],[67] Telithromycin is at least as active as azithromycin against gram- negative respiratory pathogens such as Haemophilus influenzae and Moraxella catarrhalis including beta-lactamase producing strains.[62] However, telithromycin is inactive against gram- negative enteric rods including the Enterobacteriaceae group. Telithromycin is also inactive against the non-fermentative gram-negative bacilli including Pseudomonas aeruginosa[63]
Telithromycin has potent activity and is bactericidal against Streptococcus pneumoniae including penicillin-resistant strains and macrolide-resistant strains irrespective of the underlying mechanism of resistance such as ermgene acquisition (target site modification), mef gene acquisition (efflux pumps) and ribosomal L4 mutations.[61], [63], [68]
Telithromycin is active against erythromycin-susceptible Staphylococcus aureus and isolates that can export or enzymatically degrade macrolides. Telithromycin is not active against S. aureus isolates that constitutvely express erm genes. It is also inactive against MRSA isolates.[61], [69] Although S. aureus isolates with inducible MLSB resistance are susceptible in vitro to telithromycin, erm resitance has been reported to switch from inducible to constitutive expression. This will limit the clinical efficacy of telithromycin in treating infections caused by S. aureus with MLSB inducible phenotype.[63]
Telithromycin is active against many gram-positive and gram-negative anaerobes including Peptostreptococcus spp., Clostridium spp., Bacteroides spp.[70]
Telithormycin has been shown to be active against intracellular and extracellular Helicobacter pylori with significant postantibiotic effect.[77] Telithromycin is more active than erythromycin against Rickettsia , Bartonellaand Coxiella burnettii , the causative agent of Q-fever. Telithromycin is ineffective against Ehrlichia chaffensis .[71]
Pharmacokinetics
Approximately 90% of the oral dose is absorbed and 33% undergoes first pass metabolism mainly by the liver. Oral absorption is not affected by food intake.[72] Peak plasma concentrations are achieved within 2.5 hours. Approximately 60-70% of telithromycin is protein bound. Telithromycin concentrates in white blood cells and respiratory tissues after absorption. At 8 hours after dosing, telithromycin concentrations in alveolar macrophages and epithelial fluid in the respiratory tract markedly exceed plasma concentrations.[73] Telithromycin tonsillar tissue concentration exceeds the MIC 50 of group A beta-hemolytic streptococci.[74] Elimination of telithromycin is accomplished through metabolization by the liver (37%) and excretion unchanged in feces (7%).[75] Approximately 13% of telithromycin is excreted unchanged in the urine. About 50% of telithromycin metabolism occurs through the P450 system mainly by CYP3A4 enzyme. In patients with hepatic impairment, increased renal clearance may compensate for hepatic clearance.[75], [76] Slight accumulation of telithromycin occurs (1.4 fold increase in Cmax and AUC) in patients with mild-severe renal impairment.[75] Pharmacokinetic data in children are currently not available.
Clinical studies and use
In adults telithromycin has been shown to be as effective as macrolides and fluoroquinolones in treatment of community acquired pneumonia (CAP) including cases caused by penicillin- and erythromycin-resistant S. pneumoniae.[77], [78] In preliminary studies, telithromycin has been shown to be effective in other respiratory tract infections such as chronic bronchitis, tonsillopharyngitis and acute maxillary sinusitis. Telithromycin at 800 mg/day given for 7 to 10 days was as effecticve as macrolides and fluoroquinolones in treating CAP caused by S. pneumoniae as well as atypical and intracellular organisms. Telithromycin was also effective in treating pneumococcal bacteremia accompanying CAP, including bacteremia caused by pneumococcal strains that were resistant to penicillin or erythromycin.[77],[78],[79] It has also been shown that a 5-day course of telithromycin at 800 mg/day was as effective as a 10-day course of penicillin or clarithromycin in the treatment of GABHS tonsillitis/pharyngitis in adult patients and adolescents older than 13 years of age.[80] Published data on the efficacy of telithromycin in treating pediatric infections are not available.
Drug interactions
Telithromycin inhibits the activity of CYP3A4 enzyme and therefore should not be given concomitantly with cisapride and midazolam.[77], [78] Increased QTc interval has also been reported with concomitant administration of cyclosporin, tacrolimus and sirolimus and dosage adjustment is needed. The levels of digoxin, theophylline are also increased with concomitant telithromycin therapy. Itraconazole and ketoconazole increase the AUC of telithromycin, however, no dosage adjustment is needed.[62], [78]
Adverse reactions
The most common adverse event associated with telithromycin use in adult studies of 800 mg/day was diarrhea occurring in 13.7% of patients. Telithromycin has also been associated with other adverse events such as nausea in 8.7%, headache in 6.7% and vomiting in 3.1% of patients.[77], [78]
Dosage
The adult dose is 800 mg given once daily for 7 to 10 days for most clinical indications. Pediatric dosing is currently not available.
Tigecycline (Tygacil)
Tigecycline is a new, semisynthetic glycylcycline that was approved by the US FDA for the treatment of skin, soft-tissue, and intra-abdominal infections.[81],[82]
Chemistry
Glycylcyclines gained a broader spectrum of activity due to substitution of an N -alkyl-glycylamido group at the 9 position on the D-ring of the central 4-ring carbocyclic skeleton that is essential for antibacterial activity.[83]
Mechanism of action and resistance
Tigecycline is bacteriostatic, and it acts by binding to the bacterial 30S ribosomal subunit that leads to inhibition of protein synthesis.[84], [85] Tigecycline does not seem to be affected by the two mechanisms of tetracycline resistance: active efflux of drug from inside the bacterial cell and protection of ribosomes.[86], [87] In addition, many bacterial mutants have been generated in the laboratory and have exhibited only marginal differences in susceptibility to tigecycline. Therefore, it does not seem that resistance would arise by trivial mutations in existing resistance genes.[85]
Spectrum of Activity
Tigecycline is highly effective in vitro against most gram positive organisms including: Staphylococcus aureus,coagulase-negative staphylococci, Enterococcus species, Streptococcus pneumoniae,group A streptococci, group B streptococci and viridans streptococci. MIC 90 for these organisms ranges between 0.02 ug/ml and 1.0 ug/ml.[81], [86],[87],[88],[89],[90],[91],[92],[93],[94],[95],[96],[97],[98],[99],[100],[101],[102],[103],[104] It also has good in vitro activity against most gram- negative organisms including: Escherichia More Details coli, Klebsiella pneumoniae, Klebsiella oxytoca, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia species, Shigella species, Salmonella More Details species, Citrobacter species, Enterobacter species, Serratia marcescens, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, Acinetobacter species, Burkholderia cepacia, Haemophilus influenzae, Moraxella species, Neisseria gonorrhoeae More Details and Eikenella corrodens.MIC 90 for these organisms ranged between 0.25 ug/ml and 4.0 ug/ml with the following exceptions: Proteus mirabilis, Providencia species, Acinetobacter species, and Acinetobacter baumannii( MIC 90 = 8 ug/ml), Pseudomonas aeruginosa(MIC 90 =16-32) and Burkholderia cepacia(MIC 90 = 4-32).[81], [82], [86], [88]-[91], [100], [101], [105]-[109] Tigecycline has also shown good in vitro activity against anaerobes such as: Bacteroides fragilis , Bacteroides fragilis group, Clostridium perfringens , Clostridium difficile , Propionibacterium acnes , Peptostreptococcus species , Fusobacterium species , Prevotella species and Porphyromonas species (MIC 90 range 0.03-2.0 ug/ml.[86], [90], [110]
Of interest, Tigecycline has shown some in vitro activity against some atypical organisms as follows: Mycobacterium abscessus (MIC 90 = 0.25), Mycobacterium chelonae(MIC 90 ￡ 0.13), Mycobacterium fortuitumgroup (MIC 90 ￡0.13), Mycobacterium marinum (MIC 90 3-16). In vitro activity against the following atypical organisms was reported: Chlamydia pneumoniae ( MIC 90 =0.13), Mycoplasma hominis (MIC 90 = 0.5), Mycoplasma pneumoniae(MIC 90 =0.25), Ureaplasma urealyticum(MIC 90 =8). [110],[111],[112],[113]
Phamacokinetics
Several studies of single- and multiple-dose tigecycline pharmacokinetics have shown that the half-life of tigecycline range is 37- 67 hours, and the systemic clearance of tigecycline range is 0.2 to 0.3 L/h/kg. Tigecycline binding to protein is ~78%. These studies also revealed that tigecycline had a large volume of distribution (7-10 L/kg), which suggest extensive distribution into the tissues. These studies have also shown that food increased the maximum tolerated single dose from 100 mg to 200 mg, while the duration of infusion did not affect tolerability.[114],[115],[116]
Excellent overall tissue penetration has been demonstrated in animal studies, including bone, bone marrow, salivary gland, thyroid, spleen, kidney and CSF. [117], [118]
Tigecycline elimination is done primarily by the liver. About 30% of the drug is excreted unchanged in the urine. No dosage adjustment is required in patients with renal dysfunction. There is no sufficient data about the pharmacokinetics and safety of tigecycline in patients with hepatic impairment. Therefore, clinicians should exercise caution when using tigecycline in patients with severe hepatic dysfunction.
Clinical studies and use
Tigecycline is currently approved for the treatment of patients with complicated skin and skin-structure infections and complicated intra-abdominal infections.[81], [82]
In one trial, the clinical and microbiological efficacy, pharmacokinetics, and tolerability of 2 different doses of tigecycline in the treatment of complicated skin and skin-structure infection in 14 centers in the United States were evaluated. Patients received tigecycline (25 or 50 mg) intravenously every 12 h for 7-14 days. One hundred sixty patients received at least 1 dose of tigecycline. At the test-of-cure visit, the clinical cure rate in the 25-mg group was 67% (95% CI, 53.3%-79.3%), compared with 74% (95% CI, 60.3%-85.0%) in the 50-mg group. The eradication rate was 56% in the 25-mg group (95% CI, 40.0% -70.4%), compared with 69% (95% CI, 54.2%-82.3%) in the 50-mg group. Nausea and vomiting were noted to be the most common adverse events.[81]
In another multicenter, phase 2, open-label study of hospitalized patients with complicated intra-abdominal infections requiring surgery all patients received 100 mg of tigecycline administered intravenously as a loading dose, followed by 50 mg every 12 h for 5-14 days. Sixty-six patients with perforated and gangrenous appendicitis, complicated cholecystitis, or perforated diverticulitis and peritonitis met all of the inclusion criteria and were evaluated. Cure rates at the test-of-cure visit and the end-of-treatment visit were 67% (95% CI, 54.0% -77.8%) and 76% (95% CI, 63.6%-85.5%), respectively. In the intent-to-treat analyses, the cure rate at the test-of-cure visit was 55% (95% CI, 45.2%-64.4%) and the end-of-treatment cure rate was 72% (95% CI, 62.8%-80.2%). Nausea and vomiting were noted to be the most common adverse events.[82]
Drug interactions
Limited information with regards to interaction is available at this time. Tigecycline may decrease the elimination of warfarin thereby increasing its levels in blood.
Adverse reactions
The most common side effects of tigecycline are nausea and vomiting. Both are mild or moderate and usually occur during the first two days of therapy. Other side effects include pain at the injection site, swelling and irritation. Tigecycline is similar to tetracycline antibiotics and therefore may have similar side effects such as increased sensitivity to sunlight.
Dosing
Tigecycline is administered via intravenous infusions over 30 to 60 minutes. The initial dose is 100 mg followed by 50 mg every 12 hours. The usual duration of treatment is 5-14 days. Pediatric dosing is currently not available.
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Abstract
Vancomycin is considered the workhorse for the treatment of most drug-resistant gram-positive bacterial infections. However, concerns have been raised regarding the increasing rates of vancomycin-resistant enterococci and the clinical shortcomings of vancomycin in the treatment of invasive Staphylococcus aureus infections. Resources have been committed to the development of antimicrobial agents with activity against these organisms. This review will focus on the newer antibacterial agents that have been developed for the treatment of resistant gram-positive pathogens. Included in this review are the agents: quinupristin-dalfopristin, linezolid, daptomycin, telithromycin, and tigecycline.
Keywords: Vancomycin,Gram-positive; Bacterial infections; Antibacterial agents
Antimicrobial resistance among gram-positive organisms has been increasing steadily during the past several decades. The total usage of vancomycin, which has always been considered the last resort for treatment of resistant gram-positive infections, in the United States and Western Europe, is estimated to have increased from very small quantities in 1975 to over 14,000 kilograms in 1995.[1]
However, vancomycin is facing some major challenges. Among these challenges are the increasing rates of vancomycin resistance in enterococci,[2] vancomycin tolerance in Streptococcus pneumoniae,[3] and most recently, the identification of Staphylococcus aureus isolates with reduced susceptibility[4] or full resistance to vancomycin.[5] In addition, more and more physicians and infectious diseases specialists are regarding vancomycin as an inferior antistaphylococcal antibiotic. Treatment of S. aureus infections with vancomycin has been at times associated with high clinical failure rates, prolonged duration of bacteremia,[6] higher rates of relapsing infections,[7] and worse clinical outcomes.[8]
The recent increase in the number of patients managed on an outpatient basis resulted in an increase in the use of indwelling prosthetic devices. Unfortunately, this increase in usage of these devices has been associated with increasing number of infections caused by resistant gram-positive pathogens.
For all the above reasons, the number and complexity of infections due to resistant gram-positive infections will most likely continue to rise. Therefore, much of the focus has been recently given to producing new antimicrobial agents for the treatment and prevention of resistant gram-positive pathogens. In this article, we will cover some of these newly approved agents' period.
Quinupristin-dalfopristin (Synercid)
Quinupristin-dalfopristin is a combination of streptogramins that was first approved by the U.S. Food and Drug Administration in September 1999 for use in the treatment of serious or life- threatening infections associated with vancomycin-resistant Enterococcus faecium bacteremia and complicated skin and skin structure infections caused by methicillin susceptible Staphylococcus aureus and Streptococcus pyogenes (group A streptococcus).
Chemistry
The streptogramins belong to the macrolide-lincosamide-streptogramin group of antibiotics. They are macromolecular antibiotics produced by Streptomyces pristinaepiralis.[9] Quinupristin-dalfopristin is made up of chemically modified, water-soluble, injectable derivatives of type B streptogramin (quinupristin) and type A streptogramin (dalfopristin) in a 30:70 ratio.
Mechanism of Action and Resistance
This combination of quinupristin-dalfopristin is synergistic, and is bactericidal. The main target is the bacterial 50S ribosome that results in inhibition of protein synthesis.[10] Resistance to quinupristin-dalfopristin is not common; however, it may develop through one of several mechanisms such as modification of the target- binding site, enzymatic inactivation, or active efflux.[10]
Spectrum of Activity
The antimicrobial activity of quinupristin-dalfopristin was evaluated against more than 28,000 clinical bacterial isolates from 200 centers across the United States and Canada.[10] Quinupristin-dalfopristin demonstrated in vitroactivity (MIC < 1 mg/mL) against 90% of strains of a wide variety of multidrug-resistant gram-positive organisms, including E. faecium , methicillin-susceptible S. aureus , methicllin-resistant S. aureus , and Staphylococcus epidermidis . However, strains of Enterococcus faecalis were generally resistant to quinupristin-dalfopristin. Similarly, aerobic gram-negative enteric bacilli were not susceptible to quinupristin-dalfopristin.
Of the more than 4,000 isolates of S. pneumoniae tested, 98% were susceptible to quinupristin-dalfopristin, irrespective of resistance to beta-lactam or macrolide antibiotics. Similarly, 97 % of streptococcal species other than S. pneumoniae were susceptible to quinupristin-dalfopristin.[10] Quinupristin-dalfopristin has also demonstrated in vitro activity against Haemophilus influenzae, Legionella species, Mycoplasma species, Clostridium speciesand Chlamydia pneumoniae.
Pharmocokinetics
Quinupristin and dalfopristin are the active components circulating in plasma. Both are converted to active metabolites that contribute to the antimicrobial activity of the formulation.[9] The half-life of quinupristin and its metabolites is approximately three hours, whereas the half-life of dalfopristin and its metabolites is approximately one hour. Approximately, 75 percent of the given dose is eliminated by the gastrointestinal tract, while urinary excretion accounts for 15 percent of the quinupristin dose and 19 percent of the dalfopristin dose.
The peak plasma level of quinupristin-dalfopristin after a single 7.5 mg/kg dose given intravenously is 2.3 mg/L for quinupristin and 6.5 mg/L for dalfopristin. Both components penetrate well into interstitial fluid. Quinupristin-dalfopristin has also demonstrated prolonged post-antibiotic effect.[11] The duration of this effect is about 10 hours for S. aureus and nine hours for S. pneumoniae.
Clinical Studies and Use
Moellering RC et al assessed the clinical efficacy and safety of quinupristin-dalfopristin in the treatment of 396 patients with vancomycin-resistant E. faecium infection.[12] Quinupristin-dalfopristin in a dosage of 7.5 mg/kg was administered intravenously every eight hours for a duration judged appropriate by the investigator. The most frequent indications for treatment were bacteremia with unknown focus, bone and joint infection, catheter-related bacteremia, intra-abdominal infection, skin structure infection, and urinary tract infection. The mean duration of treatment was 14.5 + 10.7 days (range:1-108 days). The clinical success rate was 74 % (95 % confidence interval [CI]: 67 to 80 %). The bacteriologic success rate was 71 % (95 % CI: 65 to 78 %). The overall clinical and bacteriologic success rate was 66 %. The worst outcomes occurred in patients who had vancomycin-resistant E. faecium bacteremia at entry into the study, in patients who were on mechanical ventilation, or in patients who had undergone laparotomy. Superinfection by gram-positive organisms was documented in 22% of patients, and resistance to quinupristin-dalfopristin developed in six (4%) of 156 patients who could be evaluated facteriologically.
Nichols RL et al compared quinupristin-dalfopristin with cefazolin, oxacillin, and vancomycin in two randomized, open-label clinical trials involving hospitalized patients with complicated gram-positive skin and skin structure infections.[14] A total of 893 patients were enrolled, 450 patients randomized to the quinupristin-dalfopristin, and 443 randomized to the comparison drug. The majority of patients had erysipelas, traumatic wound infection, or clean surgical wound infection. S. aureus was the most frequently isolated pathogen. The two trials showed comparable clinical success rates in the quinupristin-dalfopristin group (68.2 %) and the comparison group (70.7%).
Raad I et alfound quinupristin-dalfopristin to be effective in the treatment of catheter-related bacteremia caused by S. aureus or coagulase-negative staphylococci.[15] In this small study (39 patients), quinupristin-dalfopristin was compared with vancomycin. The outcomes for the two treatment groups were the same (50 % clinical and bacteriologic responses), and the safety profiles were comparable.
Drug Interactions
Quinupristin-dalfopristin inhibits the cytochrome P450-3A4 enzyme system.[13] Some of the drugs whose plasma concentrations are predicted to increase following quinupristin-dalfopristin administration are listed in table1.[13]
Adverse Reactions
The safety profile of quinupristin-dalfopristin has been evaluated in more than 2,000 patients. The most common adverse effects were pain and inflammation at the infusion site. However, treatment discontinuation was reported in fewer than 10% of patients.[13] Other side effects include arthralgias (9%) and myalgias (6%), which have led to the discontinuation of quinupristin-dalfopristin in one third to one half of affected patients. Other common systemic adverse events have been nausea (4.6%), diarrhea (2.7%), vomiting (2.7%), rash (2.5%), headache (1.6%), pruritus (1.5%) and pain (1.5%).[12]
Liver function abnormalities have occurred in approximately 1% of patients who received quinupristin-dalfopristin. However, these effects have generally been mild and transient. No significant effects on renal function have been reported. And bone marrow toxicity has been rare.[12]
Dosage
The recommended dosage of quinupristin-dalfopristin for the treatment of vancomycin-resistant E. faecium infections in adults is 7.5 mg per kg administered intravenously every eight hours. The recommended dosage for complicated skin and skin structure infections is 7.5 mg per kg given intravenously every 12 hours. For vancomycin-resistant E. faecium infections, the duration of treatment should be based on the site and severity of the infection. The recommended minimum duration of treatment for complicated skin and skin structure infections is seven days.[13] The dosage of quinupristin-dalfopristin does not have to be adjusted in patients with renal impairment. Limited clinical data are available on the use of quinupristin-dalfopristin in patients with hepatic disease, but a dosage reduction may be required in patients with cirrhosis. Pediatric dosing is currently not available.
Linezolid (0 Zyvox)
Linezolid is the first of a new class of antimicrobial agents, the oxazolidinones. It was approved by the U.S. Food and Drug Administration (FDA) in 2000 for the treatment of skin and soft tissue infections, lower respiratory tract infections due to susceptible organisms, and vancomycin-resistant Enterococcus faecium infections including cases with concurrent bacteremia.
Chemistry
The oxazolidinones are unique because they are totally synthetic. Therefore, there are no preexisting specific resistance genes among gram-positive bacteria against this group of drugs. Their mechanism of action is also unique, which decreases the possibility of cross-resistance with currently available agents.
They were originally developed as monoamine oxidase inhibitors for treatment of depression, but subsequently discovered to have antimicrobial activity. The first oxazolidinone antimicrobial agents were developed in the late 1970s for the control of bacterial and fungal foliage diseases of various plants.[16] A series of chemical modifications of the oxazolidinone nucleus led to the discovery of two agents, eperezolid and linezolid. Although both agents showed excellent in vitro activity against gram-positive bacteria, linezolid was chosen for further clinical development.[17]
Mechanism of Action and Resistance
The oxazolidinones are considered bacteriostatic. They have a unique mechanism of action that interferes with the first step of bacterial ribosomes assembly. They bind to a site on the 50S ribosomal subunit near its interface with the 30S unit, thus preventing the formation of a 70S initiation complex.[18],[19],[20] No other known antimicrobial agent inhibits this process; therefore, there is no cross-resistance.
Being a synthetic compound, naturally occurring resistance is unlikely and in vitro induced resistance to linezolid is difficult. However, mutants of linezolid-resistant Staphylococcus aureus and Enterococcus faecalis have been produced by using serial passage on spiral gradient plates. It appears to be more difficult to generate mutants of Enterococcus faecium resistant to linezolid than for quinupristin-dalfopristin.[20]
However, cases of in vivoresistance have been reported. Tsiodras et al reported linezolid resistance in a clinical isolate of Staphylococcus aureus.[21] Linezolid resistance in clinical isolates of Enterococcus faecium[22], [23] has also been reported. Resistance is most likely to occur in seriously ill patients with indwelling prosthetic devices who are receiving prolonged courses of the antibiotic.[21],[22],[23]
Spectrum of Activity
The oxazolidinones have excellent in vitro activity against the major gram-positive bacteria and some gram-negative bacteria that are pathogenic in humans. More than 90% of the following gram-positive bacteria are inhibited by < 4 μg/ml of linezolid: Staphylococcus aureus, Listeria monocytogenes, Corynebacterium species, and Bacillus species . About 90% of the following gram-positive bacteria are inhibited by < 2 μg/ml of linezolid: Staphylococcus epidermidis, Streptococcus pneumoniae,beta hemolytic streptococci and viridans group streptococci. For enterococci, < 2 μg/mL indicates susceptibility, 4 μg/mL indicates intermediate susceptibility, and 8 μg/mL or greater indicates resistance.[17], [24]
Linezolid has good activity against many gram-positive anaerobes; however, its activity against Bacteroides fragilis is borderline (MIC of 4 μg/mL).[25]
Although linezolid has demonstrated in vitro activity against Neisseria More Details gonorrhoeae and Neisseria meningitides , it only has borderline activity (MIC= 4-16 μg/mL) against Haemophilus influenzae . It is inactive against enterobacteriace and Pseudomonas species.[25], [26] There are not enough data on linezolid effectiveness in vivo against atypical organisms including Legionella pneumophila , Mycoplasma pneumoniae , and Chlamydia pneumoniae.[25] Linezolid also has excellent in vitro activity against Nocardia .[27]
Pharmacokinetics
Linezolid is 100% bioavailable, both when given orally or intravenously. Maximum plasma concentrations are achieved 1 to 2 hours after an oral dose. Taking the drug with food may slightly delay its uptake, but the total amount of drug absorbed is unchanged. Linezolid has low serum plasma protein binding (31%) and is freely distributed to well-perfused tissues.[24]
The drug does not induce or inhibit cytochrome P450 enzymes in humans.[24]
About 35% of the parent compound is recovered in the urine, and none in feces. Therefore, the pharmacokinetic characteristics of linezolid are not markedly altered in patients with renal insufficiency, and no dosage requirement is officially recommended for patients with renal or hepatic insufficiency. Both linezolid and its two metabolites are eliminated by dialysis.[24] There is no information on the effect of peritoneal dialysis on the pharmacokinetic characteristics of linezolid, but current data suggest that in patients receiving hemodialysis, supplemental or post-dialysis doses should be administered.[28]
Clinical Studies and Use
The U.S. FDA has approved linezolid for the treatment of vancomycin-resistant Enterococcus faecium infections; pneumonia caused byStreptococcus pneumoniae (penicillin-susceptible strains only) or Staphylococcus aureus (methicillin-susceptible and methicillin-resistant strains),complicated skin and soft tissue infections caused by S. aureus (methicillin-resistant and methicillin-susceptible strains), Streptococcus pyogenes, or Streptococcus agalactiae; and uncomplicated skin and soft tissue infections caused by S. aureus (methicillin-susceptible strains only) or Streptococcus pyogenes.[24] These indications are based on the results of phase III trials presented to the FDA. In all of the studies completed so far, linezolid has been shown to be equivalent to its comparator.[29],30],[31] Linezolid is indicated for community-acquired pneumonia on the basis of comparative trials with cefpodoxime and ceftriaxone both of which possess no activity against atypical pathogens like Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella species.[32] For this reason and because linezolid also lacks good activity against Haemophilus influenzae, it should not be considered a first-line choice for community-acquired pneumonia at the present time.
No comparative trials of linezolid in patients with endocarditis, osteomyelitis, or meningitis have been performed. Although linezolid was shown to be initially efficacious in the eradication of the nasal carriage of Staphylococcus aureus, the eradication was transient and most patients were recolonized after 30 days.[33]
Drug Interaction
Adrenergic agents, phenylpropanolamine and pseudoephedrine should be reduced in patients receiving linezolid because of enhanced pressor response.[24] There is no evidence of interaction of linezolid with oral or inhaled albuterol (Data on file. Pharmacia Corp.).
Adverse Effects
Although dose-dependent and time-dependent myelosuppression was noted in dogs and rats receiving prolonged, high-dose therapy with linezolid in preclinical trials, only a few cases of reversible thrombocytopenia were noted in the phase III human trials. Therefore, it is recommended that complete blood counts be monitored weekly in patients who receive linezolid, especially those receiving the drug for more than 2 weeks, those with preexisting myelosuppression, those receiving concomitant drugs that produce bone marrow suppression, and those with chronic infection who have received previous or concomitant antibiotic therapy.[24]
Dosage
In adults, a standard dosage of 600 mg every 12 hours is recommended for treatment of most serious infections except uncomplicated skin and skin structure infections, for which an oral dosage of 400 mg every 12 hours is recommended.[24] Pediatric dosing regimens are detailed in table2.
Daptomycin (Cubicin)
Daptomycin is the first agent of a new class of antibiotics called cyclic lipopetides drug. Daptomycin was approved by the U.S. FDA in 2003 for use in adults in the treatment of skin and soft tissue infections and lower respiratory tract infections due to susceptible organisms.
Mechanism of Action and Resistance
Daptomycin has a unique but not fully understood mechanism of action. It binds to bacterial membranes and causes rapid depolarization of membrane potential. This results in inhibition of protein, DNA, and RNA synthesis resulting in bacterial cell death. Daptomycin exhibits concentration-dependent and rapid bactericidal
activity. [34],[35],[36],[37],[38],[39],[40]
So far, no significant resistance has been reported against daptomycin. In one study, S. aureus(n=4), S. epidermidis(n=4), E. faecalis(n=4), E. faecium (n=2), and S. pneumoniae(n=2) strains were tested with daptomycin at concentration 8 x MIC for spontaneous resistance. None was detected.[41] However, in phase 2 & 3 clinical studies, two cases of emerging resistance have been reported. The first was a resistant S. aureus that emerged during a phase 2 endocarditis treatment study. It was noted later that the patient was given a treatment dose lower than the protocol-defined dose. The second case involved a resistant E. faecalis in a patient with a chronic infected decubitus ulcer enrolled in a salvage trial.[41]
Spectrum of Activity
Daptomycin has shown excellent in vitro activity against S. aureus(methicillin susceptible and methicillin resistant), Streptococcus pyogenes, Streptococcus agalactiae . All of these organisms were considered susceptible to daptomycin at MIC < 1mcg/mL.However, vancomycin-susceptible Enterococcus faecalis is considered susceptible at MIC < 4 mcg/mL. ([40], [42],[43],[44],[45],[46],[47],[48]) A study in vancomycin resistant enterococcus was stopped due to slow enrollment. Therefore, it is not recommended at this time for the treatment of VRE.[49]
Daptomycin was also active against all tested strains of Clostridium difficile, Clostridium perfringens, and Corynebacterium jeikeium . It had variable susceptibilities against organisms, Actinomyces group, Eubacterium group, Lactobacillus spp, Propionibacterium spp, Corynebacterium spp, had variable susceptibilities.[50]
Susceptibility studies for daptomycin against vancomycin-intermediate S. aureus (VISA) and, more recently, vancomycin-resistant S. aureus revealed variable results with MIC range of 0.5-16.[40], [45], [51],[52],[53],[54]
Sun HK et al reported linezolid and quinupristin-dalfopristin (Q-D) resistant organisms (including S. aureus, E. faecalis and E. faecium)that were susceptible to daptomycin.[55]
Pharmacokinetics
Daptomycin exhibited linear pharmacokinetics at the 4 mg/kg and 6 mg/kg dosages. The 8mg/kg dose, however, exhibited slightly less linearity, as Cmax was 2.2 times higher than that of the 4 mg/kg dose.[56] Daptomycin was also shown to penetrate well into cantharidin-induced inflammatory blisters.[57]
Clinical Studies and Use
Clinical efficacy data are available from two randomized, investigator-blinded clinical studies comparing daptomycin 4 mg/kg once daily to vancomycin 1gm q 12 hours or semisynthetic penicillin 4-12 g/day (oxacillin, nafcillin, cloxacillin, flucloxacillin) in patients with SSTI. Study outcomes were based on the post-therapy (test-of-cure visit) conducted 7-12 days post-treatment.
Daptomycin was not inferior to the comparator agents. Actually, the daptomycin group showed greater improvement in clinical signs and symptoms by the third or fourth day than the comparator group, and the median duration of therapy was 1 day shorter, with daptomycin vs comparator in one of the studies.
There is an ongoing clinical study of treatment of right-sided endocarditis/bacteremia due to S. aureus,using a once daily dose of 6 mg/kg for 14-28 days. The comparator agents are nafcillin or vancomycin + gentamicin.
Since daptomycin has shown encouraging results in the treatment of experimental osteomyelitis, the manufacturer plans to propose an osteomyelitis study to the FDA using daptomycin 6 mg/kg.[49]
Drug Interactions
Synergy studies with several antibiotics (penicillins, cephalosporins, carbapenems, quinolones, and aminoglycosides) against susceptible organisms revealed variable effects that ranged between additive, indifferent or none antagonistic.[58]
Daptomycin does not affect the activity of the CYP450 enzymes; therefore, drug interactions via this system are not expected.[41]
Adverse Reactions
The most commonly reported side effect of daptomycin is elevation of CPK which was reported in 2-2.9% (phase I studies), 5.4-5.6% (phase II studies) and 2.8% (phase III study) of patients. In addition, during the phase III study, symptoms consistent with myopathy (pain in limb, arthralgia, back pain, myalgia, muscle cramps) were reported in 7 (1.3%) of 534 patients treated with daptomycin. Therefore, it is recommended that patients be monitored for muscle pain or weakness and weekly CPK levels while on therapy. Patients developing unexplained CPK elevations should be monitored more frequently; however, those with substantially elevated CPKs (> 10 x normal values) should discontinue daptomycin. Daptomycin should also be discontinued in those who have unexplained symptoms of myopathy and elevated CPK.[41]
Another rare but serious side effect is neuropathy. Bell's palsy was reported in two patients during phase I study and in two more cases during phase II studies. In addition, during phase II studies, there was one case of neuropathy and one case of decreased nerve conduction velocity. Interestingly, none of these side effects was appreciated during phase III studies.[41]
In general, during phase III studies, adverse events were reported in 51.3% and 52.5% of patients receiving daptomycin and comparator respectively. Serious adverse events (SAE) occurred in 10.9% of those receiving daptomycin and in 8.8% receiving comparator. The SAEs were due to cellulitis, urosepsis, hypersensitivity reaction, and diarrhea. The most commonly reported adverse events were gastrointestinal, injection site reactions, and headache.[41]
Dosage
The dose of daptomycin is 4mg/kg IV once daily for 7-14 days. Patients with creatinine clearance < 30mL/min, including those receiving hemodialysis or continuous ambulatory peritoneal dialysis, should receive 4mg/kg IV every 48 hours. Pediatric dosing is currently not available.[41]
Telithromycin (Ketek)
Telithromycin belongs to a new class of 14-membered ring macrolides called ketolides. It was approved by the U.S. FDA in April of 2004 for use in the treatment of acute exacerbation of chronic bronchitis (AECB); acute bacterial sinusitis (ABS); and mild to moderate community-acquired pneumonia (CAP).[58]
Chemistry
Ketolides are semisynthetic compounds characterized by replacement of the L-cladinose fixed on the macrolactone (erythronolide A) ring with a 3-keto group. Telithromycin is also characterized by a C11-C12 carbamate side chain that increases the affinity of the drug for ribosomes including MLSB - resistant ribosomes. This side chain also reduces resistance through the efflux pump.[58]
Mechanism of Action and Resistance
Macrolides bind to domain V of the 23S rRNA within the 50S ribosomal subunit. Telithromycin blocks protein synthesis by binding to domains II and V of 23S rRNA of the 50S ribosomal subunit, causing inhibition of bacterial replication.[59] MLSB resistance caused by erm gene affects the antimicrobial binding site of domain V on the 23S rRNA. However, the binding affinity of telithromycin to domain II is 10 folds stronger than that of erythromycin. This explains the enhanced activity of telithromycin against MLSB resistant gram-positive cocci.[60] Telithromycin does not appear to induce MLSB resistance.[60]
Spectrum of Activity
Telithromycin is highly effective against many common respiratory pathogens as well as atypical and intracellular bacteria. In addition, telithromycin is active against Moraxella More Details catarrhalis , Haemophilus influenzae , Streptococcus pyogenes .[61],[62] Telithromycin has more in vitro activity against gram-positive aerobes than macrolides and azalides.[63] Telithromycin is active against atypical organisms involved in respiratory tract infections such as Mycoplasma pneumoniae , Chlamydia pneumoniae , Legionellaspp. and Bordetella pertussis. [64],[65],[66],[67] Telithromycin is at least as active as azithromycin against gram- negative respiratory pathogens such as Haemophilus influenzae and Moraxella catarrhalis including beta-lactamase producing strains.[62] However, telithromycin is inactive against gram- negative enteric rods including the Enterobacteriaceae group. Telithromycin is also inactive against the non-fermentative gram-negative bacilli including Pseudomonas aeruginosa[63]
Telithromycin has potent activity and is bactericidal against Streptococcus pneumoniae including penicillin-resistant strains and macrolide-resistant strains irrespective of the underlying mechanism of resistance such as ermgene acquisition (target site modification), mef gene acquisition (efflux pumps) and ribosomal L4 mutations.[61], [63], [68]
Telithromycin is active against erythromycin-susceptible Staphylococcus aureus and isolates that can export or enzymatically degrade macrolides. Telithromycin is not active against S. aureus isolates that constitutvely express erm genes. It is also inactive against MRSA isolates.[61], [69] Although S. aureus isolates with inducible MLSB resistance are susceptible in vitro to telithromycin, erm resitance has been reported to switch from inducible to constitutive expression. This will limit the clinical efficacy of telithromycin in treating infections caused by S. aureus with MLSB inducible phenotype.[63]
Telithromycin is active against many gram-positive and gram-negative anaerobes including Peptostreptococcus spp., Clostridium spp., Bacteroides spp.[70]
Telithormycin has been shown to be active against intracellular and extracellular Helicobacter pylori with significant postantibiotic effect.[77] Telithromycin is more active than erythromycin against Rickettsia , Bartonellaand Coxiella burnettii , the causative agent of Q-fever. Telithromycin is ineffective against Ehrlichia chaffensis .[71]
Pharmacokinetics
Approximately 90% of the oral dose is absorbed and 33% undergoes first pass metabolism mainly by the liver. Oral absorption is not affected by food intake.[72] Peak plasma concentrations are achieved within 2.5 hours. Approximately 60-70% of telithromycin is protein bound. Telithromycin concentrates in white blood cells and respiratory tissues after absorption. At 8 hours after dosing, telithromycin concentrations in alveolar macrophages and epithelial fluid in the respiratory tract markedly exceed plasma concentrations.[73] Telithromycin tonsillar tissue concentration exceeds the MIC 50 of group A beta-hemolytic streptococci.[74] Elimination of telithromycin is accomplished through metabolization by the liver (37%) and excretion unchanged in feces (7%).[75] Approximately 13% of telithromycin is excreted unchanged in the urine. About 50% of telithromycin metabolism occurs through the P450 system mainly by CYP3A4 enzyme. In patients with hepatic impairment, increased renal clearance may compensate for hepatic clearance.[75], [76] Slight accumulation of telithromycin occurs (1.4 fold increase in Cmax and AUC) in patients with mild-severe renal impairment.[75] Pharmacokinetic data in children are currently not available.
Clinical studies and use
In adults telithromycin has been shown to be as effective as macrolides and fluoroquinolones in treatment of community acquired pneumonia (CAP) including cases caused by penicillin- and erythromycin-resistant S. pneumoniae.[77], [78] In preliminary studies, telithromycin has been shown to be effective in other respiratory tract infections such as chronic bronchitis, tonsillopharyngitis and acute maxillary sinusitis. Telithromycin at 800 mg/day given for 7 to 10 days was as effecticve as macrolides and fluoroquinolones in treating CAP caused by S. pneumoniae as well as atypical and intracellular organisms. Telithromycin was also effective in treating pneumococcal bacteremia accompanying CAP, including bacteremia caused by pneumococcal strains that were resistant to penicillin or erythromycin.[77],[78],[79] It has also been shown that a 5-day course of telithromycin at 800 mg/day was as effective as a 10-day course of penicillin or clarithromycin in the treatment of GABHS tonsillitis/pharyngitis in adult patients and adolescents older than 13 years of age.[80] Published data on the efficacy of telithromycin in treating pediatric infections are not available.
Drug interactions
Telithromycin inhibits the activity of CYP3A4 enzyme and therefore should not be given concomitantly with cisapride and midazolam.[77], [78] Increased QTc interval has also been reported with concomitant administration of cyclosporin, tacrolimus and sirolimus and dosage adjustment is needed. The levels of digoxin, theophylline are also increased with concomitant telithromycin therapy. Itraconazole and ketoconazole increase the AUC of telithromycin, however, no dosage adjustment is needed.[62], [78]
Adverse reactions
The most common adverse event associated with telithromycin use in adult studies of 800 mg/day was diarrhea occurring in 13.7% of patients. Telithromycin has also been associated with other adverse events such as nausea in 8.7%, headache in 6.7% and vomiting in 3.1% of patients.[77], [78]
Dosage
The adult dose is 800 mg given once daily for 7 to 10 days for most clinical indications. Pediatric dosing is currently not available.
Tigecycline (Tygacil)
Tigecycline is a new, semisynthetic glycylcycline that was approved by the US FDA for the treatment of skin, soft-tissue, and intra-abdominal infections.[81],[82]
Chemistry
Glycylcyclines gained a broader spectrum of activity due to substitution of an N -alkyl-glycylamido group at the 9 position on the D-ring of the central 4-ring carbocyclic skeleton that is essential for antibacterial activity.[83]
Mechanism of action and resistance
Tigecycline is bacteriostatic, and it acts by binding to the bacterial 30S ribosomal subunit that leads to inhibition of protein synthesis.[84], [85] Tigecycline does not seem to be affected by the two mechanisms of tetracycline resistance: active efflux of drug from inside the bacterial cell and protection of ribosomes.[86], [87] In addition, many bacterial mutants have been generated in the laboratory and have exhibited only marginal differences in susceptibility to tigecycline. Therefore, it does not seem that resistance would arise by trivial mutations in existing resistance genes.[85]
Spectrum of Activity
Tigecycline is highly effective in vitro against most gram positive organisms including: Staphylococcus aureus,coagulase-negative staphylococci, Enterococcus species, Streptococcus pneumoniae,group A streptococci, group B streptococci and viridans streptococci. MIC 90 for these organisms ranges between 0.02 ug/ml and 1.0 ug/ml.[81], [86],[87],[88],[89],[90],[91],[92],[93],[94],[95],[96],[97],[98],[99],[100],[101],[102],[103],[104] It also has good in vitro activity against most gram- negative organisms including: Escherichia More Details coli, Klebsiella pneumoniae, Klebsiella oxytoca, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia species, Shigella species, Salmonella More Details species, Citrobacter species, Enterobacter species, Serratia marcescens, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, Acinetobacter species, Burkholderia cepacia, Haemophilus influenzae, Moraxella species, Neisseria gonorrhoeae More Details and Eikenella corrodens.MIC 90 for these organisms ranged between 0.25 ug/ml and 4.0 ug/ml with the following exceptions: Proteus mirabilis, Providencia species, Acinetobacter species, and Acinetobacter baumannii( MIC 90 = 8 ug/ml), Pseudomonas aeruginosa(MIC 90 =16-32) and Burkholderia cepacia(MIC 90 = 4-32).[81], [82], [86], [88]-[91], [100], [101], [105]-[109] Tigecycline has also shown good in vitro activity against anaerobes such as: Bacteroides fragilis , Bacteroides fragilis group, Clostridium perfringens , Clostridium difficile , Propionibacterium acnes , Peptostreptococcus species , Fusobacterium species , Prevotella species and Porphyromonas species (MIC 90 range 0.03-2.0 ug/ml.[86], [90], [110]
Of interest, Tigecycline has shown some in vitro activity against some atypical organisms as follows: Mycobacterium abscessus (MIC 90 = 0.25), Mycobacterium chelonae(MIC 90 ￡ 0.13), Mycobacterium fortuitumgroup (MIC 90 ￡0.13), Mycobacterium marinum (MIC 90 3-16). In vitro activity against the following atypical organisms was reported: Chlamydia pneumoniae ( MIC 90 =0.13), Mycoplasma hominis (MIC 90 = 0.5), Mycoplasma pneumoniae(MIC 90 =0.25), Ureaplasma urealyticum(MIC 90 =8). [110],[111],[112],[113]
Phamacokinetics
Several studies of single- and multiple-dose tigecycline pharmacokinetics have shown that the half-life of tigecycline range is 37- 67 hours, and the systemic clearance of tigecycline range is 0.2 to 0.3 L/h/kg. Tigecycline binding to protein is ~78%. These studies also revealed that tigecycline had a large volume of distribution (7-10 L/kg), which suggest extensive distribution into the tissues. These studies have also shown that food increased the maximum tolerated single dose from 100 mg to 200 mg, while the duration of infusion did not affect tolerability.[114],[115],[116]
Excellent overall tissue penetration has been demonstrated in animal studies, including bone, bone marrow, salivary gland, thyroid, spleen, kidney and CSF. [117], [118]
Tigecycline elimination is done primarily by the liver. About 30% of the drug is excreted unchanged in the urine. No dosage adjustment is required in patients with renal dysfunction. There is no sufficient data about the pharmacokinetics and safety of tigecycline in patients with hepatic impairment. Therefore, clinicians should exercise caution when using tigecycline in patients with severe hepatic dysfunction.
Clinical studies and use
Tigecycline is currently approved for the treatment of patients with complicated skin and skin-structure infections and complicated intra-abdominal infections.[81], [82]
In one trial, the clinical and microbiological efficacy, pharmacokinetics, and tolerability of 2 different doses of tigecycline in the treatment of complicated skin and skin-structure infection in 14 centers in the United States were evaluated. Patients received tigecycline (25 or 50 mg) intravenously every 12 h for 7-14 days. One hundred sixty patients received at least 1 dose of tigecycline. At the test-of-cure visit, the clinical cure rate in the 25-mg group was 67% (95% CI, 53.3%-79.3%), compared with 74% (95% CI, 60.3%-85.0%) in the 50-mg group. The eradication rate was 56% in the 25-mg group (95% CI, 40.0% -70.4%), compared with 69% (95% CI, 54.2%-82.3%) in the 50-mg group. Nausea and vomiting were noted to be the most common adverse events.[81]
In another multicenter, phase 2, open-label study of hospitalized patients with complicated intra-abdominal infections requiring surgery all patients received 100 mg of tigecycline administered intravenously as a loading dose, followed by 50 mg every 12 h for 5-14 days. Sixty-six patients with perforated and gangrenous appendicitis, complicated cholecystitis, or perforated diverticulitis and peritonitis met all of the inclusion criteria and were evaluated. Cure rates at the test-of-cure visit and the end-of-treatment visit were 67% (95% CI, 54.0% -77.8%) and 76% (95% CI, 63.6%-85.5%), respectively. In the intent-to-treat analyses, the cure rate at the test-of-cure visit was 55% (95% CI, 45.2%-64.4%) and the end-of-treatment cure rate was 72% (95% CI, 62.8%-80.2%). Nausea and vomiting were noted to be the most common adverse events.[82]
Drug interactions
Limited information with regards to interaction is available at this time. Tigecycline may decrease the elimination of warfarin thereby increasing its levels in blood.
Adverse reactions
The most common side effects of tigecycline are nausea and vomiting. Both are mild or moderate and usually occur during the first two days of therapy. Other side effects include pain at the injection site, swelling and irritation. Tigecycline is similar to tetracycline antibiotics and therefore may have similar side effects such as increased sensitivity to sunlight.
Dosing
Tigecycline is administered via intravenous infusions over 30 to 60 minutes. The initial dose is 100 mg followed by 50 mg every 12 hours. The usual duration of treatment is 5-14 days. Pediatric dosing is currently not available.
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