Linezolid Linezolid representS the first member of a novel class of oxazolidinone derivatives and encompasses an effective activity spectrum that covers all of the most important Gram-positive organisms, including MRSA and VRE.
Linezolid exhibits a bacteriostatic mode of action against most targeted pathogens by inhibiting bacterial protein synthesis. The drug is administered twice a day either intravenously or orally (100% bioavailability). From a pharmacokinetic perspective, around 30% of the linezolid is protein-bound, and this molecule favorably penetrates at elevated and fully active concentrations into a broad variety of tissues, such as fat, bone and joints, muscle, cerebrospinal fluid and wound sites, beyond the known elevated penetration into the lungs and the entire respiratory tract.[58,59]
Linezolid is primarily metabolized through oxidation, which does not involve or induce cytochrome P450. No dosage adjustment is necessary in patients with renal failure or those with mild or moderate liver failure.[60,61] Linezolid suppresses in vitroS. aureus toxin production, offering a theoretical advantage in toxin-mediated diseases. It could be of particular value in the treatment of infections caused by CA-MRSA producing PVL. This is based on the finding that protein synthesis inhibitors such as linezolid reduce the production of PVL, unlike cell-wall active agents.[63,64]
The 2003 Zyvox Annual Appraisal of Potency and Spectrum (ZAAPS) program compared the MIC90 levels of linezolid with 13–15 comparator agents in over 8000 bacterial isolates, and confirmed a maintained 99.93% linezolid susceptibility rate of tested Gram-positive organisms, as previously predicted. The recently published continuation of this study until 2004 confirmed this figure on 20,158 overall tested isolates, pointing out that 99.5% of isolated S. aureus organisms had a MIC90 value of linezolid ranging from 0.5 to 2 mg/l, with only one bacterial strain tested susceptible only at a MIC90 value of 4 mg/l.
Linezolid has been approved by the US FDA for cSSSIs (including diabetic foot infections and surgical wound infection). A prospective, randomized, multinational trial compared linezolid with vancomycin in 1200 hospitalized patients with cSSSIs suspected to be caused by MRSA. Intravenous vancomycin could be switched to one of the antistaphylococcal penicillins orally or intravenously if methicillin-susceptible S. aureus (MSSA) was recovered from the infection site. Linezolid could be started intravenously or orally or switched to the oral formulation at any time over the course of treatment. In the study, 52% of patients in the linezolid arm were initiated on oral rather than intravenous linezolid. The primary end point, clinical cure, was defined as resolution of the signs and symptoms of infection. Overall clinical cure rates in the clinically evaluable patient population were 94% for linezolid and 90% for vancomycin (p = 0.023). Among patients in the MRSA subgroup, the clinical cure rate for linezolid was 94% compared with 84% for vancomycin (p = 0.011).
In an open-label study of complicated staphylococcal cSSSIs, oral linezolid and intravenous vancomycin were compared at the same dosage regimens for 7–21 days, and a higher clinical response was obtained with linezolid (p < 0.02), associated with a lower rate of failure, including major surgical procedures (i.e., limb amputation; p < 0.02). This study was small, with a total of 60 patients enrolled and the trial was confined to a single research site, thus possibly limiting widespread applicability of the data.
Resistance to linezolid among strains of S. aureus, including hospital and CA-MRSA isolates, is extremely uncommon.[70,71] However, resistance emerging during treatment with linezolid has been reported in patients with MRSA infections.[72–74] Such resistance has typically been associated with single-nucleotide changes in varying numbers of copies of the genes encoding 23S ribosomal RNA. Sánchez García et al. have published a clinical outbreak of linezolid-resistant S. aureus in a Spanish intensive care unit associated with extensive usage of linezolid. Reduction of linezolid use and infection-control measures were associated with termination of the outbreak.
Linezolid is usually well tolerated, although selected adverse events are important to underscore. It should be mentioned that prolonged administration of linezolid carries an increased risk for the development of specific types of adverse events, such as myelosuppression (primarily thrombocytopenia) or peripheral neuropathy that may not be reversible.[77,78] Linezolid is also a weak monoamine oxidase inhibitor and can rarely produce serotonergic syndrome and lactic acidosis, particularly with long-term use, associated with other serotonergic agents, or both (e.g., serotonin reuptake inhibitors).
From a tolerability point of view, within the maximum allowed treatment duration of 28 days (as presently recommended), linezolid showed a favorable safety profile, as showed in a very extensive meta-analysis of 2046 adult patients enrolled in seven different comparative, controlled studies.[80,81] The 85% of reported adverse events was mild-to-moderate in intensity: the most common clinical events were diarrhea (4.0–5.3%), nausea (3.3–3.5%) and headache (1.9–2.7%), while the most common laboratory disturbances included anemia and thrombocytopenia, especially when linezolid treatment is prolonged, as in some experimental indications, such as bone and joint infections.[80–82]
Daptomycin Daptomycin is a cyclic lipopeptide with a spectrum of antimicrobial activity that includes, among various Gram-positive pathogens, staphylococci and enterococci, regardless of their resistance profile to methicillin or vancomycin, respectively.
Daptomycin exerts its effect through calcium-dependent binding to the bacterial membrane producing depolarization that disrupts DNA, RNA and protein synthesis resulting in cell death. Daptomycin is given intravenously at a dose of 4–6 mg/kg once daily and its primary route of excretion is via the kidneys with approximately 78% urinary recovery (~50% as active compound) and little fecal excretion (~5%),[85,202] therefore it needs to be adjusted in patients with renal failure (creatinine clearance <30 ml/min).
Daptomycin (4 mg/kg once daily) has been compared with vancomycin or antistaphylococcal penicillins for the treatment of cSSSI in two multicenter investigator-blinded randomized trials. A total of 64 microbiologically evaluable patients had MRSA, and cure rates were 75% for daptomycin and 69% for vancomycin (95% CI for the difference: -28.5–17.4).
Clinical success was comparable between the compared treatment arms, including the subgroup of patients with diabetic foot infections. It is noteworthy that significantly more patients allocated to the daptomycin arms required therapy of rather short duration (4–7 days). Relevant findings have also been produced in a study comparing prospective daptomycin-treated patients with a matched cohort of historical vancomycin-treated patients.
To date, daptomycin-resistant bacteria (MIC >1 mg/ml) among S. aureus isolates have rarely been isolated from patients, although increases in vancomycin MIC may be linked to reduced susceptibility to daptomycin. However, all strains of vancomycin-resistant S. aureus (VRSA) in this report were susceptible to daptomycin, suggesting that mechanisms other than vanA may be mediating this potential association. To date, most of the resistant isolates have been derived from severely ill patients with serious underlying conditions (often immunocompromised) and in many cases pretreated with other antibiotics or receiving an inappropriate dose. Recent in vitro studies using large bacterial inocula on solid and liquid media containing various daptomycin concentrations have demonstrated that the plasma daptomycin concentration is above the mutant prevention concentration throughout treatment using approved doses, a finding consistent with the comparative rarity of the selection of daptomycin-resistant mutants in the clinic. In the clinical setting, resistance has been associated with prolonged use,[92,93] multiple comorbidities, osteomyelitis,[95,96] acute myeloid leukemia and leukocyte adhesion deficiency syndrome.
Close monitoring of resistance is essential to maintain the clinical utility of the drug. Using once-daily dosing, daptomycin has been generally well tolerated; however, weekly monitoring of creatine phosphokinase is recommended, as myopathy in skeletal muscles has been observed, albeit rarely. In animals, daptomycin-induced muscle damage correlates better with the frequency of antibiotic administration than with peak drug concentration. In cSSSI trials, employing a dose of 4 mg/kg once a day, creatine phosphokinase elevation was reported as an adverse event in 15 out of 534 patients (~3%).
Tigecycline Tigecycline is a glycylcycline antibiotic derived from minocycline that is active in vitro against a variety of Gram-positive and Gram-negative organisms, including nosocomial resistant pathogens such as MRSA, VRE, ESBL-producing Enterobacteriaceae and MDR Acinetobacter spp.[100,101] Tigecycline has limited activity against P. aeruginosa, and reduced activity against indole-positive Proteae and P. mirabilis has been noted.[102,103] Tigecycline inhibits protein synthesis through binding of 30S ribosomal subunits and blocking the entrance of tRNA molecules into site A of the ribosome and appears to overcome the common mechanisms of tetracycline resistance (ribosomal protection and active drug efflux) because of steric hindrance due to a large substituent at position 9.
For human therapy, tigecycline is administered twice daily over a 30–60-min infusion and it has a large and variable volume of distribution (7–10 l/kg) and good penetration into tissues, including the lung (AUC 32% higher than in serum). Tigecycline is excreted unchanged in the feces and urine and is metabolized primarily by liver glucuronidation. In another pharmacokinetic study of tigecycline performed with healthy adults and in individuals with renal impairment, slight trends for different tigecycline pharmacokinetics were noted, possibly due to age, gender or race. The pharmacokinetics of tigecycline were not changed by severe renal disease or hemodialysis.
Tigecycline has been approved by the FDA for the treatment of cSSSI including MRSA. Infections caused by VRE are not included among its indications as they have not been adequately represented in relevant pivotal clinical trials. Regarding cSSSI, tigecycline has been compared with vancomycin plus aztreonam in two multicenter double-blind randomized trials that included a total of 1129 patients. The clinical and microbiological outcomes of patients treated with tigecycline were comparable with those of patients treated with the comparator regimen. The microbiological eradication rates of MRSA isolated from a total of 65 microbiologically evaluable patients also did not appear to differ between the compared treatments. Pooling of two randomized, double-blind studies with a resistant pathogen identified 71 microbiologically evaluable MRSA-infected patients. Cure rates were 78% for tigecycline and 77% for vancomycin.
In addition, in a double-blind, randomized study in patients with cSSSI due to resistant pathogens, another 82 patients due to MRSA were identified. Cure rates were again comparable between the two treatment groups (tigecycline 86% and vancomycin 87%).
Tigecycline has very good antimicrobial activity against ESBL-producing E. coli and K. pneumoniae and constitutes one of the few potential therapeutic options against carbapenem-resistant A. baumannii.
An open-label trial evaluated the efficacy and safety of tigecycline in patients with selected serious infections caused by resistant Gram-negative bacteria, or failures that had received prior antimicrobial therapy or were unable to tolerate other appropriate antimicrobials (mostly A. baumannii, Enterobacter spp., E. coli and K. pneumoniae). Most of the 112 tigecycline-treated patients had cSSSI; the remainder were complicated intra-abdominal infections, pneumonia and bacteremia.
The clinical cure rate was 72.2% in the 36 patients that comprised the microbiologically evaluable population, whereas it was 53.3% in the 75 patients that comprised the microbiological modified intention-to-treat population. Similar findings have been noted for additional cases of infection by MDR Gram-negative pathogens reported in the literature; in these cases, tigecycline has mainly been used as part of combination regimens.[110,111,113]
The rate of total drug-related adverse events was greater in the tigecycline-treated patients, whereas the rate of serious adverse events or study withdrawals because of adverse events was similar in both treatment arms. Principal adverse events associated with tigecycline are gastrointestinal (nausea and vomiting). In the cSSSI studies, nausea and vomiting were reported in 35 and 20% of patients receiving tigecycline, respectively. However, less than 2% of patients discontinued the drug because of nausea, vomiting, or both.
Minocycline is an old tetracycline that has the potential to become an important part of the armamentarium against emerging infections such as MRSA and A. baumanni. As intravenous minocycline once again becomes available in the US market, we feel that studies using initial intravenous minocycline followed by the oral formulation could potentially offer physicians another choice of antibiotic, especially where oral agents are lacking.
On the basis of pharmacokinetic considerations, minocycline achieves very high blood levels that are above the MIC90 values for MRSA (0.5 µg/ml) and A. baumannii (8 µg/ml). There are no specific trials using minocycline in cSSSI, however it penetrates into most tissues (skin and soft tissue included) and, in most instances, its tissue levels exceed simultaneous serum levels. Pharmacokinetic properties of minocycline and available in vitro data of minocycline against MRSA and A. baumannii suggest that this agent should be studied in the clinical setting.
Telavancin Telavancin is a glycopeptide derivative of vancomycin that is bactericidal against staphylococci, including MRSA, vancomycin-intermediate S. aureus (VISA) and VRSA, with MIC90 ranges of 0.25–1, 0.5–2 and 2–4 mg/l, respectively.[115–118] Telavancin is also active against vancomycin-susceptible Enterococcus faecium and Enterococcus faecalis. However, MICs are increased against vancomycin-resistant E. faecium and E. faecalis.[115–119]
Telavancin has been approved by the FDA for the treatment of cSSSIs caused by susceptible isolates of the following Gram-positive microorganisms: S. aureus (including methicillin-susceptible and -resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group (includes S. anginosus, Streptococcus intermedius and Streptococcus constellatus) or E. faecalis (vancomycin-susceptible isolates only). Infections caused by VRE are not included among its indications as they have not been adequately represented in relevant pivotal clinical trials.
Telavancin inhibits cell wall synthesis by binding to peptidoglycan chain precursors and also produces bacterial membrane depolarization. It has a half-life of 7–9 h, is predominately eliminated by the kidneys, and will probably require dose adjustments in patients with renal impairment.[115,119]
A set of two Phase III trials of telavancin for cSSSI was conducted. The two identical trials, Assessment of Telavancin in Complicated Skin and Skin Structure Infections (ATLAS) I and II, compared telavancin 10 mg/kg/day to vancomycin 1 g every 12 h and found telavancin to be noninferior to vancomycin with a combined clinical cure rate in patients with MRSA infection of 90.6 and 86.4% for telavancin and vancomycin, respectively (p = 0.06). Telavancin has been well tolerated in clinical trials, with the most common adverse effects being taste disturbances, headache and dizziness. Other potentially serious adverse effects include elevations in serum creatinine, microalbuminuria and decreased platelet counts, each of which occurred at rates similar to comparator agents.[115,119,120]
Antibacterial Agents Under Clinical Development
Dalbavancin Dalbavancin is an investigational lipoglycopeptide that possesses a lipophilic side chain that leads to both high protein binding and an extended half-life, which allows for a unique once-weekly dosing of the drug.[121,122]
Dalbavancin is more potent than vancomycin against staphylococci, and is highly active against both MSSA and MRSA with MIC90 values of less than 0.13 and 0.25 mg/l, respectively.
Dalbavancin is also active against VISA, and enterococci with the VanB or VanC phenotype. However, dalbavancin is not active against enterococci with the VanA phenotype.[123–125]
Dalbavancin is administered intravenously, and the most commonly used dose in clinical trials has been 1000 mg on day 1 and 500 mg weekly thereafter.
Dalbavancin 1000 mg intravenously on day 1 followed by 500 mg intravenously on day 8 was compared with linezolid 600 mg twice daily for 14 days in a randomized, double-blind, Phase III trial for treatment of cSSSI. The overall success rates at the test of cure visit were similar for both dalbavancin and linezolid at 88.4 and 86.8%, respectively (p-value not given).
Dalbavancin has been well tolerated throughout clinical trials, with the most commonly seen adverse effects being fever, headache and nausea. No significant nervous, auditory, vestibular or cardiac adverse effects have been noted in either dose-escalation or clinical trials.[129,130]
Following feedback from regulatory authorities in the USA and Europe, Pfizer Inc. plans to conduct an additional Phase III clinical trial with dalbavancin for the treatment of adults with cSSSI caused by Gram-positive bacteria, including MRSA. The global multicenter study will generate additional clinical data to support planned future regulatory submissions. A pediatric program with dalbavancin is also planned.
Oritavancin Oritavancin, another investigational glycopeptide, contains novel structural modifications that allow it to dimerize and anchor itself in the bacterial membrane. These modifications also confer an enhanced spectrum of activity over traditional glycopeptide antibiotics.[131,132] Oritavancin has similar in vitro activity to vancomycin against staphylococci and is equipotent against both MSSA and MRSA.[123–124] Oritavancin also has activity against VISA and VRSA, but MICs are increased to 1 and 0.5 mg/l, respectively.[124,133] Oritavancin is active against enterococci, including VRE; however, MICs are significantly higher against VRE versus vancomycin-sensitive strains.[123,124]
Oritavancin was compared with vancomycin in two randomized, double-blind trials of patients with cSSSIs. In the first study, oritavancin was dosed at 200 mg once daily, and in the second study, two different doses were administered (1.5 and 3 mg/kg). In the first study, cure rates among 171 patients with MRSA were 56% for oritavancin and 68% for vancomycin. In the second study, cure rates for patients with MRSA were 57% for vancomycin and 40 and 63% for oritavancin at 1.5 and 3 mg/kg, respectively.
Oritavancin has been well tolerated in clinical trials, with the most predominant adverse effects being headache, nausea, vomiting, sleep disorders and injection site reactions. Elevated transaminases seen in early trials of oritavancin were not seen in either of the Phase III clinical trials in patients with cSSSIs.[134,135]
The FDA indicated that they cannot approve oritavancin for the treatment of cSSSI in its current form and will require an additional well-controlled clinical study to demonstrate efficacy and safety in order to gain approval. The FDA requested that a sufficient number of patients with methicillin-resistant MRSA as the cause of cSSSI be enrolled in the study to demonstrate the effectiveness of oritavancin in this subset of patients. The FDA further suggested that the clinical study evaluate the effect of oritavancin on macrophage function and monitor for the potential for subsequent infections that could possibly be related to macrophage dysfunction due to the long terminal half-life of oritavancin.
Ceftaroline Ceftaroline is a new cephalosporin with expanded activity against Gram-positive cocci, including MRSA, VISA and VRSA. Ceftaroline has broad-spectrum activity similar to that of ceftriaxone against relevant Gram-negative pathogens. However, MICs are generally higher than those of cefepime against most nonfermenting Gram-negative bacteria and Enterobacteriaceae, and the drug is expected to be inactive against Pseudomonas and Acinetobacter spp..[137–139] Ceftaroline appears to be a weak inducer of AmpC β-lactamases and, like other clinically available cephalosporins (besides cefepime), is labile to AmpC and expected to be clinically ineffective against such isolates.[136–138] As with other advanced-generation cephalosporins, ceftaroline is not reliably active against ESBL-producing strains of Enterobacteriaceae.[137–139]
Ceftaroline has a time-dependent bactericidal effect. Ceftaroline is given intravenously at a dose of 600 mg twice a day. The drug is primarily eliminated through the urine and needs to be adjusted in patients with renal impairment. Ceftaroline was compared with vancomycin in patients with cSSSI; six subjects in each treatment group had MRSA identified as a baseline pathogen, and five of these subjects from each group were included in the microbiological evaluable population. Five out of five standard therapy subjects and four out of five ceftaroline subjects with MRSA infection achieved clinical cure.
Adverse effects in all ceftaroline studies to date have been minor, and include headache, nausea, insomnia and abnormal body odor.[140–142] It appears safe to assume that ceftaroline is likely to have an adverse effect profile consistent with currently available cephalosporins, until proven otherwise.
Ceftaroline appears to be a promising new alternative in the treatment of Gram-positive infections in general, and serious MRSA infections specifically.
Ceftobiprole Ceftobiprole is a new intravenous broad-spectrum cephalosporin with expanded spectrum to include MRSA, VISA and VRSA. Ceftobiprole has broader Gram-negative activity than ceftaroline, and appears to have a Gram-negative spectrum of activity intermediate between ceftriaxone and cefepime, largely due to its increased stability to AmpC β-lactamases as compared with ceftriaxone and ceftaroline.[144–147] Ceftobiprole also has activity against P. aeruginosa, and MICs against this pathogen are generally similar to those of cefepime and ceftazidime.[144–148] Activity against Acinetobacter spp. appears to be highly variable.[144–148] As with other advanced-generation cephalosporins, ceftobiprole is not reliably active against ESBL-producing bacteria.[146,147]
Similar to other cephalosporins, ceftobiprole exerts a bactericidal effect in a time-dependent manner. Due to its extensive renal clearance, dose adjustments have been proposed for patients with mild-to-moderate renal impairment.[149,150]
Two large, randomized, double-blind studies have shown that ceftobiprole is noninferior to vancomycin in patients with cSSSI. In the first study (ceftobiprole 500 mg every 12 h), cure rates among 123 patients with MRSA were 90% for ceftobiprole and 86% for vancomycin (95% CI for the difference: -8–19.7). In the second study (ceftobiprole 500 mg every 8 h),[151,152] cure rates among 121 evaluable patients with MRSA were 92 and 90% for ceftobiprole and vancomycin, respectively (95% CI for the difference: -8.4–12.1).
The adverse effect profile identified thus far in Phase III clinical trials were nausea, diarrhea and taste disturbances at rates of less than 15%.[37,38] It appears safe to assume that ceftobiprole is likely to have an adverse effect profile consistent with currently available cephalosporins, until proven otherwise.
Ceftobiprole is the only agent currently in Phase III clinical trials that is active against both Pseudomonas spp. and MRSA, and therefore has potential for use as empiric monotherapy for serious infections in the intensive care unit (ICU).
Iclaprim Iclaprim is an investigational intravenous diaminopyrimidine antibacterial agent that, like trimethoprim, selectively inhibits dihydrofolate reductase of both Gram-positive and Gram-negative bacteria and exerts bactericidal effects.[153,154] Iclaprim is active against MSSA, community and nosocomial MRSA, VISA and VRSA, and is variably active against enterococci.[155,156] Iclaprim appears to have similar Gram-negative activity to that of trimethoprim, including activity against E. coli, K. pneumoniae, Enterobacter spp., Citrobacter freundii and Proteus vulgaris[156,157] but is not active against P. aeruginosa or anaerobes.[155,158]
Although iclaprim is metabolized in the liver through the cytochrome P450 system, it does not appear to have significant hepatic drug interactions. Iclaprim has been compared with linezolid in two double-blind studies of patients with cSSSI. According to the FDA analysis, iclaprim failed to prove noninferiority to the comparator (Arpidas Skin and Skin Structure Infection Study 1 [ASSIST-1]). Overall, bacterial eradication in patients with MRSA was 76% for iclaprim and 79% for linezolid.
Optimization of the Classic Antibiotics
Optimization of antimicrobial dosing based on individual patient characteristics, causative organism, site of infection, and pharmacokinetic and pharmacodynamic characteristics of the drug is an important part of antimicrobial stewardship. Most of the guidelines also emphasize the critical role of the microbiology laboratory in antimicrobial stewardship by facilitating this patient-specific resistance-surveillance dynamic. A systematic plan for parenteral-to-oral conversion of antimicrobials with excellent bioavailability, when the patient's condition allows, can also decrease the in-hospital length of stay and healthcare costs. Clinical criteria and guidelines can be developed to facilitate a switch to the use of oral agents, which can further streamline its implementation at the institutional level.
Carbapenems are characterized pharmacodynamically as time-dependent killers. In other words, bacterial killing is optimized with the extension of the time that the antibiotic concentration exceeds the MIC of the infecting pathogen. The time above MIC requirements for optimal efficacy of carbapenems varies by pathogen and happens to be the least amount of time required compared with other β-lactam antimicrobials (40%). Certain adverse events are dose-dependent or concentration-dependent, including seizures, nausea and vomiting. Consequently, extending the duration of the carbapenem infusion can maximize time above the MIC and can be a particularly useful tool when dealing with pathogens such as P. aeruginosa, which have higher MIC values but remain within the susceptible or potentially intermediate resistant breakpoint range. In some cases, in which high MIC values are noted for the infecting organism, both increasing the dose and prolonging the infusion interval can result in an optimized time above MIC and improve the probability of a clinical response. Selecting a drug within the class that possesses the lowest MIC value for a particular pathogen also helps in resolving the pharmacodynamic equation, in simple terms, because lower MIC values require less drug to maintain an adequate time above the MIC. This is commonly done in clinical practice, but for concentration-dependent killing agents such as the aminoglycosides. In this context, Jaruratanasirikul et al. demonstrated that 3-h intravenous infusion of meropenem resulted in greater time above MICs than those seen after bolus injection, indicating that intermittent infusion may be an appropriate mode of administration of meropenem under certain clinical conditions. The most effective dosing regimen for the treatment of infections caused by isolated pathogens with intermediate resistance was a 3-h infusion of 2 g of meropenem every 8 h, which provided serum concentrations above the MIC of 16 µg/ml for almost 60% of the 8-h interval. This regimen seems to be justified in infections due to MDR pathogens in which the therapeutic options are limited.
A study of patients with ventilator-associated pneumonia (VAP) by Lorente et al. compared intermittent with continuous infusion of meropenem in two contemporary cohorts. No significant differences were found between the cohorts in baseline characteristics. Patients treated by intermittent infusion received meropenem 1 g every 6 h over 30 min; those treated by continuous infusion received a loading dose of 1 g over 30 min, then 1 g every 6 h (i.e., over 360 min). All patients received tobramycin in combination with meropenem for 14 days. The continuous-infusion cohort showed a significantly greater clinical cure rate than the intermittent-infusion cohort in all VAP patients (90.47 vs 59.57% overall; OR: 6.44; 95% CI: 1.97–21.05; p < 0.001); continuous infusion also provided higher cure rates specifically when VAP was due to P. aeruginosa (84.61 vs 40%; OR: 8.25; 95% CI: 1.33–51.26; p = 0.02) and when the MIC of the microorganism responsible for VAP was 0.5 µg/ml or greater (80.95 vs 29.41%; OR: 7.84; 95% CI: 2.26–46.09; p = 0.003).
Other studies provide additional support for this pharmacokinetic/pharmacodynamic principle as a rationale for designing antibiotic regimens. An open-label study compared continuous versus intermittent administration of piperacillin/tazobactam in 98 patients at a large community teaching hospital. The study found that the difference in the clinical and microbiologic success rates were not statistically significant (94 vs 82% and 89 vs 73%, respectively). The continuous-infusion regimen, however, was associated with a significantly shorter time to temperature normalization (1.2 ± 0.8 days vs 2.4 ± 1.5 days; p = 0.012) and a trend toward faster normalization of the white blood cell count (2.8 ± 2.4 days vs 3.9 ± 2.2 days; p = 0.065).
The results of a randomized, multicenter, open-label study comparing continuous infusion piperacillin/tazobactam (12/1.5 g administered continuously over 24 h) with the standard intermittent infusion (3/0.375 g administered over 30 min intermittently every 6 h) in patients with complicated intra-abdominal infections were recently reported. Patient demographics were similar among groups, as were the percentages of those clinically cured or improved (86.4% of those treated with continuous infusion vs 88.4 of those treated with intermittent infusion; p = 0.817). Bacteriologic success was not statistically different between the two treatment groups (p = 0.597). Moreover, drug-related adverse events were similar, despite the differing administration techniques utilized.
Lodise et al. have published the results of a retrospective cohort study among patients who received piperacillin/tazobactam for P. aeruginosa infection by standard administration (a 30-min intermittent intravenous infusion of 3.375 g every 4 or 6 h) or by a new extended-infusion protocol (a 4-h infusion of 3.375 g intravenously every 8 h). Among critically ill patients with APACHE II scores of 17 or higher, the 14-day mortality rate was significantly lower among patients who received extended-infusion therapy than among patients who received intermittent-infusion therapy (12.2 vs 31.6%, respectively; p = 0.04). The hospital length of stay was also significantly lower in the extended-infusion group (21 days vs 38 days; p = 0.02).
Vancomycin MIC 'Creep'
A number of studies have examined the phenomenon of vancomycin MIC 'creep' in relation to various clinical response outcomes; these analyses provide good examples of how antimicrobial stewardship could augment clinical success (Figure 1). In lower respiratory tract infections treated with vancomycin, Moise-Broder et al. demonstrated that the likelihood of clinical success is maximized when the vancomycin area under the 24-h concentration–time curve (AUC24)/MIC ratio is at least 350. The authors found that for patients with these values, the odds of a successful clinical response were approximately seven-times greater than for patients in whom this value was below 350 (OR: 7.19; 95% CI: 1.91–27.3; p = 0.0036).
Worldwide vancomycin minimum inhibitory concentrations in methicillin-resistant Staphylococcus aureus (n = 8249) (Tigecycline Evaluation and Surveillance Trial Program 2004–2010).
MIC: Mininum inhibitory concentration.
Data from .
Additional studies have addressed the obvious concern related to the risk of vancomycin nephrotoxicity when aiming for necessarily high antimicrobial exposure with this agent. Hidayat et al. found that 66% (63/95) of patients attained a high corrected average vancomycin trough of 15–20 µg/ml, and 11 of these 63 patients developed nephrotoxicity (significantly predicted by concomitant therapy with other nephrotoxic agents), in contrast to none in the low-trough group (p = 0.01).
Lodise et al. also noted a significant difference in nephrotoxicity between patients receiving vancomycin at 4 g/day or higher, those receiving vancomycin at less than 4 g/day and those receiving linezolid, with incidences of nephrotoxicity of 34.6, 10.9 and 6.7%, respectively. Data from another study by Lodise et al. compared the outcomes between high and low vancomycin MICs, revealing that clinical failure (36.4 vs 15.4%; p = 0.049) and an increased median hospital length of stay (21 vs 10.5 days; p = 0.02; Table 3 ) were significantly associated with the high vancomycin MICs.
In fact, several authors have reviewed evidence that vancomycin susceptibility in MRSA is decreasing over time and in ways that are very difficult to detect using standard methods employed in hospital laboratories. Infections caused by vancomycin-susceptible MRSA organisms with MICs of up to 1 mg/l appear to respond more effectively to vancomycin than infections caused by organisms with MICs of 1 mg/l and higher. The use of high doses of vancomycin, as currently recommended by some authorities (e.g., the American Thoracic Society) may not be sufficient to improve outcome. Although linezolid and daptomycin are available alternatives, resistance to these agents looms on the horizon.
Another glycopeptide, teicoplanin, is commonly used to treat Gram-positive infections, particularly those caused by MRSA; however, Logman et al. have recently pubished a systematic review in which no MRSA data in cSSSI were found for this antibiotic.
What is certain is that MRSA has adapted to glycopeptide exposure in ways that have made infections caused by these organisms very difficult to treat. Such adaptations not only allow for the development of resistance but may also select for virulence properties, such as resistance to endogenous peptides, which are important in the clearance of bacteremia. Whether it is virulence, glycopeptide resistance or both that is driving the changes in MRSA is unknown. As clinicians, we will continue to remain challenged by S. aureus infections, and our practices will need to adapt to this constantly evolving pathogen.
Expert Rev Anti Infect Ther. 2010;8(9):1019-1036. © 2010
Expert Reviews Ltd.
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