Tolerance of once-daily dosing of netilmicin and teicoplanin, alone or in combination, in healthy volunteers.

The purposes of this study were to test the pharmacokinetics and renal and otologic tolerances of a once-daily regimen of netilmicin and teicoplanin administered intramuscularly, alone or in combination (4.5 and 6 mg/kg, respectively), for 7 days in 30 healthy male volunteers. Teicoplanin induced only a mild increase in enzymuria. Nephrotoxicity was moderate and reversible with netilmicin; there was increased enzymuria and alteration in diluting ability, without significant changes in urinary beta 2-microglobulin levels, concentrating ability, and glomerular filtration rate. Ototoxicity was not detected in any of the subjects. Our results suggest that (1) teicoplanin and netilmicin given once daily induced only slight, reversible tubular damage, without any sign of ototoxicity; (2) their combination was not more toxic; and (3) clinical studies can be envisaged to evaluate the efficacy and tolerance of once-daily regimens in long-term treatment.

Clinical pharmacokinetics of enzyme inhibitors in antimicrobial chemotherapy.

The effectiveness of some antimicrobial agents can be enhanced by using them in combination; such combinations are termed synergistic. Where one compound potentiates the effect of a second drug they may be coformulated. Inhibition of the bacterial degradation of an active antimicrobial is the basis of clavulanate and sulbactam-potentiated penicillin combinations, and inhibition of degradative pathways in the host is the rationale behind imipenem/cilastatin therapy. Trimethoprim/sulphonamide combinations depend on the maintenance of an effective ratio for synergistic action. In order to achieve potentiation the coformulated drugs should have similar pharmacokinetics. Trimethoprim was originally matched with sulphamethoxazole, since these two drugs have similar elimination half-lives, but the significantly poorer penetration of sulphonamides, their greater non-renal clearance, the emergence of resistance, and the adverse reactions attributable to them argue against the rationale that underlies their coformulation. Time-dependent inhibition of bacterial beta-lactamases by clavulanic acid and sulbactam has extended the use of penicillins which are highly susceptible to beta-lactamase inactivation. The beta-lactamase inhibitors must penetrate to the same extent as the penicillin used with them, and be present long enough to effect inhibition; thus, rapid penetration, similar or slower elimination and equivalent volume of distribution are necessary. These requirements are met for amoxycillin/clavulanic acid, ticarcillin/clavulanic acid and ampicillin/sulbactam combinations. Clavulanic acid is absorbed orally and is given with amoxycillin. However, since sulbactam is labile by this route, the combination of sulbactam with ampicillin to form the prodrug sultamicillin has been necessary to enable an oral form to be developed. Imipenem is metabolised by renal brush-border dehydropeptidases, and may cause proximal tubular necrosis. Cilastatin was designed to inhibit this metabolism, which it effectively does, thereby both potentiating the effect of imipenem and avoiding toxicity. Appropriate matching of the kinetics of coformulated drugs is intended to maximise potentiation and minimise the risk of emergent resistance. The kinetics of the above combinations are discussed in the light of these requirements and the effects of age and disease.

Amoxicillin/clavulanic acid: a review of its use in the management of paediatric patients with acute otitis media.

UNLABELLED: Amoxicillin/clavulanic acid (Augmentin), Augmentin ES-600 is a well established, orally administered combination of amoxicillin (a semisynthetic antibacterial agent) and clavulanic acid (a beta-lactamase inhibitor). Amoxicillin/clavulanic acid shows good activity against the main pathogens associated with acute otitis media (AOM), including penicillin-susceptible and -intermediate strains of Streptococcus pneumoniae, and beta-lactamase producing strains of Haemophilus influenzae and Moraxella catarrhalis. It has moderate activity against penicillin-resistant S. pneumoniae; a high-dose formulation has been developed with the aim of providing better coverage for penicillin-resistant strains. Amoxicillin/clavulanic acid (conventional formulations, mostly 40/10 mg/kg/day in three divided doses) produced clinical response rates similar to those of oral cephalosporin comparators and similar to or significantly greater than those for intramuscular ceftriaxone in randomised trials in paediatric patients with AOM (mean age approximately 2 to 5 years). Clinical response rates were generally similar for amoxicillin/clavulanic acid and macrolide comparators (mean patient age approximately 1 to 6 years), although significantly better clinical and bacteriological responses were seen versus azithromycin in one randomised trial (mean patient age approximately 1 year). The high-dose formulation of amoxicillin/clavulanic acid (90/6.4 mg/kg/day in two divided doses) eradicated a high proportion of penicillin-resistant S. pneumoniae (penicillin MICs 2 or 4 mg/L) in a large noncomparative trial in children with AOM (upper limit of the US indication for S. pneumoniae is 2 mg/L). Amoxicillin/clavulanic acid is generally well tolerated. A low total incidence of adverse events (3.6%) and no serious events were reported from a large paediatric postmarketing study. The most frequently reported adverse events in children are mild gastrointestinal disturbances. Diarrhoea is generally less frequent with twice-daily than with three-times-daily treatment. The new high-dose formulation showed similar tolerability to a conventional twice-daily formulation (45/6.4 mg/kg/day) in a well controlled trial. CONCLUSIONS: Amoxicillin/clavulanic acid is a well established broad-spectrum antibacterial treatment which is effective and well tolerated in the treatment of AOM in paediatric patients. The high-dose combination should prove valuable in treating AOM caused by penicillin-intermediate and -resistant S. pneumoniae (approved in the US for penicillin MIC < or =2 mg/L). Based on recent recommendations and the available data, high-dose amoxicillin/clavulanic acid can be considered a treatment of choice for recurrent or persistent paediatric AOM (after failure of amoxicillin alone) where involvement of resistant pathogens is suspected.

Panipenem/betamipron.

Panipenem is a parenteral carbapenem antibacterial agent with a broad spectrum of in vitro activity covering a wide range of Gram-negative and Gram-positive aerobic and anaerobic bacteria, including Streptococcus pneumoniae and species producing beta-lactamases. Panipenem is coadministered with betamipron to inhibit panipenem uptake into the renal tubule and prevent nephrotoxicity. In large, randomised clinical trials, panipenem/betamipron demonstrated good clinical and bacteriological efficacy (similar to that of imipenem/cilastatin) in adults with respiratory tract or urinary tract infections. Panipenem/betamipron was also effective in adults with surgical or gynaecological infections, and in paediatric patients with respiratory tract and urinary tract infections in noncomparative trials. In small trials in elderly patients reported as abstracts, panipenem/betamipron demonstrated clinical efficacy similar to intravenous piperacillin and greater than oral ofloxacin in urinary tract infections. Elderly patients with respiratory tract infections also responded to therapy. Panipenem/betamipron is well tolerated with few adverse events reported in clinical trials, most commonly elevated serum levels of hepatic transaminases and eosinophils, rash and diarrhoea.

Sultamicillin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use.

Sultamicillin is the tosylate salt of the double ester of sulbactam plus ampicillin. Sulbactam is a semisynthetic beta-lactamase inhibitor which, in combination with ampicillin, extends the antibacterial activity of the latter to include some beta-lactamase-producing strains of bacteria that would otherwise be resistant. The combination of sulbactam plus ampicillin for parenteral use has previously been shown to be clinically and bacteriologically effective in a variety of infections. The chemical linkage of sulbactam and ampicillin has now produced an orally effective compound, sultamicillin, with antibacterial activity and clinical efficacy which are similar to those of the parenteral formulation. Sultamicillin has been shown to be clinically effective in non-comparative trials in patients with infections of the respiratory tract, ears, nose and throat, urinary tract, skin and soft tissues, as well as in obstetric and gynaecological infections, and in the treatment of gonorrhoea. In a small number of controlled trials, sultamicillin has shown comparable clinical efficacy to phenoxymethyl penicillin (penicillin V) and to amoxycillin (alone and in combination with clavulanic acid) in the treatment of paediatric streptococcal pharyngitis and acute otitis media, respectively; to cefaclor in the treatment of acute otitis media in adults; and to bacampicillin, cloxacillin and flucloxacillin plus ampicillin in skin and soft tissue infections in adults, children and adult diabetic patients, respectively. Sultamicillin was superior in efficacy to bacampicillin in the treatment of chronic respiratory infections, to cefaclor in the treatment of acute otitis media in adults, and to cefadroxil in the treatment of patients with complicated urinary tract infections. However, in single-dose treatment of uncomplicated gonorrhoea, sultamicillin (1500mg plus probenecid 1g) was inferior to a 2g intramuscular dose of spectinomycin. While in several studies the incidence of diarrhoea associated with sultamicillin was greater than that with comparative antibacterials, sultamicillin-associated diarrhoea was generally mild and transitory, although occasionally severe enough to necessitate discontinuation of treatment. Further studies in larger groups of patients are needed to clarify the therapeutic efficacy and safety of sultamicillin in comparison with other antibacterial regimens, and to determine the optimum single dosage for the treatment of gonorrhoea. Nonetheless, sultamicillin appears to provide a similar pharmacodynamic and pharmacokinetic profile to that of parenteral sulbactam plus ampicillin and, as such, will extend the therapeutic efficacy of ampicillin, with the further advantage of allowing treatment of patients with an oral formulation, thus avoiding the potentially adverse clinical and financial effects of prolonged parenteral therapy.

Drug treatment of pneumonia in the hospital. What are the choices?

Mortality and morbidity of nosocomial pneumonia remain high. Successful treatment of pulmonary infections depends on several factors including type of infection, offending pathogen, status of host defences, and adequate choice of antibiotic therapy. The physician's decision should aim at achieving antibiotic concentrations beyond the MIC at the site of infection. Gram-negative bacilli, notably Pseudomonos aeruginosa, Klebsiella pneumoniae and Escherichia coli, remain the most frequent agents in nosocomial pneumonia. Staphylococcus aureus and Streptococcus pneumoniae predominate among the Gram-positive cocci. Pneumocystis carinii predominates in immunocompromised patients. Protected sample bronchoscopy associated with quantitative cultures of samples, and quantification of intracellular microorganisms in cells recovered by broncho-alveolar lavage are two promising procedures which might replace previous, more aggressive methods. Penetration of antibiotics into lung tissue depends on physicochemical properties of the drug and the degree of inflammation of lung tissue. Quinolones, macrolides, tetracyclines and trimethoprim penetrate well into bronchial secretions. Penetration is moderate to low for aminoglycosides and beta-lactams. Fluoroquinolones and new beta-lactam agents, including third-generation cephalosporins imipenem, aztreonam and ticarcillin-clavulanate, showed comparative clinical efficacy in treatment of nosocomial pneumonia, with an efficacy rate close to 80%. Aminoglycosides should not be used alone. Combination therapy reduces but does not eliminate the risk of selection of Gram-negative resistant mutants. It should not be used routinely except for P. aeruginosa, Enterobacter cloacae and Serratia marcescens infections.

Amoxicillin/clavulanate for infections in infants and children: past, present and future.

Chemical synthesis of the penicillin nucleus in the 1950s made introduction of a broad array of new and important antimicrobials, including ampicillin and amoxicillin, possible. Ampicillin was introduced in 1962 in oral and parenteral forms as the first of the semisynthetic penicillins to provide increased activity against Gram-negative bacteria. Amoxicillin replaced oral ampicillin beginning in 1974 because amoxicillin resulted in higher and more prolonged serum concentrations than did equivalent doses of ampicillin. Amoxicillin/clavulanate (Augmentin) was introduced in the United States in 1984 to enhance the activity of amoxicillin by addition of the beta-lactamase inhibitor, clavulanic acid. During the past 20 years, amoxicillin/clavulanate has proven effective for a variety of pediatric infectious diseases, particularly acute otitis media (AOM). In 2001, a new pediatric formulation, high dose amoxicillin/clavulanate (Augmentin ES-600) was approved for use in the United States. The high dose preparation addressed the needs of pediatricians by providing greater amounts of amoxicillin while maintaining the same daily dose of clavulanic acid as the regular strength formulation. Doubling the dose of amoxicillin for management of recurrent and persistent AOM was recommended in 1999 by the Centers for Disease Control and Prevention because of concern about the increased incidence of nonsusceptible strains of Streptococcus pneumoniae. The original formulation combined amoxicillin/clavulanate in a 4:1 ratio and was followed by a 7:1 ratio formulation. The high dose formulation (600 mg of amoxicillin per 5 ml) provides a 14:1 ratio of amoxicillin to clavulanate. Although management of AOM will likely undergo changes in the coming years, amoxicillin is expected to remain first line therapy for AOM. For children who fail initial therapy with amoxicillin, high dose amoxicillin/clavulanate, an oral cephalosporin or parenteral ceftriaxone is recommended.

Teicoplanin: a well-tolerated and easily administered alternative to vancomycin for gram-positive infections in intensive care patients.

A prospective, randomized multicentre study was conducted in order to evaluate the potentially superior tolerability profile of teicoplanin plus netilmicin compared with vancomycin plus netilmicin in patients in ICUs. We considered that these glycopeptides have been shown to have comparable efficacy and that comparative tolerability is of paramount importance, particularly in severely ill patients. A total of 56 patients were enrolled into the study (36 males and 20 females). Twenty-four patients were included in the teicoplanin plus netilmicin group (15 males, 9 females: mean age 56.8 years). The mean simplified acute physiological score (SAPS) was 9.4 (range 4-20). Thirty-two patients were randomized to receive vancomycin plus netilmicin (21 males, 11 females; mean age 56.4 years). The mean SAPS was 9.3 (range 2-16). Septicaemia was the most common infection (14 cases in each group). Most infections were caused by Staphylococcus aureus or coagulase-negative staphylococci. The mean daily doses were: for teicoplanin, 457 mg (6.7 mg/kg); for vancomycin, 1678 mg (24.4 mg/kg); and for netilmicin 263.3 mg (3.9 mg/kg) in the teicoplanin group and 248 mg (3.8 mg/kg) in the vancomycin group. The trough levels of teicoplanin in the serum remained mostly between 7 and 10 mg/l, while more fluctuation was seen in patients receiving vancomycin. The mean trough levels of netilmicin in the serum were 1.2 (SD 0.9) mg/l in the teicoplanin group, compared with 1.7 (SD 1.4) mg/l in the vancomycin group (NS: p > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and pharmacodynamics of antibiotics in meningitis.

The penetration of antimicrobials into the CSF is dependent on lipid solubility, molecular size, capillary and choroid plexus efflux pumps, protein binding, and the degree of inflammation. Penicillins, certain cephalosporins, carbapenems, fluoroquinolones, vancomycin, and rifampin provide the highest ratios of CSF levels to the MBC for common infecting organisms. For beta-lactam antibiotics, it is the duration of time that CSF concentrations exceed the MBC that determines the rate of bactericidal activity. It appears that levels should exceed the MBC for more than 50% of the dosing interval. The peak/MBC and AUC/MBC ratios are important determinants of efficacy for aminoglycosides and fluoroquinolones. Once-daily dosing of aminoglycosides is as effective as multiple-daily dosing regimens in experimental meningitis, probably because of drug-induced prolonged persistent effects. Fluoroquinolones do not produce as prolonged persistent effects and are slightly less effective when administered once daily. Although steroid use can reduce the penetration and decrease the bactericidal activity of some antimicrobials, such as vancomycin, in experimental meningitis, the clinical impact of steroid use in human meningitis is still unclear.

Effect of antibiotic sequence on combination regimens against Pseudomonas aeruginosa in a multiple-dose, in vitro infection model.

The goal of this study was to investigate the effect of antibiotic sequence on combination regimens against Pseudomonas aeruginosa in an in vitro infection model. Ceftazidime plus ciprofloxacin and ceftazidime plus tobramycin were dosed every 12 h for 48 h using simultaneous or staggered administration. Simultaneous dosing and ceftazidime followed by ciprofloxacin or tobramycin were significantly more active at both 24 h (p = 0.03) and 48 h (p < 0.0001) than ciprofloxacin or tobramycin followed by ceftazidime. Final bacterial kill was sixfold greater with the former regimens. This study showed that antibiotic sequence had a significant and class dependent effect on antibacterial response. The clinical relevance of these observations warrants further investigations in animal models.

Role of pharmacokinetics and pharmacodynamics in the design of dosage schedules for 12-h cefotaxime alone and in combination with other antibiotics.

Pharmacodynamic principles have provided important tools to evaluate and compare antimicrobial agents, and well as to guide dosing. For beta-lactams, time above the minimum inhibitory concentration (MIC) has surfaced as the most important factor. However, the area under the inhibitory serum concentration time-curve (AUIC) may be superior when appropriate dosing intervals are selected. Although the target time over the MIC is unclear in humans even when concentrations remain continuously above the MIC, a higher AUIC predicts better clinical outcome up to a maximum. This article provides a pharmacodynamic assessment of 1- and 2-g doses of cefotaxime every 12 h. AUIC24 values and published MIC values for common pathogens (grouped into four groups based on MIC90) were used to predict organisms suitable for treatment with every-12-h regimes. Cefotaxime was inadequate for group 4 organisms including: Pseudomonas aeruginosa, Acienetobacter sp., and Enterococcus sp. Organisms such as Enterobacter cloacae, Serratia marcescens, Staphylococcus aureus, and B. fragilis may be suboptimally treated with cefotaxime every 12 h. Cefotaxime in doses of 1-2 g every 12 h should be useful in patients with normal renal function infected with organisms having MICs < 0.5 microgram/ml. This regimen should obtain AUIC24 values > 125 and ensure adequate time above the MIC. In patients with impaired renal function, because of a longer half-life and higher area under the curve, pathogens with MIC values in the 0.5-2 micrograms/ml range may be treated with cefotaxime every 12 h while maintaining AUICs > 125. Data are also presented for cefotaxime 2 g every 8 h alone and in combination with ofloxacin.(ABSTRACT TRUNCATED AT 250 WORDS)

Cefotaxime and desacetylcefotaxime in neonates and children: a review of microbiologic, pharmacokinetic, and clinical experience.

Over the past 5 yr, we have conducted two clinical and two pharmacokinetic investigations of cefotaxime (CTX) and desacetylcefotaxime (dCTX) in neonates, infants, and children. A total of 50 children with culture-proven bacterial meningitis were randomized to receive either 200 mg/kg/day of CTX (n = 23, mean age 24.4 mo) or standard doses of ampicillin (AMP) and chloramphenicol succinate (CAPS; n = 27, mean age 16.6 mo). Results were similar between the CTX and Amp/CAPS groups for clinical/microbiological cures (100% versus 96%, respectively) and for survival without sequelae (78% vs. 77%, respectively). All bacterial isolates were sensitive to CTX, and the comparison of the MIC/MBC values for CTX to the CSF bactericidal titers suggested antimicrobial activity for dCTX. In a second clinical trial, 20 infants (1 wk-3 mo) were treated with 200 mg/kg/day of CTX for Gram-negative enteric bacillary meningitis. Cultures of CSF obtained 24 hr after the initiation of treatment were sterile in all subjects. Survival and complication rates of 95% and 21%, respectively, were observed. This compared favorably to previously published experiences with alternate treatment regimens for Gram-negative meningitis in the newborn. In both meningitis studies, the safety profile for CTX was excellent.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacodynamic profiling of continuously infused piperacillin/tazobactam against Pseudomonas aeruginosa using Monte Carlo analysis.

Standard doses of piperacillin/tazobactam (9-13.5 g over 24 h) administered by continuous infusion (CI) routinely provide serum concentrations in excess of the susceptibility breakpoint (< or =16/4 micro g/ml) for most Enterobacteriaceae. Since the breakpoint of this agent for Pseudomonas aeruginosa is considerably higher (< or=64/4 micro g/ml), the likelihood of obtaining adequate drug exposures with these doses against this bacterium is currently unknown. Monte Carlo simulation was utilized to determine the probability of obtaining adequate piperacillin concentrations above its MICs for P. aeruginosa in patients receiving CI. MICs of 557 P. aeruginosa isolates were determined by E-test and a distribution was constructed for the 496 susceptible isolates. Using a previously validated population pharmacokinetic equation, steady-state serum concentrations were estimated for 210 patients who received piperacillin/tazobactam via CI. A Monte Carlo simulation was performed to predict the probability of obtaining concentrations at the MIC, 2 x MIC, 4 x MIC, 5 x MIC, and 6 x MIC for patients infected with susceptible P. aeruginosa isolates. MICs ranged from 0.09 to 64 micro g/ml with modal and median values of 3 and 4 micro g/ml, respectively. Steady-state concentrations of 51.14 +/- 17.52 micro g/ml were estimated in our patient population. The simulation resulted in a median level of exposure 12.62 times the MIC. The level of certainty of obtaining concentrations at the MIC, 2 x MIC, 4 x MIC, 5 x MIC, and 6 x MIC for piperacillin administered by CI was 97, 93, 85, 81, and 77%, respectively. Despite concern for the place of CI piperacillin/tazobactam in the management of P. aeruginosa infections due to the higher established breakpoint, these data suggest a high probability of achieving adequate drug exposure against susceptible isolates with this dosing regimen.

Pharmacokinetic-based ticarcillin/clavulanic acid dose recommendations for infants and children.

The pharmacokinetic characteristics of ticarcillin and clavulanic acid were determined after the first dose (n = 22) and again under steady-state conditions (n = 16) in a group of infants and children. Study subjects ranged in age from 1 month to 9.3 years; all but 3 study patients were 6 months of age or older. Each patient received 50 mg of ticarcillin and 1.7 mg of clavulanic acid (30:1 ratio) per kg of body weight given intravenously every 4 hours. Elimination half-life, steady-state volume of distribution, and body clearance averaged 1.1 hours, 0.22 L/kg, and 2.7 mL/min/kg, respectively, for ticarcillin, and 0.9 hours, 0.4 L/kg, and 6.2 mL/min/kg, respectively, for clavulanic acid. A total of 71% of the ticarcillin and 50% of the clavulanic acid dose were excreted unchanged in the urine over the 4-hour sampling period. Corresponding renal clearances averaged 2.1 and 3.2 mL/min/kg for ticarcillin and clavulanic acid, respectively. No differences were observed between first dose and steady-state evaluations in the pharmacokinetic behavior of either agent. In contrast, the pharmacokinetic behavior of clavulanic acid was significantly different from that observed for ticarcillin. These pharmacokinetic data combined with known in vitro susceptibilities of important clinical pathogens support a dose of 80 mg of ticarcillin and 2.7 mg/kg clavulanic acid per kg body weight given as a fixed dose combination every 8 hours for the treatment of most systemic infections that occur outside the central nervous system.

Multiple-dose pharmacokinetics and safety of two regimens of quinupristin/dalfopristin (Synercid) in healthy volunteers.

Quinupristin/dalfopristin (Q/D) is a novel streptogramin antibiotic for the treatment of severe gram-positive infections. The purpose of this open, nonrandomized, parallel-group, phase I trial was to evaluate Q/D pharmacokinetics after single and repeated doses under the two different dosing regimens corresponding to the effective doses and to evaluate tolerability. Two groups of 10 healthy volunteers received multiple 1-hour intravenous infusions of 7.5 mg/kg Q/D either every 8 or 12 hours for 4 or 5 days, respectively. Plasma concentrations of Q, D, and metabolites were determined using high-performance liquid chromatography and selective microbiological assays. The two regimens q8h and q12h lead to the same disposition profile after single and repeated administration. Single-dose data confirmed the high plasma clearances of Q and D (about 0.90 l/h/kg) obtained previously. Unchanged drugs were the main components in plasma, with each of the three metabolites representing about 20% (in terms of the AUC ratio) of the parent drugs. Comparable steady-state concentrations were reached from day 2 of both regimens. A similar moderate increase in Cmax and AUC (about 20%) of parent drugs was observed between the first and last day of treatment. This phenomenon, which was also observed for the metabolites, was not expected considering the short terminal disposition half-lives of the parent drugs and trough plasma concentrations of all components mostly below the limits of quantitation at steady state, whatever the dosing regimen. The clearances of parent drugs at steady state were about 20% lower as compared with that observed following the first drug administration (statistically significant difference). No trend suggesting a treatment effect on any laboratory parameter, vital signs, or electrocardiographic parameters was identified. However, 80% of subjects reported venous adverse events probably related to treatment.

Ampicillin/sulbactam in lower respiratory tract infections: a review.

The pathophysiology and microbiology of lower respiratory tract infections are outlined and diagnostic and therapeutic problems considered. The use of sulbactam/ampicillin in the treatment of these infections is evaluated. The two drugs have similar pharmacokinetic characteristics; predictable and dose-dependent peak serum concentrations of both agents are achieved after parenteral administration. More than 90% of strains of Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, Klebsiella sp, Escherichia coli, and Acinetobacter sp were inhibited by ampicillin/sulbactam concentrations of 16/8 micrograms/ml. Serum concentrations of ampicillin and sulbactam were 18 to 28 micrograms/ml and 13 micrograms/ml, respectively, after intramuscular administration of 1 gm/0.5 gm of ampicillin/sulbactam and 58 micrograms/ml and 30 micrograms/ml, respectively, after intravenous administration of the same dose. Good distribution of ampicillin/sulbactam into lung tissue, sputum, and bronchial fluid has been demonstrated. In over 2,250 patients treated with ampicillin/sulbactam, the rate of discontinuance of treatment because of side effects was less than 1%. Satisfactory clinical and bacteriologic outcome has been reported in over 80% of patients treated with ampicillin/sulbactam. The cost of ampicillin/sulbactam treatment is generally lower than that of other comparable antibiotic regimens.

Pharmacokinetics and pharmacodynamics of piperacillin/tazobactam when administered by continuous infusion and intermittent dosing.

BACKGROUND: Although intermittent bolus dosing is currently the standard of practice for many antimicrobial agents, beta-lactams exhibit time-dependent bacterial killing. Maximizing the time above the minimum inhibitory concentration (MIC) for a pathogen is the best pharmacodynamic predictor of efficacy. Use of a continuous infusion has been advocated for maximizing the time above the MIC compared with intermittent bolus dosing. OBJECTIVE: This study compared the pharmacokinetics and pharmacodynamics of piperacillin/tazobactam when administered as an intermittent bolus versus a continuous infusion against clinical isolates of Pseudomonas aeruginosa and Klebsiella pneumoniae. METHODS: Healthy volunteers were randomly assigned to receive piperacillin 3 g/ tazobactam 0.375 g q6h for 24 hours, piperacillin 6 g/tazobactam 0.75 g continuous infusion over 24 hours, and piperacillin 12 g/tazobactam 1.5 g continuous infusion over 24 hours. Five clinical isolates each of P aeruginosa and K pneumoniae were used for pharmacodynamic analyses. RESULTS: Eleven healthy subjects (7 men, 4 women; mean +/- SD age, 28 +/- 4.7 years) were enrolled. Mean steady-state serum concentrations of piperacillin were 16.0 +/- 5.0 and 37.2 +/- 6.8 microg/mL with piperacillin 6 and 12 g, respectively. Piperacillin/tazobactam 13.5 g continuous infusion (piperacillin 12 g/tazobactam 1.5 g) was significantly more likely to produce a serum inhibitory titer > or = 1:2 against P aeruginosa at 24 hours than either the 6.75 g continuous infusion (piperacillin 6 g/tazobactam 0.75 g) or 3.375 g q6h (piperacillin 3 g/ tazobactam 0.375 g). There were no statistical differences against K pneumoniae between regimens. The median area under the inhibitory activity-time curve (AUIC) for the 13.5 g continuous infusion was higher than that for 3.375 g q6h and the 6.75 g continuous infusion against both P aeruginosa and Kpneumoniae (P < or = 0.007, 13.5 g continuous infusion and 3.375 g q6h vs 6.75 g continuous infusion against K pneumoniae). The percentage of subjects with an AUIC > or = 125 was higher with both 3.375 g q6h and the 13.5 g continuous infusion than with the 6.75 g continuous infusion against P aeruginosa and K pneumoniae (both, P < 0.001 vs 6.75 g continuous infusion against K pneumoniae). CONCLUSIONS: Piperacillin 12 g/tazobactam 1.5 g continuous infusion consistently resulted in serum concentrations above the breakpoint for Enterobacteriaceae and many of the susceptible strains of P aeruginosa in this study in 11 healthy subjects. Randomized controlled clinical trials are warranted to determine the appropriate dose of piperacillin/tazobactam.

Elements of design: the knowledge on which we build.

The time the free drug serum concentration of antibiotic remains above the pathogen MIC (T > MIC) determines bacteriological efficacy and emergence or selection of resistance for penicillin and amoxicillin with or without clavulanate. Multiple studies in animal and in-vitro models now support this conclusion. The size of the T > MIC (the pharmacokinetic/-dynamic target) is > 40-50% to maximise antibacterial effect and pathogen eradication for Streptococcus pneumoniae and probably also Haemophilus influenzae. The size of the T > MIC for optimal antibacterial effect is changed by host immune status but not by bacterial inoculum or mechanism of resistance. There is good animal evidence to support the prediction that, as long as the target T > MIC is achieved, strains of S. pneumoniae with amoxicillin MICs of 0.016 mg/L will respond to amoxicillin in the same way as those with MICs of 1-2 mg/L. Emergence of resistance to amoxicillin/clavulanate in S. pneumoniae is related to low T > MIC (< 20%) and also to the degree of population heterogeneity to amoxicillin. Selection of resistant strains of S. pneumoniae is also related to T > MIC. Monte Carlo simulations based on the pharmacokinetics of amoxicillin with or without clavulanate in humans are needed to best predict the likely efficacy of different amoxicillin dosing regimens. This approach adequately allows the considerable pharmacokinetic variability in amoxicillin handling by infected patients to be accounted for as well as differences in pathogen beta-lactam susceptibility.

Evaluation of a triple-drug combination for treatment of experimental multidrug-resistant pneumococcal meningitis.

To evaluate the therapeutic efficacy of ceftriaxone + vancomycin + rifampicin (CVR) in the treatment of pneumococcal meningitis caused by a multidrug-resistant strain, single-drug regimens (ceftriaxone 100 mg/kg, rifampicin 15 mg/kg, or vancomycin 20 mg/kg), double-drug regimens (ceftriaxone + vancomycin [CV] and ceftriaxone + rifampicin [CR]) and a triple-drug combination (CVR) with or without dexamethasone were compared in a rabbit meningitis model. Meningitis was induced by a highly penicillin-resistant (MIC 2 mg/l) and ceftriaxone-resistant (MIC 4 mg/l) pneumococcal strain. Final therapeutic efficacy was evaluated by the bacterial concentration at 24 h, and the bacterial killing rate was also evaluated. All combination regimens were superior to ceftriaxone or vancomycin single-drug regimens with regard to sterilisation of CSF and bacterial killing rate. Rifampicin was as effective as combination regimens. Regardless of dexamethasone, therapeutic efficacy of CVR and CR were superior to that of CV. CVR showed comparable therapeutic efficacy to CR. Data suggested that CVR would not have additional therapeutic benefit over CR during the initial 24 h of treatment.

Target site bacterial killing of cefpirome and fosfomycin in critically ill patients.

We employed an in-vivo pharmacokinetic/in-vitro pharmacodynamic method to simulate bacterial killing in plasma and the interstitium of skeletal muscle tissue after intravenous administration of 2 g of cefpirome and 8 g of fosfomycin alone and in combination to patients with sepsis. Interstitial antimicrobial concentrations were determined by use of in-vivo microdialysis. CFU/ml of Staphylococcus aureus (ATCC 29213) and Pseudomonas aeruginosa (clinical isolate) decreased by approximately 2log(10) for plasma and muscle tissue 6 h after cefpirome and fosfomycin administration compared with the baseline, respectively. The simulation of plasma and tissue pharmacokinetics for the combined administration of these antibiotics resulted in complete eradication of S. aureus within 5 h after drug exposure. No bacterial re-growth occurred in any of the simulations within 6 h. The in-vitro simulation of in-vivo plasma and tissue pharmacokinetics of cefpirome and fosfomycin has shown that both antimicrobial agents kill S. aureus and P. aeruginosa strains effectively after single dose administration. This effect was most pronounced by the combined use of these antimicrobial agents. Therefore, this data corroborates antimicrobial strategies of simultaneous administration of cefpirome and fosfomycin in patients with severe soft tissue infection.