W. Eugene Sanders

Antimicrobial Resistance with Focus on β-Lactam Resistance in Gram-Negative Bacilli

beta-Lactam antibiotics are the most frequently prescribed antibiotics worldwide. Therefore, it is not surprising that resistance to this very important class of agents poses an increasingly complex and perplexing problem for physicians. Among the variety of mechanisms that can provide resistance to beta-lactam antibiotics in gram-negative bacilli, the production of beta-lactamase is by far the single most important factor. With the introduction of newer beta-lactam agents observed changes in beta-lactamases include the increased prevalence of older enzymes, the appearance of new enzymes, and alteration in the level of expression of the enzymes. These changes have been responsible for resistance to newer cephalosporins, monobactams, carbapenems, and beta-lactamase inhibitor/beta-lactam drug combinations. Resistance to beta-lactam antibiotics has also emerged through alterations in the targets of the drugs, the penicillin-binding proteins, and through alterations in outer membrane permeability of the organisms to the drugs. With some beta-lactam agents, multiple mechanisms must be acquired before clinically relevant levels of resistance are attained. This is especially true for carbapenems and fourth generation cephalosporins. Nevertheless, resistance to beta-lactam antibiotics is on the rise among clinical isolates of gram-negative bacilli, and only through more judicious use of these agents can their usefulness for treatment and prevention of infections be preserved.

Colonization of the oropharynx with gram-negative bacilli: A major antecedent to nosocomial pneumonia

The initiating event in the development of gram-negative nosocomial pneumonia is usually colonization of the oropharynx with gram-negative bacilli. Normally, the bacterial equilibrium of the oropharynx excludes gram-negative bacilli. This equilibrium is maintained by dynamic interactions involving recognition mechanisms and bacterial interference. Broad-spectrum antimicrobial therapy or serious illness may alter these interactions and lead to adherence of gram-negative bacilli to the oropharyngeal epithelial cells. Antibiotics appear to suppress normal bacterial inhibitors, allowing proliferation of gram-negative bacteria. Serious illness appears to result in availability of epithelial cell receptors for gram-negative bacteria. Conventional infection control measures often fail to prevent colonization. Effective additional measures may include (1) reduction of total antibiotic usage in the hospital, (2) selective administration of antimicrobial prophylaxis, and (3) exploitation of the natural interactions among bacteria and between bacteria and host cells to enhance resistance to colonization.

Toxic shock syndrome: An ecologic imbalance within the genital microflora of women?

Epidemiologic data suggested that toxic shock syndrome (TSS) may be caused by an imbalance among the flora of the female genital tract. Since natural defense mechanisms often involve antagonistic interactions between the flora and potential pathogens, the ability of genital lactobacilli to inhibit Staphylococcus aureus was determined in agar overlay assays. Lactobacilli were chosen for study because previous investigations had suggested an important role for this genus in maintenance of health of the female genital tract. Fourteen of 50 strains of lactobacilli and Lactinex inhibited the growth of certain staphylococci, including strains from cases of TSS. The inhibitory activity of some lactobacilli was variable and could be enhanced by exogenously supplied substrates. Growth of one consistently inhibitory lactobacillus was inhibited by Staphylococcus aureus. A model for the etiology of toxic shock syndrome in menstruating women is proposed. The model includes antagonistic interactions between lactobacilli and staphylococci and the influence of tampons on these interactions to favor the staphylococcus.

Microbiological Characterization of Everninomicins B and D

Everninomicins B and D are components of a complex of antibiotic substances produced by Micromonospora. Both were shown to be highly active inhibitors of growth of all gram-positive bacteria, Neisseria, and Bacteroides studied in vitro. Potency of activity appeared to be greater than that of chloramphenicol, but less than that of penicillin G, when assayed against strains susceptible to each of the drugs. The everninomicins were bacteriostatic for all strains tested, except group A streptococci. No facultatively anaerobic gram-negative bacilli were susceptible. Resistant mutants were selected with difficulty from susceptible staphylococci in the laboratory, and these demonstrated no cross-resistance to available antimicrobial agents. Most variations in media, growth conditions, or procedure of assay had little or no effect on antimicrobial activity. Only addition of serum or increase in inoculum size reduced antibacterial activity. Significant differences in activity of the two components were encountered infrequently; the B component was four- to sixfold more active against gonococci and group A streptococci, whereas the D component was fourfold more active against enterococci. Because of the high degree of in vitro activity and lack of resistance among susceptible genera of bacteria, the everninomicins clearly merit further careful study as potential therapeutic agents.

Long term epidemiological analysis of Citrobacter diversus in a neonatal intensive care unit.

A prolonged outbreak of Citrobacter diversus central nervous system infection among hospitalized term infants, peaking in 1979, ceased with establishment of nurse-patient cohorting. The outbreak was attributed to dissemination of an epidemic strain among infants in an antiquated neonatal intensive care unit. When C. diversus colonization recurred within the new neonatal intensive care unit in 1984, cohorting and bacteriologic surveillance were reinstituted. By utilizing biotypes, plasmid profiles and antibiograms, four different C. diversus strains were identified circulating during 1979. Strains recovered between 1984 and 1988 from neonatal intensive care unit infants were similar to those from community-acquired sources. A strain considered avirulent in 1979 was found causing bacteremia in two infants (one with central nervous system disease) in 1984 to 1988. During cohorting C. diversus acquisition was 0.019/patient-month; after cohorting ceased it was 0.017/patient-month. Multiple source introductions appeared to occur with different C. diversus strains, some causing infant disease. No efficacy of cohorting was evident.

Resistance to Antibacterial Agents

There are three major mechanisms whereby bacteria initially susceptible to an antimicrobial agent may acquire the ability to resist the effects of this agent. These include prevention of intracellular drug accumulation, alteration in the target of the drug, and production of a drug-inactivating enzyme. The relative importance of each of these mechanisms varies depending upon the organism involved, the antimicrobial agent, and the location of the target of the antimicrobial agent within the bacterial cell (Table 1).

Sisomicin: An Aminoglycoside Antibiotic that is Highly Effective against Pseudomonas

The in vitro activity of sisomicin against Pseudomonas is two- to eight-fold greater then gentamicin or amikacin, and similar to tobramycin. Minimal inhibitory concentrations of sisomicin are usually <1.0 μg/ml. Sisomicin interacts synergistically with a variety of penicillins against many Pseudomonas, including strains resistant to gentamicin. The degree of cross-resistance between sisomicin and other aminoglycosides varies depending upon mechanism. Many strains with inactivating enzymes are resistant to sisomicin, gentamicin and tobramycin. However, due to high intrinsic potency, sisomicin is active against many strains that are resistant to other aminoglycosides as a result of impermeability. Thus sisomicin is active against 4% to 66% of strains resistant to gentamicin, tobramycin or amikacin. The ability of sisomicin to protect animals from fatal Pseudomonas infections has been assessed in 29 paired tests with tobramycin and 36 paired tests with gentamicin. The dose of sisomicin in mg/kg required to protect 50% of animals from death is, on average, 1.5 times lower than tobramycin and 3.1 times lower than gentamicin. Sisomicin also interacts synergistically with carbenicillin or ticarcillin in treatment of experimental infections in animals. The human pharmacology of sisomicin is similar to gentamicin. Rates of adverse reactions to sisomicin are comparable to those seen with gentamicin or tobramycin. Clinical trials have shown sisomicin to be as effective, and in some instances more effective, than gentamicin, tobramycin, or amikacin. In several studies, the efficacy of sisomicin, administered in lower doses than gentamicin, was equal to or greater than gentamicin. Infections caused by gentamicin-resistant Pseudomonas have responded to sisomicin. Also, several patients who failed to respond to either gentamicin or tobramycin have been successfully treated with sisomicin. In view of its high intrinsic potency both in vitro and in vivo, sisomicin may become a preferred agent for treatment of serious Pseudomonas infections due to sensitive strains.