Antimicrobial agents are most often tested against bacteria in the log phase of multiplication to produce the maximum bactericidal effect. In an infection, bacteria may multiply less optimally. We examined the effects of several classes of antimicrobial agents to determine their actions on gram-positive and gram-negative bacteria during nongrowing and slowly growing phases. Only ciprofloxacin and ofloxacin exhibited bactericidal activity against nongrowing gram-negative bacteria, and no antibiotics were bactericidal (3-order-of-magnitude killing) against Staphylococcus aureus. For the very slowly growing gram-negative bacteria studied, gentamicin (an aminoglycoside), imipenem (a carbapenem), meropenem (a carbapenem), ciprofloxacin (a fluoroquinolone), and ofloxacin (a fluoroquinolone) exhibited up to 5.7 orders of magnitude more killing than piperacillin or cefotaxime. This is in contrast to optimally growing bacteria, in which a wide variety of antibiotic classes produced 99.9% killing. For the gram-positive and gram-negative bacteria we examined, antibiotic killing was greatly dependent on the growth rate. The clinical implications of slow killing by chemotherapeutic agents for established bacterial infections and infections involving foreign bodies are unknown.

Reference strains of Escherichia coli (ampicillin-susceptible and -resistant ATCC strains, and known TEM-1 and TEM-2 beta-lactamase producers) were tested in vitro and in the in-vivo mouse thigh infection model against four beta-lactamase inhibitor compounds (BICs: amoxycillin/clavulanic acid, ampicillin/sulbactam, ticarcillin/clavulanic acid, and piperacillin/tazobactam), selected cephalosporins, and imipenem. The ATCC strains (ampicillin-susceptible and -resistant) were susceptible to the BICs in disc and MIC tests. Three or more logs of killing were observed at the NCCLS breakpoint concentrations. However, the TEM-1 and TEM-2 producers were resistant in disc tests to ampicillin/sulbactam and amoxycillin/clavulanic acid, and showed intermediate susceptibility to ticarcillin/clavulanic acid. MICs were at or near the breakpoint, but bactericidal activity was only noted at the probable breakpoint concentration of piperacillin/tazobactam. Cefoxitin, cefotaxime, cefpirome and imipenem, but not cephalothin, showed greater bactericidal activity and lower MICs for the TEM-producing strains than the BICs. The viable count of the TEM-1 producer was not reduced in the mouse thigh model by ampicillin/sulbactam or amoxycillin/clavulanic acid, but cefpirome and cefotaxime reduced the viable count by approximately three logs. There was a 50% mortality rate in mice receiving the two BICs. The ampicillin-susceptible ATCC strain of E. coli was killed to a similar degree by all agents tested. Overall, the BICs appeared inferior, in both in-vivo and in-vitro tests to selected cephalosporins and imipenem when tested against reference strains of E. coli producing TEM-1 or TEM-2 beta-lactamase. The large inoculum effect and poor bactericidal activity observed with the BICs suggest they could be less effective in certain clinical situations.

Thirty patients were treated for colonization or for skin and soft tissue infections caused by methicillin-resistant Staphylococcus aureus. Three treatment regimens were evaluated, each progressively more aggressive. Our regimen was 750 mg of ciprofloxacin twice daily for 5 days, the second regimen was 750 mg of ciprofloxacin twice daily for 10 to 14 days, and the final regimen was 750 mg of ciprofloxacin twice daily plus 300 mg of rifampin twice daily for 21 days. It appears that ciprofloxacin alone produced an initial eradication rate in at least one site in 50% of the patients, regardless of whether the treatment was for 5 or up to 14 days. All of the patients with eradication became recolonized within 1 week posttherapy. When rifampin was combined with ciprofloxacin, the eradication rate was 100% when the isolates were susceptible to both agents, and these patients remained free of methicillin-resistant S. aureus at 1-week and 1-month follow-ups.

A review of the world literature on the penetration (ratio of concentrations of cerebrospinal fluid to concentrations of serum) and attainable antibiotic concentrations in the cerebrospinal fluid in humans for cefuroxime, cefoxitin, cefotaxime, ceftizoxime, cefmenoxime, cefamandole, cefoperazone, moxalactam, ceftazidime, and ceftriaxone indicates that, with the exceptions of cefamandole and cefoperazone, all agents appear equivalent. We conclude that the choice of cephalosporin for the treatment of acute bacterial meningitis should depend mainly on the potency of the agent for the specific meningeal pathogens in question. For the treatment of common meningeal pathogens (Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis) and for gram-negative bacilli, mainly Escherichia coli and Klebsiella (excluding Pseudomonas aeruginosa), the cefotaxime-ceftriaxone group of cephalosporins has accrued the most clinical experience and the most pharmacokinetic data, while for P. aeruginosa the major interest has centered on ceftazidime.

This study explored the use of D-lactic acid as a marker for bacterial infections. D-Lactic was produced by frequently encountered human bacterial pathogens under anaerobic growth conditions; Bacteroides fragilis produced the largest amount. Orally administered D-lactic acid was absorbed from the intestines of rats and later found in measurable quantities in the blood and urine. Eunephric and anephric rats that received D-lactic acid intravenously showed similar quantities of this metabolite in the blood. These quantities are consistent with the distribution of D-lactic acid to total body water. Isolated liver and lung tissues from rats did not metabolize or produce D-lactic acid. Rats with experimentally induced, sublethal klebsiella peritonitis had D-lactic acidemia of 0.2 mM and 25.6 mM at 0 and 6 hr of infection, respectively. In a normal human, D-lactic acid was detected in the urine and blood after a subcutaneous injection of D-lactic acid, and pharmacokinetics of elimination similar to those of rats were found.

Ciprofloxacin, a carboxy quinolone antibiotic with a broad spectrum of activity, was tested against 54 strains of methicillin-resistant Staphylococcus aureus. The ciprofloxacin MICs for 50 and 90% of the isolates were 0.25 and 0.5 micrograms/ml, respectively, and its MBC for 90% of the isolates was 1.0 microgram/ml. Killing kinetic studies were conducted in vitro with ciprofloxacin and vancomycin individually and in combination. The results of these studies showed that ciprofloxacin at 2 micrograms/ml and vancomycin at 10 micrograms/ml decreased the number of organisms by approximately 1.5 log10 after 6 h. The combination of ciprofloxacin plus vancomycin did not alter the rate of killing over that achieved by ciprofloxacin alone. The in vitro killing of resistant staphylococci was rapid, and the potential use of ciprofloxacin for infections caused by methicillin-resistant S. aureus should be further explored.

Recovery from the urine of organisms causing bacteraemia may depend on the bacterial species involved. The survival of the more common species of bacteria which cause bacteraemia was examined in human urine, serum and normal saline. All species survived well or grew in serum. Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus sanguis and group A streptococci were killed in all urine samples. The number of colony-forming units of Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus and group B streptococci either remained the same or increased in the urine, while the numbers of Escherichia coli and Klebsiella pneumoniae increased rapidly. These data suggest that the observed differences in recovery from urine of these bacterial species that cause bacteraemia are related to the viability of the species in human urine.

A fresh extract of garlic (Allium sativum) was administered orally to human volunteers. At intervals, serum and urine were collected and assayed for antifungal activity. The maximum tolerable dose was determined to be 25 ml of garlic extract. Larger amounts caused severe burning sensations in the esophagus and the stomach and vomiting. After oral ingestion of 25 ml of the extract, anticandidal and anticryptococcal activities were detected in undiluted serum 0.5 and 1 h after ingestion. No detectable antifungal activity was found in the excreted urine at any time after oral ingestion. Oral garlic is of limited value in the therapy of human fungal infections.

The dematiaceous fungi comprise a group of organisms that are deeply pigmented and found in soil or on decaying organic material, such as wood. The majority of infections with these fungi presumably results from traumatic inoculation. Although various forms of infection have been appreciated for some time, none of the presently available antifungal drugs have been shown to have predictable activity against these organisms. We report on the activity in vitro of various antifungal agents alone and in combination against various dematiaceous fungi.