Serum Antibiotic Concentrations Research Articles

Pharmacokinetics and pharmacodynamics of aztreonam administered by continuous intravenous infusion

The pharmacodynamic parameter that appears to correlate best with a successful therapeutic outcome with beta-lactam antibiotics is the length of time the serum antibiotic concentration remains above the minimum inhibitory concentration (MIC) for the infecting pathogen. By maximizing this parameter, continuous administration of beta-lactam and related antibiotics by intravenous infusion could represent the optimal mode of drug administration. The pharmacokinetic and pharmacodynamic properties of ceftazidime administered by continuous intravenous infusion have been evaluated previously. Aztreonam is a monobactam antibiotic with similar pharmacokinetic and microbiologic activity to that of ceftazidime. This study evaluated the pharmacokinetic and pharmacodynamic characteristics of aztreonam administered as a continuous intravenous infusion in healthy volunteers against multiple clinical isolates. Five men and 3 women received 6 g of aztreonam administered by continuous intravenous infusion over 24 hours. Blood samples were collected before the infusion and at 0.5, 1 through 8, 12, 18, and 24 hours after the start of the infusion. Pharmacokinetic parameters were determined by standard equations. In vitro susceptibility testing was performed using National Committee for Clinical Laboratory Standards guidelines for 4 clinical isolates of gram-negative bacteria (2 each of Escherichia coli and Pseudomonas aeruginosa). Serum inhibitory titers (SITs) were determined in duplicate for each clinical isolate at 0 and 24 hours. The subjects' mean (D) age was 29.3 .4 years; mean weight, 74.6 4.0 kg; and calculated mean creatinine clearance, 107 3 mL/min. For the pharmacokinetic parameters, mean (D) values were as follows: steady-state serum concentration, 40.9 .8 μg/L; halflife, 1.5 .4 hours; elimination rate constant, 0.50 ±0.13 hours −1; steady-state volume of distribution, 0.18 .04 L/kg; and total body clearance, 6.1 .2 L/h. The MICs were 0.0625 and 0.125 μg/mL against the 2 E coli isolates and 4 μg/mL against both P aeruginosa isolates. The median SITs against the E coli isolates were 1:256 and 1:512, and against the P aeruginosa isolates were 1:8 and 1:16. At steady state, 11 subjects had serum concentrations of aztreonam ≥4 times the MIC for each organism. These findings suggest that further clinical study of the administration of aztreonam by continuous intravenous infusion is warranted.

Pharmacokinetics of antibiotics in burn patients.

Drug pharmacokinetics are significantly altered in the burned patient but the interplay of a large number of variables is involved in deciding how an individual will deal with a drug. Consequently the burn patient population shows significant inter- and intrapatient variation. In 1976 altered aminoglycoside pharmacokinetics and the need for increased dosage in burn patients was reported but, despite this early study, a review of the currently available literature shows that for many drugs there is a paucity of information to support current dosage recommendations. In addition, many reports are based upon small numbers of patients, and even in larger studies there is no standardization of the study population with regard to the important variables known to affect drug handling. For the sub-population of burn patients who eliminate drugs extremely rapidly, a concern exists over the adequacy of antibiotic dosing. It is suggested that antibiotic serum concentrations be measured for all drugs in every patient to ascertain whether there is a significant problem with dosing. Additionally, future pharmacokinetic studies need to be standardized in burn patients.

Antibiotic resistance: a current perspective.

Antibiotic resistance: a current perspective.

Pharmacodynamics of fluoroquinolones.

Fluctuating concentrations of three fluoroquinolones (moxifloxacin, sparfloxacin and ofloxacin) and a beta-lactam (amoxycillin) were used in vitro to simulate antibiotic concentrations in human serum after oral doses of antibiotics. The antibiotics were tested against Staphylococcus aureus 12241 and Streptococcus pneumoniae 4241. Moxifloxacin and sparfloxacin were also tested against Escherichia coli Neumann. Human serum concentrations of moxifloxacin and ciprofloxacin were also simulated in an in-vivo murine thigh muscle model against S. aureus, S. pneumoniae and E. coli. Ciprofloxacin, sparfloxacin and ofloxacin had a dose-independent effect on gram-positive organisms beyond their optimal dose that gave a maximum effect, as did amoxycillin. In contrast, moxifloxacin had a dose-dependent and therefore concentration-dependent effect on both gram-positive and beta-lactam-susceptible and-resistant gram-negative organisms. The marked activity of moxifloxacin against both gram-positive and gram-negative organisms was confirmed in an in-vivo model. A human dose equivalent of 200 mg moxifloxacin reduced viable counts of S. pneumoniae below the limit of detection and regrowth did not occur. S. aureus was eliminated almost as effectively as S. pneumoniae. A 200 mg dose of moxifloxacin completely eliminated the original inoculum of E. coli within 6 h. Treatment of S. aureus with ciprofloxacin (250 or 500 mg) resulted in a dose-independent decrease in viable counts by approximately 3.5 log10 cfu/mL. A 125 mg dose of ciprofloxacin almost completely eliminated the original inoculum of E. coli within 8 h, whereas both the 250 mg and 500 mg doses reduced viable counts below the limit of detection. Thus, the in-vitro and in-vivo pharmacodynamic models used in this study established that moxifloxacin was highly effective against both gram-negative and gram-positive bacteria.

Randomised Trial of Pivampicillin Plus Pivmecillinam vs. Pivampicillin in Children and Young Adults with Chronic Obstructive Pulmonary Disease and Infection with Haemophilus lnf luenzae

SummaryA prospective, randomised, single-blind comparative trial was carried out to determine whether double β-lactam treatment with pivampicillin plus pivmecillinam is more effective than pivampicillin alone in the treatment of recurrent and chronic lung infections with Haemophilus influenzae in patients with chronic obstructive pulmonay disease (COPD) or cystic fibrosis (CF). Fifty-six children and young adults with COPD or CF were randomised to the clinical study. The patients were allocated at random to receive perorally either pivmecillinam, 40mg/kg/day, combined with pivampicillin, 50 mg/kg/day, or pivampicillin 50 mglkglday alone for 14 days. A crossover pharmacokinetic study using the same drugs was carried out in 10 CF patients to determine the antibiotic concentrations in serum and sputum after a single dose of each drug. The clinical study showed no signifcant differences in clinical scoring, lung function tests or adverse events after treatment with pivampicillin plus pivmecillinam or pivarnpicillin alone. Follow-up microbiological evaluation 2 and 6 weeks after the end of treatment showed that the offending pathogen was eradicated in 68% of the patients treated with pivampidin plus pivmecillinam and in 67% of the patients treated with pivampicillin alone. Reinfection with another biotype was more common in the combination group (50% vs. 21%) than in the pivampicillin group. In the pharmacokinetic study the median peak serum concentration occurred two hours after intake of tablets.The eficacy of double β-lactam treatment in lung infections with H. influenzae appears to be equivalent to that ofampicillin on clinical lung symptoms, lung function tests, adverse effects and bacteriology.

Influence of Fever on Cefazolin Pharmacokinetics

The influence of fever on the pharmacokinetics of cefazolin was investigated in patients with acute febrile diseases. Nine patients were included in the study. Antibiotic serum concentrations were determined using high performance liquid chromatograpy (HPLC). An analog computer and the SIMULINK software package were used to identify the pharmacokinetic model and PCNONLIN software package to obtain the secondary parameters. In 6 patients a two-compartment pharmacokinetic model of cefazolin was observed during fever and after defervescence. In 2 patients a two-compartment model changed to a one-compartment after defervescence, and a one-compartment model was observed in one patient during both periods. Cefazolin-treated patients with a two-compartment model (6/9) had higher Cmax, mean steady state serum concentrations (Css), and area under the plasma concentration-time curve (AUC0→∞) smaller central compartment volume (V1), and lower clearance (Cl) during fever. The varying distribution of antibiotics during fever probably reflects different hemodynamic responses to fever.

Does intraoperative blood loss affect antibiotic serum and tissue concentrations?

Does intraoperative blood loss affect antibiotic serum and tissue concentrations?

Does intraoperative blood loss affect antibiotic serum and tissue concentrations?

To determine the effect of intraoperative blood loss on prophylactic cefazolin and gentamicin serum and tissue concentrations. A prospective study of elective spinal instrumentation surgical procedures with an expected large blood loss. Tertiary care, inner-city university hospital. Eleven adult patients who underwent an elective surgical procedure that involved spinal instrumentation. Standard perioperative administration of a combination of cefazolin and gentamicin. Serum and tissue samples were obtained consecutively throughout the surgical procedure. The effect of intraoperative blood loss on serum and tissue cefazolin and gentamicin concentrations and their pharmacokinetics. At the time of the incision, serum cefazolin concentrations were greater than tissue concentrations (P = .07). A mean dose of 1.8-mg/kg gentamicin yielded low or nontherapeutic serum and tissue gentamicin concentrations. Cefazolin and gentamicin were eliminated from the tissue compartment slower than from the serum compartment (P < .03), while the half-life of cefazolin was significantly (P = .06) longer in the tissue compartment. The volume of distribution of cefazolin was normal (ie, 12.5 L), while the volume of distribution of gentamicin was 5-fold greater than expected. At 60 minutes after the incision, blood loss correlated with cefazolin tissue concentrations (r = -0.66, P = .05). Blood loss correlated with the change in tissue antibiotic concentrations for cefazolin (r = 0.73, P = .04). In addition, the clearance of gentamicin from the tissues correlated with blood loss (r = 0.82, P = .01). Based on measured pharmacokinetic values, additional doses of cefazolin should be administered when the operation exceeds 3 hours and blood loss is greater than 1500 mL. Doses of gentamicin greater than 1.8 mg/kg should be administered more than 30 minutes prior to the surgical incision.

Pharmacokinetics of a single dose of teicoplanin in burn patients.

Patients with severe burns are susceptible to infection with Gram-positive organisms including methicillin-resistant Staphylococcus aureus, and often require higher antibiotic dosages compared with other patients. This study examined the pharmacokinetics of a single iv dose of teicoplanin (12 mg/kg) in 15 adults and five children with severe burns. Adults were aged 21-82 years with a median total body surface area (TBSA) burn of 30% (range 15-60%). Children were aged 10 months-l0 years with median TBSA burn of 15% (10-30%). At 12 h, the median serum teicoplanin concentration was 12.8 mg/L (9.027.1 mg/L) in adults and 7.6 mg/L (6.6-l0.8 mg/L) in children, (P < 0.01); at 24 h, the corresponding values were 8.3 mg/L (4.6-l2.9 mg/L) and 5.2 mg/L (4.2-6.0 mg/L). Using a three-compartment model, the median terminal half life in adults was 114 h (47-278 h). Children fitted a two-compartment model with a terminal half-life of 38 h (2l-41 h). The median concentration of teicoplanin in fluid from the burn wound was 60% of the serum antibiotic concentration. A single iv dose of 12 mg/kg of teicoplanin was sufficient to produce therapeutic serum concentrations in burn patients for 24 h, but monitoring of antibiotic levels in serum may be advisable in those with high total clearance, especially children.

Preincisional single-dose ceftriaxone for the prophylaxis of surgical wound infection

Background: Preincisional intraparietal injection of antibiotics is used for the prophylaxis of postoperative surgical infections. Whether topically injected antibiotics remain primarily in the surgical wound or are systematically absorbed is uncertain, however. Patients and methods: The pharmacokinetics of preincisional injection of 2 g ceftriaxone were studied in 20 patients who have undergone abdominal surgery, with determination of serum, wound tissue, and wound fluid antibiotic concentrations. Results: Preincisional injection of ceftriaxone resulted in high antibiotic concentrations in the wound tissue and wound fluid. The highest plasma concentrations were achieved at 1.50 hours (99.47 ± 14.67 μg/mL). Plasma concentrations exceeded the minimal inhibitory concentrations of most aerobic gram-positive and gramnegative organisms with the exception of Pseudomonas aeruginosa, Acinetobacter species, and Streptococcus faecalis for 24 hours (10.42 ± 4.12). No local or general complications arose in any of the patients. Conclusion: Our results suggest that preincisional administration of ceftriaxone for prophylaxis is very effective.

Neurosyphilis

Neurosyphilis is a symptom of the tertiary stages of syphilis (a chronic systemic infection of Treponema pallidum subspecies pallidum). Classical neurosyphilis has become a rare condition in Western countries because of the use of penicillin for the treatment of early or latent syphilis. Although textbook neuro syphilis is now uncommon, modified neuro syphilis as a consequence of intercurrent antibiotic use for other conditions may be more common. This latter condition is harder to diagnose than classical neurosyphilis because of atypical clinical and cerebrospinal fluid (CSF) findings. The coexistence of HIV infection and syphilis has further complicated the picture. There have been no well controlled trials of treatments for neurosyphilis. Nevertheless, the treatment of choice for established neurosyphilis has been shown to be benzylpenicillin (penicillin G). The drug is administered as an intensive therapy of frequent intravenous high doses or high doses of an intramuscular repository formulation with probenecid. Other agents that can be used include high dose amoxicillin (amoxycillin) with probenecid (but compliance cannot be monitored), tetracyclines, macrolides or ceftriaxone. If the individual is HIV-positive or of unknown serostatus, benzylpenicillin should be used to prevent or treat neurosyphilis. In patients who are allergie to penicillin, rush desensitisation can be used to allow administration of benzylpenicillin. Alternatively, non-penicillin antibiotics can be used. Much work has been performed to establish the bactericidal concentrations of penicillin and other antibiotics in serum and CSF. However, the significance of these values is uncertain because the causative pathology of neurosyphilis may lie in the perivascular space. Follow-up and counselling of patients with neurosyphilis, and repeat lumbar puncture for analysis of CSF where initially abnormal, are recommended.

Infection of the pancreatic duct following pancreas transplantation with bladder drainage.

Combined kidney-pancreas transplantation represents a widely accepted therapy for endstage diabetic nephropathy. Drainage of the pancreatic juice into the urinary bladder is the preferred surgical technique in most centers. Between January 1987 and December 1994 a total of 85 pancreas transplantations with pancreatocystostomy were performed at the Innsbruck University Hospital. In all cases a polyvinylcatheter was placed into the pancreatic duct and drained transvesically to the exterior. During several weeks after transplantation pure pancreatic juice was harvested for immunological and microbiological monitoring. Whenever a patient required antibiotic treatment, antibiotic concentrations in pancreatic juice, urine or serum were determined by means of a biological test system using Bacillus subtilis. Nine different ATCC bacterial strains were incubated in pancreatic juice collected from transplant recipients and tested for their multiplication rate. Thirteen patients acquired an infection of the pancreatic duct. Non-fermentative bacteria, gram-negative rods, Enterococcus spp. and Candida spp. were the most often isolated organisms. The in vitro tests revealed that Pseudomonas aeruginosa, Acinetobacter calcoaceticus and Escherichia coli grew very well whereas Streptococcus agalactiae was unable to multiply in pancreatic juice. Ampicillin/sulbactam was found to be excreted in high concentrations into the pancreatic juice. Many other tested antibiotics (cephalosporins, carboxypenicillins and aminoglycosides) achieved levels below the minimum inhibitory concentrations (MICs) for most bacteria. Antibiotic treatment was required for up to 5 weeks to eliminate the pathogens from the pancreas but was successful in 11 out of the 13 patients at the end. The results of this study led to changes in our antibiotic policy and helped to improve the results after pancreatic transplantation.

Effectiveness of antimicrobial treatment against Borrelia burgdorferi infection in mice

Although antimicrobial agents are effective therapy for early Lyme disease, optimal treatment schedules have not been conclusively established. The efficacy of various dosages of eight antibiotics used for borreliosis treatment was evaluated for C3H/HeNCrIBR mice, which reproducibly develop persistent infection, arthritis, and carditis when inoculated with Borrelia burgdorferi. Amoxicillin-clavulanic acid, ceftriaxone, and high-dose penicillin G effectively eliminated infection and disease. Oxytetracycline, doxycycline, chloramphenicol, erythromycin, and azithromycin failed to cure infected mice. There was a correlation between peak serum antibiotic concentrations in mice, as determined by agar well diffusion bioassays, and therapeutic levels in humans. When experimentally inoculated mice were treated at 1 week postinfection with ceftriaxone (16 mg/kg of body weight twice daily for 5 days) and monitored for up to 90 days, all treated mice were free of spirochetes and had no gross or histologic lesions. This antibiotic regimen at days 7 to 11 postinoculation eliminated the spirochetes so that there were no relapses during the 90-day observation period. For experimentally inoculated mice treated with ceftriaxone at 7 or 14 days postinfection, arthritis, carditis, and infection were eliminated. When treatment began at 30 and 90 days after inoculation, infection and active cardiac and arthritic lesions were eradicated; however, residual mild synovitis and vasculitis persisted in some mice. In comparison with inoculated, untreated mice, ceftriaxone therapy at 7, 14, 30, and 90 days postinfection abrogated the development of antibody titers against B. burgdorferi. Having the potential to determine the presence of the spirochete through culture and histologic lesions makes the B. burgdorferi-inoculated C3H mouse model a valuable adjunct in evaluating chemotherapeutic options for Lyme disease.

Critères pharmacocinétiques du choix d'un antibiotique pour l'antibioprophylaxie en chirurgie

The prevention of surgical infections with perioperative prophylactic antibiotics is experimentally and clinically well founded in both principle and practice. The evaluation of the role of antimicrobial agents in the success or failure of infection prophylaxis in surgery involves a discussion of both the pharmacokinetic and the pharmacodynamic properties of particular agents. A main concern in surgical prophylaxis is the relation between the respective time course of antibiotic concentrations in serum and in the tissue (wound). Several problems arise in both the measurement and the interpretation of drug concentrations in tissues and the results of this approach are still controversial. However, the knowledge of the numerous factors influencing the penetration into a tissue and the characteristics of the relative distribution of the antibiotic between the compartments inside the tissue, i.e. the vascular, interstitial and intracellular spaces, could allow a valuable approach to this problem. The concentrations of free drugs in serum are valuable predictors of the time course of unbound drug in interstitial fluid, where the bacteria are generally located. An increase in protein binding does not reduce the area under the curve (AUC) of free drug for β lactam agents eliminated predominantly by glomerular filtration, but prolonges their climination half life. Timing and route of administration are also important factors to consider in relation with the parmacokinetic profile of the drug. Pharmacodynamic studies of persistent growth suppression and bactericidal activity predict that the period during which the free drug concentration exceeds the MIC is an important parameter of the efficacy of β lactam antibiotics. In the opposite, the Cmax and/or the AUC are the major parameters of the efficacy of aminoglycosides and quinolones against Gram negative bacteria. Thus, the goal of prophylaxis with β lactams could be to provide levels of free drug above the MIC for the whole surgical period, while the obtention of a high Cmax with a one-day therapy should be required for aminoglycosides. Further clinical trials are warranted to assess this approach.

Pharmacokinetic Properties of Gentamicin and Amikacin in the Cockatiel

Gentamicin and amikacin are commonly used in veterinary medicine to treat a variety of gram-negative bacterial infections. The present study evaluates the pharmacokinetics of gentamicin sulfate and amikacin sulfate in the cockatiel (Nymphicus hollandicus), a small (approximate body weight = 100 g) psittacine bird, utilizing treatment regimens developed in larger parrot species. Serum antibiotic concentrations were determined in cockatiels following twice-daily intramuscular treatment with 5 mg gentamicin/kg body weight and 15 mg amikacin/kg body weight. In the present study, peak values of gentamicin were 4.6 +/- 1.45 micrograms/ml, and trough values were 0.17 +/- 0.04 micrograms/ml. Amikacin administration resulted in peak values of 27.3 +/- 6.9 micrograms/ml and trough concentrations of 0.9 +/- 0.3 micrograms/ml. Based on the present study, an appropriate intramuscular dose regimen for gentamicin in cockatiels is 5 to 10 mg/kg body weight either two or three times per day. An intramuscular amikacin dosage of 15 to 20 mg/kg body weight either two or three times per day is recommended for treatment of infections caused by susceptible bacteria.

Clinical Pharmacokinetics of Newer Antibacterial Agents in Liver Disease

Liver disease may produce significant, albeit highly variable, effects on the pharmacokinetic behaviour of antibiotics in serum. Drug disposition may be altered through several pathophysiological mechanisms including reduced hepatobiliary clearance, and modifications in the volume of distribution induced by albumin synthesis deficiency or portal hypertension-related ascites. Antibacterial agents are not affected by potential alteration in hepatic first-pass effects. Only liver cirrhosis-induced effects on serum pharmacokinetics of antibiotics have been extensively studied, unlike those possibly produced by other forms of liver disease. In liver cirrhosis, pharmacokinetic alterations of nearly all beta-lactam or quinolone agents appear not to be marked enough to require dosage adjustment, provided that renal function stays normal. Adaptation in therapeutic schedule, however, is warranted for those drugs that are substantially cleared by the hepatobiliary system, namely mezlocillin, clindamycin, erythromycin, pefloxacin, enoxacin, antituberculous agents or nitroimidazole derivatives. Special caution should also be exercised when using aminoglycosides or vancomycin because of the wide interpatient variability of their pharmacokinetic disposition and their toxic potential. When renal function is impaired and there is an increased volume of distribution due to ascites, as frequently observed in severe liver insufficiency, the elimination half-life of most antibiotics is markedly prolonged, resulting in potential side effects due to drug accumulation. Accordingly, dosage adjustment applies to all drugs. In this regard, it should be remembered that delineating the dosage guidelines for a given antibiotic on the basis of reported pharmacokinetic parameters in patients with liver cirrhosis is awkward and probably of limited value. This pattern is ascribed to large interpatient variability in the active hepatic cell mass, the degree of portal hypertension and the alteration of serum binding capacity. Furthermore, there is no way of predicting accurately the extent of liver insufficiency in an individual patient. Dosage reduction is thus done empirically in most cases. Whenever possible, direct measurements of serum antibiotic concentrations should be the reasonable approach to manage antibiotic therapy in this kind of clinical condition.

Prospective audit of an aminoglycoside consultative service in a general hospital

To investigate the impact of the introduction of a consultative service on the use, efficiency of dosing and clinical toxicology of the aminoglycoside antibiotics, gentamicin and tobramycin, in a general hospital. Two audits were conducted six months and 18 months after the introduction of the consultative service. The audits reviewed the use of drug assay services, the adequacy of drug administration (as measured by serum antibiotic concentrations), indications for prescription, adverse outcomes (by noting markers of nephrotoxicity) and the antibiotic sensitivity of Gram-negative pathogens. The results were compared with the results of an audit conducted before the consultative service was instituted. There was a significant (P < 0.001 by chi 2 test) increase in the use of assays, with drug assays performed in 67% (first audit) and 77% (second audit) of aminoglycoside courses compared with 48.2% in the pre-intervention audit. Sample timing was greatly improved, with more than 70% of the samples collected at the appropriate times. Assay wastage in terms of uninterpretable assay results decreased significantly (P < 0.001) from 42.9% of total assays to 6.3% at the first audit and 3.8% at the second audit. The percentage of assay results in the desirable range increased significantly (P < 0.001) from 39.1% to 71.9% (first audit) and 75.4% (second audit). Pharmacokinetic recommendations were made in 39.1% and 64% of all aminoglycoside courses during the first and second audits respectively, with clinician acceptance of dosage recommendations at 83.1% and 82.8% respectively. For aminoglycoside courses prescribed for therapeutic reasons, 97.9% (first audit, n = 325) and 98.6% (second audit, n = 280) of indications for use were judged as clinically appropriate. The incidence of suspected aminoglycoside-induced nephrotoxicity was reduced from 8.9% of patients to 1.6% (first audit, P < 0.001) and 2.4% (second audit). Bacterial sensitivity audits showed that the great majority of clinical isolates of target organisms (n = 3523, Year 1 and n = 3385, Year 2) were sensitive to gentamicin (92.2% and 91.5% respectively) and tobramycin (98.1% and 98.8% respectively); these aminoglycosides exceeded all alternative agents in effectiveness, including first and third generation cephalosporins. The overall results indicate that introduction of the consultative service had a positive impact on the effective use of aminoglycosides, with a marked decrease in clinical toxicity. These influences were shown to persist for at least 18 months. The availability of reliable predictive techniques to reduce toxicity allows active promotion of aminoglycosides as the agents of choice on grounds of efficacy and economy.

Identification of factors affecting in vivo aminoglycoside activity in an experimental model of gram-negative endocarditis.

Aminoglycoside bactericidal activity during the first 24 h of treatment probably is a determining parameter in the prognosis of severe gram-negative infections in immunocompromised patients. To identify the predictive factors involved in the definition of the best therapeutic regimen for Enterobacter cloacae and Serratia marcescens infections, we studied different gentamicin, tobramycin, and amikacin regimens by using an experimental model of rabbit endocarditis. Two factors appear to play an important role in predicting in vivo efficacy: (i) the level of in vivo bactericidal activity, which can differ widely from one aminoglycoside to another for the same bacterial strain and from one strain to another of the same species, and (ii) the critical serum drug concentration (CSC, in milligrams per liter), defined as the lowest serum antibiotic concentration capable of producing a significant CFU reduction (P less than 0.05) in endocarditis vegetations 24 h after the beginning of a continuous infusion. Stepwise regression analysis showed that for gentamicin and S. marcescens, the area under the concentration-time curve above the CSC and then the time above the CSC are the determining parameters for efficacy (R = 0.69; F = 13.5; P = 0.001), whereas for amikacin and S. marcescens, the time above the CSC and then the area under the concentration-time curve above the CSC predict efficacy (R = 0.74; F = 24.0; P = 0.0001). The lowest CSC is that of amikacin (about 8 mg/liter); those of gentamicin and tobramycin are about 15 mg/liter. In severe S. marcescens infections, intermittent amikacin dosing offers excellent bactericidal activity within the first 24 h.

Antibiotic Therapy for Severe Infections in Infants and Children

In infants and children, the absorption, distribution, metabolism, and excretion of drugs may differ considerably in comparison with these factors in adults; consequently, differences exist in therapeutic efficacy and toxicity of various antibiotic agents. Because of known toxicity, certain drugs--such as chloramphenicol in high doses, the sulfonamides, and tetracycline--should not be used in neonates. Antibiotic therapy should be modified in neonates because of biologic immaturity of organs important for the termination of drug action. Because of poor conjugation, inactivation, or excretion, the serum concentrations of many antibiotics may be higher and more prolonged in neonates than in older infants; thus, lower doses and longer intervals between administration may be necessary. In this article, we suggest dosages of antimicrobial agents for severe infections in children, older infants, and neonates. Included in the discussion are the cephalosporins, especially the third-generation cephalosporins that have assumed an important role in empiric treatment of bacterial meningitis in pediatric patients because of their ability to penetrate the central nervous system and their effectiveness against beta-lactamase-positive and negative strains of Haemophilus influenzae type b, Streptococcus pneumoniae, Neisseria meningitidis, and many gram-negative bacteria in the Enterobacteriaceae group. In patients with congenital or acquired immunodeficiencies, antifungal, antiviral, or anti-Pneumocystis agents are often added to the antimicrobial regimen for severe infections. We review the agents available for such treatment in children, the drugs used for childhood tuberculosis, and certain new antibiotics (aztreonam, ticarcillin-clavulanate, ciprofloxacin, and imipenem-cilastatin) that have proved useful in select cases but whose precise role in pediatric practice will necessitate additional clinical experience.

Antibiotic Therapy for Gram-negative Bacteremia

Although antibiotic therapy is the mainstay of therapy for gram-negative bacillary bacteremia, the amelioration of the underlying conditions, the correction of predisposing factors, the drainage of abscesses, the removal of infected foreign bodies, and adequate supportive care are also of paramount importance for curing the infection and should not be neglected. Beginning in the late 1960s, most of the clinical work on gram-negative infections has focused on the evaluation of new antibiotics. Numerous studies have shown that early, appropriate antibiotic treatment of gram-negative bacteremia significantly improved patients' outcomes and prevented the development of septic shock. Prescribing standard doses of antibiotics does not necessarily mean that therapeutic levels will be reached in all patients, and relapses of infections or breakthrough bacteremias can occur in patients with subinhibitory serum levels of antibiotics. The monitoring of serum concentrations of antibiotic is therefore recommended in critically ill septic patients. Whereas initial studies on the antibiotic treatment of gram-negative bacteremia were carried out in nonneutropenic patients, more recent clinical investigations have been performed almost exclusively in cancer patients with neutropenia. Studies conducted in the 1970s and 1980s among these patients have shown the following: (1) early empirical therapy reduced the mortality of gram-negative bacteremia; (2) therapy with a combination of two antibiotics, be it an extended spectrum penicillin plus an aminoglycoside or a third-generation cephalosporin, has significantly improved patients' outcomes; and (3) triple-drug combinations (i.e., a penicillin plus a cephalosporin plus an aminoglycoside) are not superior to combinations of beta-lactams and aminoglycosides. For the treatment of gram-negative bacteremia, clinicians today have a choice between well-established antibiotic combinations and broad-spectrum single-agent therapy with third-generation cephalosporins or carbapenem antibiotics. Although recent studies suggested that monotherapy could be as effective as combination therapy for the empirical treatment of fever in the neutropenic host, no definitive study has so far unquestionably demonstrated the equivalence of these treatments in patients with gram-negative bacteremias, especially those caused by P. aeruginosa, or in patients with adverse prognostic conditions, such as persistent and profound granulocytopenia. This literature should however be reviewed with great caution. Indeed, only a minority of studies have included a sufficient number of patients to confidently assess the impact of therapy on patients' outcomes. Obviously, small studies can have a significant risk of type II errors, that is, making false-negative conclusions.(ABSTRACT TRUNCATED AT 400 WORDS)