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Netilmicin and clindamycin were administered to 47 patients with an intraabdominal infection who underwent emergency laparotomy. Thirty-one patients were cured, seven were improved, and therapy failed in nine patients despite the fact that all aerobic bacteria isolated from these patients were sensitive to netilmicin as determined by standard in vitro susceptibility tests. The pH of peritoneal and drainage fluid collected intraoperatively and during follow-up correlated with clinical outcome. Acidic pH was found in 21 of 33 (64%) specimens sampled from patients with therapeutic failure compared to 17 of 80 (21%) obtained from the categories "cured" and "improved" (p < 0.001). Netilmicin concentrations in serum or peritoneal/drainage fluid did not correlate with clinical outcome. Netilmicin levels were above the minimal inhibitory concentration of the pathogens in 59 of 64 (92%) drainage fluid specimens in which aerobic bacteria were isolated. Aerobic bacteria were isolated in 91% of drainage fluid specimens if the pH was less than 7.0, compared to 37% if pH was more than 7.0 (p < 0.001). Reduction of pH antagonized aminoglycoside activity in vitro against clinical isolates of Escherichia coli. Surgical reexploration should be considered in cases of deterioration following a laparotomy associated with detection of acidic drainage fluid.

Milieu factors such as pH, pO2, and pCO2 have previously been shown to permit reliable intraoperative discrimination of infected and non-infected peritoneal or drainage fluid. The presence of infection was associated with pH less than 7.1, pO2 less than 6.5 kPa and pCO2 greater than 8 kPa. These variables were monitored in the immediate postoperative period to quantify clinical improvement and to evaluate their potential for the early detection of infective complications. 21 patients underwent laparotomy for intraabdominal infections such as perforated appendicitis or perforated sigmoid diverticulitis. 5 were operated on for reasons other than infection. Fluid was sampled from a drainage tube every second day for a mean period of 7 days for determination of pH, pO2, and pCO2. A score ranging from 0 (normal) to 6 (severely ill) was calculated from these measurements. Specimens were obtained intraoperatively from 14 patients with documented infections and their mean score averaged 5 (range 3-6). Specimens were obtained on days 4 and 6 from 18 patients whose progress was uneventful and their mean score was 0.3 (range 0-2). 4 of these 26 patients developed postoperative infections after anastomotic breakdown, and each of their scores increased 1-2 days before the infection became clinically obvious, reaching values ranging from 3-6. In contrast, only 1 of 18 patients who made uneventful progress scored greater than 2 after day 3 (p less than 0.01). We conclude that assessment of milieu factors in peritoneal or drainage fluid permits quick and easy monitoring of the postoperative course.

Interactions of combinations of netilmicin, amikacin, piperacillin, imipenem, azlocillin, ceftazidime or moxalactam were studied in vitro against Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus. Microtiter checkerboard technique was compared with standard killing curve method and with killing curves obtained in kinetic in vitro models mimicking single or multiple dosing regimens according to human pharmacokinetics. Antibiotic combinations were classified as antagonistic, indifferent or synergistic. Disagreement between classification by checkerboard and by kinetic model was found in 14 of 33 combinations studied (42%). Further analysis by standard killing curve method demonstrated that synergism or antagonism is a relative, not an absolute feature of drug combinations against given pathogens. Factors contributing to disagreements included the concentrations studied relative to the bacterial sensitivity, the ratio of concentrations of the two drugs tested, the size of the bacterial inoculum and the endpoint of the interaction assessment. Standard in vitro methods do not consider changes of antibiotic concentrations over time during combination therapy. Concentrations studied are defined according to bacterial sensitivity (fractions of MIC). Therefore, they may or may not relate to those at the infected site. The observed discrepancies between standard methods for testing drug interaction and a model which more closely reflects human pharmacokinetics support the argument that standard synergy testing provides incomplete data to reliably design clinical combination therapy.

Cefotaxime (HR 756) is a new semisynthetic parenteral cephalosporin with exceptional activity against gram-negative organisms and considerable stability against their beta-lactamases. To study its pharmacokinetic properties, 0.5-, 1-, and 2-g doses were administered to each of six volunteers intravenously over 15 min, followed by a sustaining infusions of 0.5, 1, and 2 g/h, respectively, for 3 consecutive hours. The loading doses produced mean peak levels of 41, 93, and 160 mug/ml, and mean steady-state serum concentrations were 27, 64, and 138 mug/ml, respectively. The mean terminal half-life was 75 +/- 7 min. The total volume of distribution averaged 0.22 +/- 0.03 liters/kg of body weight. Total body and renal clearances were 232 +/- 30 and 145 +/- 24 ml/min per 1.73 m(2), respectively; 63 +/- 9% of the administered dose was excreted through the kidneys in 24 h. To determine the effect of cefotaxime on the renal tubules, urinary alanine aminopeptidase excretion was measured before, during, and after the infusions. It remained within the normal range in all instances; however, 48 +/- 14% of the total daily alanine aminopeptidase output was recovered during the infusion period. Side effects were dose related and included fatigue, loose stools, and night sweats. No significant changes in hematology, serum chemistry, or urinalysis were recorded.

Ceftazidime, a new cephalosporin, is characterized by very good in-vitro action against P. aeruginosa. Nonetheless, clinical and (or) microbiological failure occurred in four patients with severe P. aeruginosa infections being treated with ceftazidime. Main cause infections being treated with ceftazidime. Main cause of the discrepancy between in-vitro and in-vivo results during treatment of three patients was a rapid drop in bacterial sensitivity. Superinfection with resistant microorganisms was excluded by the identity of the isolated bacteria in the different epidemiological markers before and during treatment. This rise in resistance was also demonstrated in-vitro by culturing clinically isolated material in ceftazidime-containing media: a 16-fold decrease in sensitivity was demonstrated within three subcultures. Increased beta-lactamase activity of the resistant strains makes it likely that enzymatic inactivation was part of the resistance mechanism. Good inducibility of beta-lactamases and absent resistance transfer argue for chromosomal localisation of the resistance. Because of the development of resistance, severe infections caused by P. aeruginosa should not be treated by ceftazidime alone. In order early to discover the development of resistance, microbiological samples should be taken periodically and examined for their sensitivity.

The pharmacokinetics of cefotaxime, moxalactam, and ceftazidime were investigated in six human volunteers who received in a crossover fashion doses of 0.5, 1.0, and 2.0 g of each drug by a 5-min infusion. Doses of 1.0 g were repeated after the administration of probenecid. Serum and urine concentrations were assayed with an agar diffusion method. Serum concentrations of moxalactam exceeded those of ceftazidime at all times and were distinctly higher than those of cefotaxime. The normalized area under the concentration time curve (defined as the ratio of the area under the curve per dose) reflects this relationship: compared with cefotaxime the normalized area under the curve of moxalactam was 3 to 4 times higher, and that of ceftazidime was 2 to 3 times higher. By intra-individual comparisons, the area under the curve of moxalactam was 44% larger than that of ceftazidime. With increasing doses, cefotaxime exhibited a nonlinear increase of the area under the curve. The half-lives of moxalactam, ceftazidime, and cefotaxime were 2.34, 1.95, and 1.16 h, respectively. The volume of distribution averaged 0.20 +/- 0.03, 0.23 +/- 0.02, and 0.25 +/- 0.04 liters per kg, and the mean total body clearance was 84, 131, and 328 ml/min for moxalactam, ceftazidime, and cefotaxime, respectively. The 24-h urinary recovery was highest for moxalactam (75 +/- 4%) followed by ceftazidime (68 +/- 11%) and cefotaxime (53 +/- 6%). The influence of probenecid on serum concentrations, half-life, area under the curve, and clearance was most apparent with cefotaxime, whereas the pharmacokinetics of moxalactam and ceftazidime were only slightly affected. After the 0.5- and 2.0- g doses of cefotaxime, desacetyl-cefotaxime activity (determined by high-pressure liquid chromatography) reached a peak of 2.7 and 9.9 mug/ml and declined with a half-life of 1.9 and 1.4 h. The ratio of the R(-) and S(-) epimers of moxalactam, which could be differentiated by high-pressure liquid chromatography, fell rapidly from 0.81 at 0.17 h to 0.5 at 5 h, indicating the presence of twice as much of the microbiologically less active S(-) epimer. From a pharmacokinetic standpoint it appears reasonable to conclude that moxalactam and possibly ceftazidime could be administered twice daily and that cefotaxime could be administered three or even four times daily.

Most conventional methods for in vitro testing of antibiotics involve exposure of a bacterial inoculum to a constant, static concentration of drug. The in vivo concentrations of antibiotics change continually according to their pharmacokinetics. When two drugs are used, the ratios of their concentrations also change with time. The usual checkerboard tests for combined activity of two or more antibiotics do not consider the pharmacokinetic properties. An in vitro two-compartment pharmacokinetic model has been developed that presents changing concentrations of one or two antibiotics to isolated bacterial inocula. This model simulates the treatment of a bacterial infection in the absence of host defenses and thus mimics infection in a neutropenic patient. This model has been used to study the synergistic activity of beta-lactam/aminoglycoside combinations compared with conventional checkerboard and time-kill methods. Also, in this model, the addition of azlocillin or ceftazidime to netilmicin prevented the selection of resistant subpopulations of Pseudomonas aeruginosa that occurred with the aminoglycoside alone. In vitro pharmacokinetic models add kinetic parameters to conventional susceptibility testing and may prove useful in the design of trials of the optimal dosing and administration of antibiotics for infected neutropenic patients.

The microbiology laboratory plays an important role both in choosing initial antimicrobial therapy and in monitoring such therapy during the course of treatment. In septicemic patients who have few, if any, clinical findings suggesting a specific etiologic diagnosis, it is useful to know the antibiotic susceptibility patterns for the given hospital or community. This type of empiric approach to therapy might require a larger variety of antibiotics than that usually considered for treatment of infected neutropenic patients. In the absence of neutropenia, there is perhaps more latitude in the initial choice, and single-drug therapy often can be considered. While patients are receiving antibiotics that should be appropriate for an identified pathogen, several laboratory procedures can be used to monitor this treatment. Antibiotic synergism studies may be useful in neutropenic patients, as well as assays of serum bactericidal activity. The serum bactericidal activity may be useful also in monitoring therapy for bacterial endocarditis or for osteomyelitis, especially when oral or home therapy is considered. Similarly, drug levels may be measured by a variety of techniques to ensure appropriate serum concentrations and to minimize drug toxicity. In addition, the preclinical evaluation of antibiotics alone and in combination can be used in guiding the design of clinical studies of these drugs in certain patient groups, such as neutropenic patients.

A double-blind study was designed to test the hypothesis that local side-effects during i. v. administration of erythromycin lactobionate depend on the drug concentration and that they can therefore be minimized by dissolving erythromycin in a larger infusion volume. Forty healthy students were assigned in a randomized sequence to four 30 min infusions: 120 and 250 ml of erythromycin lactobionate (1 g in 0.9% NaCl) and 120 and 250 ml of placebo (0.9% NaCl). An unexpectedly high incidence (95% and 80% for the infusion volumes of 120 and 250 ml, respectively) of severe systemic side-effects was observed during the first 79 infusions. Because all of these systemic side-effects were associated with the infusion of erythromycin, the study was terminated at this point. Side-effects included abdominal cramps, nausea, vomiting, dizziness and profuse sweating. The postulated positive effect of lower erythromycin concentrations in the infusion on local side-effects (pain at the infusion site, erythema) was marginal (63% vs. 45%). Compared to the systemic side-effects, the problem of local tolerance is less important. In young adults, 30 min infusions of 1 g erythromycin lactobionate are associated with a high incidence of systemic side-effects which may be due to an age-dependent effect of the drug on smooth muscle.

Recommendations for optimal therapeutic peak concentrations of aminoglycosides are often not differentiated with respect to duration of infusion and timing of peak sample thereafter. To document the relevance of the timing, 139 dose intervals were analyzed in 58 patients during administration of gentamicin, amikacin, and netilmicin. Serum concentrations measured immediately after 30-min infusions were compared with concentrations obtained 90 min later (2 h values). The ratio of 30 min/2 h concentrations showed considerable variability. This ratio was less than 1.5 in 15% of the dose intervals analyzed and greater than 3 in 8% of the intervals. The poor correlation between concentrations measured at 30 min and at 2 h was documented by the coefficients of variation of 0.82, 0.30, and 0.67 for gentamicin, amikacin, and netilmicin, respectively. This variability was not explained by interindividual differences, renal function, or drug half-life. However, the initial decrease in concentrations was significantly lower in patients with impaired renal function (p less than 0.001). These data suggest that timing is critical for the sampling of serum to determine peak levels in patients and the definition of optimal therapeutic concentrations.

Neutropenic patients are at risk of serious infection caused by gram-negative bacilli and staphylococci. The mortality rate associated with gram-negative bacteremia in these patients is extremely high, especially in those with persistent and profound granulocytopenia. In these latter patients, the best results have been obtained by administering combinations of antibiotics in which both agents are active and/or show in vitro synergism against the infecting organism. Most combinations include an aminoglycoside such as amikacin and a broad-spectrum beta-lactam antibiotic, such as azlocillin, mezlocillin, piperacillin, or ceftazidime. The International Antimicrobial Therapy Project Group of the European Organization for Research and Treatment of Cancer has completed several studies evaluating various antibiotic combinations in the empiric treatment of febrile neutropenic patients. These trials have evaluated cephalothin plus gentamicin, carbenicillin plus gentamicin, and cephalothin plus carbenicillin; carbenicillin plus amikacin and carbenicillin plus amikacin plus cefazolin; azlocillin plus amikacin, ticarcillin plus amikacin, and cefotaxime plus amikacin; and azlocillin plus amikacin versus ceftazidime plus long- or short-course amikacin. The preclinical evaluation of antibiotic combinations usually involves the in vitro testing of antibiotics alone and in combination by the checkerboard method or with the use of time-kill curves. However, these methods expose the bacterial culture to a static or constant concentration of the drugs. During the in vivo treatment of infections, bacteria are exposed to changing concentrations of antibiotics, which are contingent on the individual pharmacokinetics of these drugs. We have designed a two-compartment in vitro pharmacokinetic model that allows the simultaneous study of the activity of two antibiotics with similar or different half-lives against a number of bacteria. Amikacin and azlocillin have been studied alone and in combination in this model against Pseudomonas aeruginosa, a frequent cause of bacteremia in neutropenic patients. In pharmacologically relevant doses, amikacin alone produced rapid bacterial killing, followed by regrowth of resistant subpopulations. Azlocillin alone produced a more gradual reduction of the bacterial inoculum, with ultimate bacteriostasis. Amikacin plus azlocillin produced rapid and complete eradication of the organism. In vitro pharmacokinetic models may prove to be more predictive of clinical outcome than are traditional static in vitro methods used to study antibiotic combinations.

The prevalence of HIV antibodies in various groups at risk was studied in 1,546 persons in Zürich. The prevalence was 17% (39/236) in homosexual men, 7% (13/180) in bisexual men, and 45% (14/31) and 42% (22/53) in female and male intravenous drug abusers, respectively. Heterosexual transmission appeared to be the route of infection in four seropositive persons (two women and two men) who had no homosexual contacts and were not drug abusers (4/1050).