Clinical relevance of bacteriostatic versus bactericidal mechanisms of action in the treatment of Gram-positive bacterial infections.

The distinction between bactericidal and bacteriostatic agents appears to be clear according to the in vitro definition, but this only applies under strict laboratory conditions and is inconsistent for a particular agent against all bacteria. The distinction is more arbitrary when agents are categorized in clinical situations. The supposed superiority of bactericidal agents over bacteriostatic agents is of little relevance when treating the vast majority of infections with gram-positive bacteria, particularly in patients with uncomplicated infections and noncompromised immune systems. Bacteriostatic agents (e.g., chloramphenicol, clindamycin, and linezolid) have been effectively used for treatment of endocarditis, meningitis, and osteomyelitis--indications that are often considered to require bactericidal activity. Although bacteriostatic/bactericidal data may provide valuable information on the potential action of antibacterial agents in vitro, it is necessary to combine this information with pharmacokinetic and pharmacodynamic data to provide more meaningful prediction of efficacy in vivo. The ultimate guide to treatment of any infection must be clinical outcome.

Circadian hypo- and hyper-amplitude-tension (CHAT) associated with putative pheochromocytoma and 12-hourly phenoxybenzamine treatment.

A 26-year-old white woman had an ablated sino-atrial node and ventricular pacemaker as an unusual feature of a pheochromocytoma-compatible history. Her status quo included, on three occasions, elevated 24-hour urinary epinephrine and metanephrine excretion. She monitored her blood pressure (BP) and heart rate (HR) at 15- to 60-minute intervals over several days, with interruptions, before and after the institution of 10 mg phenoxybenzamine per os every 12 hours (between 7:30 and 8:00 and between 19:30 and 20:00), with continued monitoring over several months. Her data were summarized for consecutive 3-day intervals by sphygmochron. Circadian parameters and original data are compared with gender- and age-specified reference values, yielding also non-parametric endpoints, such as the percentage time elevation, the extent of excess, and the timing of excess, that all can be acceptable for some days but unacceptable for other days. In her broader time structure, or chronome, cosinor analyses revealed a prominent and statistically significant circadian rhythm in BP and HR before and during the 12-hourly therapy. The 12-hour component of BP was more prominent during therapy than prior to it. A statistically significant decreasing trend occurred before therapy, and recurred during treatment. Chronomically interpreted monitoring revealed: 1) the persistence of a statistically significant circadian rhythm during 12-hourly phenoxybenzamine treatment; 2) days-long changes in BP MESOR, the duration of which could not be previously determined based on spotchecks; 3) changes in the circadian amplitude of BP, which can be either very small or very large, compatible with the diagnosis of intermittent circadian hyper-amplitude-tension (CHAT); and 4) a very wide range of BP and HR values, so that occasional (casual) measurements fail to convey the dynamics that may underlie this infrequently found clinical condition of an elevated catecholamine excretion compatible with a pheochromocytoma. All findings support the need for long-term monitoring of BP and HR that may account for controversy in earlier publications.

In vitro activity of ceftriaxone and other cephalosporins against 602 clinical isolates of staphylococci from geographically diverse medical centers.

The in vitro activity of ceftriaxone and six additional antimicrobial agents (ceftizoxime, cefoperazone, cefuroxime, fleroxacin, ciprofloxacin, and trimethoprim/sulfamethoxazole) was assessed or 602 recent clinical isolates of staphylococci from six geographically distinct medical centers in North America. All seven antimicrobial agents were active (90-100% of strains susceptible) against oxacillin-susceptible (OS) strains of Staphylococcus aureus (OSSA) and coagulase-negative staphylococci (OSCNS) but had limited activity against oxacillin resistant (OR) staphylococci. Our assessment of the in vitro antistaphylococcal activity of ceftriaxone against contemporary isolates of Staphylococcus aureus and coagulase-negative staphylococci indicates that the activity versus OS staphylococci has not changed over the past decade despite widespread use of the drug. It appears that these agents will continue to be useful for empiric therapy in those centers in which OR strains are uncommon.

Therapeutic and epidemiologic recommendations to reduce the spread of type-I beta-lactamase resistance.

The objectives of this United States Consensus Panel meeting were to evaluate the effectiveness of current surveillance systems for the detection of bacterial resistance as well as to formulate recommendations that can assist hospitals in determining actions that should be taken when a resistance problem is detected. These recommendations may be particularly helpful in controlling the emergence and spread of type-I beta-lactamase resistance. Numerous case reports of antimicrobial resistance among Enterobacter species, Pseudomonas aeruginosa, and other Gram-negative nosocomial pathogens known to produce type-I beta-lactamases have appeared in the literature since the introduction of the newer "third-generation" cephalosporins. The widespread use of these newer antimicrobial agents, often selected as standard therapy for serious hospital-acquired infections, has been associated with a corresponding increase in resistance to them. The failure of hospitalwide surveillance methods to describe the scope of this problem, especially among the most critically ill patients, may have resulted in a false sense of security among some infectious disease specialists and clinicians prescribing these antimicrobials as empiric therapy. High-level resistance in individual hospital units may be masked in hospitalwide antibiograms. A variety of conclusions and recommendations were formulated based on the collective experiences of the Consensus Panel members. Microbiology laboratories must make it a high priority to identify markers that will assist in rapidly identifying resistant organisms. Cooperative efforts are needed among users of commercial and automated microbiology test instruments to standardize results and to improve quality control, thereby making the data more directly comparable between laboratories.(ABSTRACT TRUNCATED AT 250 WORDS)

Penetration of aztreonam into human cerebrospinal fluid in the presence of meningeal inflammation.

Cerebrospinal fluid of aztreonam were measured in 11 patients with meningeal inflammation. Two to eight hours after a single 2 gm intravenous dose, CSF aztreonam levels ranged from 0.76 to 16.6 mg/l. The mean CSF concentration in four patients with viral meningitis was 1.28 mg/l, which was lower than the mean concentration of 7.2 mg/l in the five with bacterial, cryptococcal or carcinomatous meningitis. Two patients with infected subdural drains were also sampled serially and had CSF levels greater than 1 mg/l between 1 and 8 h post dose. Penetration of aztreonam into the CSF in the presence of meningeal inflammation appears adequate to warrant therapeutic trials in patients infected with susceptible organisms.

Increased minimum inhibitory concentrations with anaerobiasis for tobramycin, gentamicin, and amikacin, compared to latamoxef, piperacillin, chloramphenicol, and clindamycin.

Minimum inhibitory concentrations (MICs) were determined under both routine aerobic and anaerobic conditions for a total of 93 organisms representing nine genera. MICs for the aminoglycosides amikacin, gentamicin, and tobramycin were significantly increased under anaerobic conditions. Tobramycin was most sensitive to the loss of antimicrobial activity with anaerobiasis. MICs for staphylococci were increased by a higher factor than were MICs for gram-negative rods, but even within the latter group increases in MICs for Proteus species were greater than for Salmonella, Klebsiella and Escherichia coli. No change of anaerobic versus aerobic activity was seen for latamoxef, piperacillin, chloramphenicol, or clindamycin.

Biochemical and physiologic basis for susceptibility and resistance of Pseudomonas aeruginosa to antimicrobial agents.

The mechanisms involved in the susceptibility and resistance of Pseudomonas aeruginosa to antimicrobial agents are varied. For the beta-lactam agents, susceptibility of the organism is dependent on penetration of the outer membrane, binding to target proteins, absence of significant beta-lactamases, and, possibly, the initiation of cell wall lysis. Susceptibility to aminoglycosides is based on membrane permeation and transport and specific binding to the 30S ribosomal subunit. Antipseudomonal activity of the polymyxins is related to their binding to membrane phospholipids, with subsequent disruption of the membrane; and activity of tetracycline and erythromycin, which is pH-dependent, affects protein synthesis. Resistance to beta-lactam agents is mediated through beta-lactamases, the Id and V enzymes being especially important in P. aeruginosa. Other postulated mechanisms of resistance include the presence of a permeability barrier, insensitivity of target sites, decreased binding, and "trapping." Decreased binding to the S12 protein (often termed the P10 protein in references to streptomycin), decreased active transport, and enzyme-mediated modification are the major mechanisms responsible for resistance to aminoglycosides. The factors involved in resistance to tetracycline and erythromycin remain unclear. The emergence of resistance during a single course of beta-lactam therapy is a special problem with P. aeruginosa and may be due to acquisition of resistance genes, cross-infection, selection or induction of resistance in some variants, or mutation.

The outlook for prevention and treatment of infections due to Pseudomonas aeruginosa.

Control measures based on careful hospital surveillance are aimed primarily at minimizing environmental sources of Pseudomonas aeruginosa. Other important aspects of epidemiologic control include aggressive evaluation of outbreaks and limitation of antimicrobial use. Potent new antimicrobial chemotherapy has been developed, with most new agents of the beta-lactam and aminoglycoside classes. In spite of these developments, the likelihood of drug resistance seems great and the search for novel compounds continues. Of greatest appeal are approaches that augment host defences. Replacement or supplementation of circulating phagocytic cells is conceptually attractive, but this approach has encountered major technical problems and complications. More recently, there has been important progress in developing immunologic approaches aimed at augmenting circulating antibodies. Development of monoclonal antibodies and new methods for preparing hyperimmune globulins has produced forms of intervention that must be tested by clinical trials, but not all patients may benefit from augmentation of circulating antibodies to P. aeruginosa.

Mechanisms of resistance to beta-lactam antibiotics in strains of Staphylococcus aureus.

There are three major mechanisms of resistance of Staphylococcus aureus to beta-lactam antibiotics: enzyme mediated (penicillinase or beta-lactamase) by which the antibiotic is inactivated; intrinsic, which is not due to drug inactivation, and accounts for methicillin-resistance; and tolerance, in which there is a dissociation of the inhibitory and killing actions of beta-lactam antibiotics. In enzyme-mediated resistance, there are at least three different staphylococcal beta-lactamases, which probably account for differences in the inoculum effect with different cephalosporins. The intrinsic resistance is associated with differences in the affinity of beta-lactams for penicillin-binding proteins, but intrinsic resistance is probably more complex, because the pH of the medium, chelating agents, visible light, and temperature also effect its expression. Tolerance is clearly due to decreased autolytic enzyme activity (reflecting persistence of an enzyme inhibitor) of those tolerant organisms that need 32 (or more) times as much antibiotic for a bactericidal effect as for simple inhibition.

Comparison of 4 and 10 days of doxycycline treatment for urinary tract infection.

A total of 105 ambulatory patients presenting with symptoms suggestive of cystitis was allocated randomly to a 4 or a 10-day course of doxycycline therapy. Of these patients 62 (59 per cent) had documented infections and 41 (66 per cent) were infected with doxycycline-sensitive organisms: 24 were randomized to a 4-day course and 17 to a 10-day course of antibiotic. The groups were similar with respect to age, history of urinary tract infection, bacteriology and site of infection. Of the 4-day treatment group 90 per cent were free of infection 42 days after completion of therapy, compared to 92 per cent in the 10-day treatment group. Thus, patients with symptoms of cystitis may be treated with a short course of an appropriate antibiotic, provided careful followup is made 4 to 6 weeks after cessation of therapy. The site of urinary infection of doxycycline-resistant and sensitive organisms was determined by the antibody-coated bacteria techniques in 56 episodes: 13 (23 per cent) originated in kidneys, 34 (61 per cent) originated in bladder foci and the results in 9 (16 per cent) were indeterminate. Results of the antibody-coated bacteria technique did not predict therapeutic outcome.

Urinary tract infections in the female.

Special problems peculiar to urinary tract infections (UTIs) in the female include higher frequency than in males, recurrent infections, restrictions on antibiotic use during pregnancy, and the "urethral syndrome." Current concepts in the management of UTI include recognition of significant infection with total count of less than 100,000 organisms per milliliter; awareness that untreated UTI usually does not lead to progressive renal failure; importance of differentiating between upper and lower UTI; use of antibody coating of bacterial for distinguishing upper from lower UTI; evidence that 1-day (or single-dose) therapy may be adequate for cystitis, whereas pyelonephritis usually requires treatment beyond 2 weeks; evidence of effective prophylaxis; and indications that Chlamydia may be responsible for some cases of urethral syndrome.

Achievements and problems from the view of a physician.

Penicillin made possible the cure of many common, and also the most serious, infections, such as meningococcal meningitis and bacterial endocarditis, often with few or no sequelae. Endocarditis had been invariably fatal. Semisynthetic penicillins added new dimensions of convenience of administration and a broader spectrum in the presence of many beta-lactamases. A quantum step forward was permitted by the derivatives of cephalosporin C. Specific clinical advances were (1) the opportunity to use these in some penicillin-allergic patients, (2) activity against wider range of Gram-negative bacilli, (3) activity against Bacteroides fragilis (cefoxitin), (4) more complete renal excretion after oral cephalosporins than with oral penicillins, and (5) delayed renal excretion. Major remaining problems limiting beta-lactam use are (1) allergy, (2) resistant organisms, (3) relatively poor entry into the cerebrospinal fluid (especially of cephalosporins, (4) some nephrotoxicity, (5) local irritation of veins and tissues during administration, and (6) poor results in patients with agranulocytosis.

Isolation of Chlamydia trachomatis from the lower respiratory tract of adults.

Chlamydia trachomatis was isolated from the lower respiratory tract of six patients who had pulmonary infection, the severity varying from acute bronchitis to severe diffuse interstitial pneumonia. The latter appeared in four immunosuppressed patients, from three of whom cytomegalovirus was also isolated. Therapy directed against C. trachomatis resulted in prompt clinical improvement in three patients. Two patients died. C. trachomatis causes disease in the adult respiratory tract, the prevalence of which has yet to be determined, and it may be an important cause of morbidity and mortality in the immunosuppressed patient.

Antibiotic sensitivity and synergism of 'penicillin-tolerant' Staphylococcus aureus.

15 Staphylococcus aureus strains were isolated from 15 patients with staphylococcal bacteremia. Eight of these strains were shown to be tolerant for cloxacillin. Cloxacillin-tolerant strains were also tolerant for most of the cephalosporins tested except for cephapirin. Strains were not tolerant for clindamycin and gentamicin. Penicillin-tolerant staphylococci showed a high degree of synergism between gentamicin and cloxacillin or cephalothin and gentamicin.