[P&S Medical Review:Nov:93] Antibiotic Resistance--Its Impact on a Great Medical Center in the Last 30 Years

P&S Medical Review: Nov 1993, Vol.1, No.1
Antibiotic Resistance--Its Impact on a Great Medical Center in the Last 30 Years

HAROLD C. NEU, M.D.
Departments of Medicine and Pharmacology Columbia University College of Physicians and Surgeons, New York, NY.

In the 30 years that I have been at the Columbia-Presbyterian Medical Center (CPMC) and Columbia University, many new antibiotics have been discovered in nature or synthesized. In 1960, there were only two penicillins (penicillin G and V), three oral tetracyclines, three sulfonamides, one aminoglycoside for parenteral use (streptomycin), chloramphenicol, and one macrolide (erythromycin). Today there are more than 50 penicillins, 75 cephalosporins, 12 tetracyclines, nine aminoglycosides, three carbapenems, one monobactam, nine macrolides, three dihydrofolate reductase inhibitors, and at least 20 fluoroquinolones. Given this huge array of antimicrobial agents, it would seem that an individual could not possibly die of an infection in a hospital such as the Milstein Hospital at CPMC. Unfortunately, that is not true, and indeed one could not only die in CPMC but also in New York Hospital, San Francisco General, or the Massachusetts General Hospital. This is a result of the development of resistance by many of the bacteria that one encounters both in the hospital and more recently in the community setting.[1]

This article will address what particular effect resistance has had upon antimicrobial therapy at CPMC over the last 30 years. During this period of time our division has studied virtually every class of antimicrobial agent available throughout the world. In many cases we have been the first to study the human pharmacology of the drug and to perform the initial clinical trials which have been published in the American and European literature (Table 1).

Antibiotics that effectively inhibit bacterial cell wall synthesis include the beta-lactams, penicillins, cephalosporins, monobactams, carbapenems, penems and drugs such as the glycopeptides, vancomycin, and the soon to be available teicoplanin (Table 2). Many drugs interfere with protein biosynthesis. These include 50S ribosome inhibitors such as clindamycin, chloramphenicol, and the macrolides, three of which are now available in the United States. The 30S ribosome inhibitors include the tetracyclines and aminoglycosides. Within the last two decades, DNA directed RNA polymerase inhibitors such as rifampin for Mycobacterium tuberculosis and recently rifabutin, for the therapy of Mycobacterium avium infection, have become available. There are a large number of DNA gyrase inhibitors such as ciprofloxacin and ofloxacin. The brilliant work of George Hitching and Gertrude Elliot showed that a combination of trimethoprim with a sulfonamide (TMP/SMX) would synergistically inhibit bacterial folic acid metabolism. This provided an important antibiotic combination for bacterial infections, but now TMP/SMX is also a mainstay for treatment and prevention of Pneumocystis carinii in AIDS patients.

Unfortunately, bacterial antibiotic resistance can develop as a result of a chromosomal mutation, inductive expression of a latent chromosomal gene, or by exchange of genetic material through transformation, transduction or conjugation by plasmids or transposons. Plasmid transfer of DNA is extremely common among the Enterobacteriaceae, Haemophilus, Neisseria gonorrhoeae, and Pseudomonas species which cause infections both within the hospital and within the community.

Most recently it has been shown that organisms such as Enterococcus have the ability to transfer genetic material to other gram-positive species, thereby providing resistance to hemolytic streptococci, pneumococci, and recently to Staphylococcus aureus.[2] Over the last 30 years, organisms such as Streptococcus pneumoniae have acquired multiple genes controlling production of transpeptidases from oral streptococci, making it extremely difficult to inhibit some S. pneumoniae with beta-lactams.

Table 1

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TABLE 1.  ANTIBIOTICS INVESTIGATED BY THE DIVISION OF INFECTIOUS
          DESEASES AT CPMC
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Carbenicillin*           Cefazaflur          Amoxicillin*
Cefsulodin*              Tobramycin*         Cefsulodin*
Cefacetrile              Moxalactam          Cefanone
Cefuperazone*            Cefoxitin*          Trimethoprim/
Cefamandole*             Ticarcillin         sulfamethoxazole*
Ceftizoxime*             Macillinam*         Thiamphanicol
Netilimicin*             Imipenem*           Sisomicin 
Piperacillin*            Amikacin*           Ceftazidime*
Iperacillin*             Aztreonam*          Cefaclor*
Tigemonam                Cefuroxime*         Apalcillin
Azlocillin*              Norfloxacin*        Mezlocillin*
Cefmenoxime              Netilmicin*         Temocillin
Ipemacin                 Fosmidomycin        5-episisomicin
0-demethylfortimicin     Cefotaxime*         Cefodizime
Clavulanate*             Ofloxacin*          Sulbactamm*
Enoxacin*                Enoxacin*           Cefutriazine
Pefloxacin               Courmermycin        Cefixime*
Amoxicillin/             Tecarcillin/        Ampicillin/
  clavulanate*             clavulanate*        sulbactam*
Cefpirome                Cefepime            Cefotetan*
Cefpiramide              Cefbuperazone       Foramidocillin
Clarithromycin*          Ceftetrame          Cefetamet
Daptomycin               Teicoplanin         Temafloxacin
Lomefloxacin*            Tosufloxacin        Tazobactam
Azithromycin*            Dirithromycin       Levofloxicin
Loracarbef*              Cefdinar            Fosfomycin
Cefprozil                Fleroxacin          Meracidin
Fluconazole*             Cefcanel            Mithromycin

*Available in US
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Antimicrobial agents are rendered inactive by three major mechanisms. The first is inactivation either by destruction, such as occurs with the beta-lactamases, or by a major modification of the compound so that it does not bind to its target as is seen with the aminoglycosides and chloramphenicol. A second mechanism is prevention of access to the target. For example, in gram negative organisms the outer membrane proteins may be altered such that antibiotics are unable to cross the cell wall. In some organisms, such as those which cause sexually transmitted disease, resistance to tetracycline is due to a protein which modifies the receptor on the 30S ribosome. The third mechanism of resistance which has become increasingly important is change in the target site. For example, in staphylococci a new transpeptidase which is generally referred to as a penicillin binding protein (PBP) is produced by the microorganism. This new PBP2a does not bind any beta-lactam compound, i.e., penicillin, cephalosporin, monobactam, or carbapenem. This mechanism has also been utilized to change the target of drugs such as erythromycin and the new macrolides, clarithromycin and azithromycin. Methylation of adenine in a loop of the 16S component of the 23S rRNA allows protein synthesis to procede normally. Organisms causing urinary tract infections and diarrhea such as Escherichia coli, Salmonella and Shigella have plasmids which produce a new dihydrofolate reductase that has a low affinity for trimethoprim and sulfonamides.

REFERENCES

1. Neu HC. The crisis in antibiotic resistance. Science 1992;257:1064-1073.

2. Courvalin P. Resistance of enterococci to glycopeptides. Antimicrob Agents Chemother 1990;34:2291-2296.

3. Neu HC, Davidson S, Briones F. Intravenous/oral ciprofloxacin therapy of infections caused by multiresistant bacteria. Am J Med 1989;87(Suppl 5A):209-212.

4. Neu HC and Swarz H. Carbenicillin: clinical and laboratory experience with a parenterally administered penicillin for treatment of Pseudomonas infections. Ann Intern Med 1969;71:903-911.

5. Parry MF, Neu HC. A comparative study of ticarcillin plus tobramycin versus carbenicillin plus gentamicin for the treatment of serious infections due to gram-negative bacilli. Am J Med 1978;64:961-966.

6. Pancoast SJ, Jahre JA, Neu HC. Mezlocillin in the therapy of serious infections. Am J Med 1979;67:747-752.

7. Prince AS, Neu HC. Use of piperacillin, a semisynthetic penicillin in the therapy of acute exacerbations of pulmonary disease in patients with cystic fibrosis. J Pediatr 1980;97:148-151.

8. Scully BE and Neu HC. Clinical efficacy of ceftazidime. Arch Intern Med 1984;144:S7-62.

9. Scully BE, Neu HC. Use of aztreonam in the treatment of serious infections due to multiresistant gram-negative organisms, including Pseudomonas aeruginosa. Am J Med 1985;78:251-261.

10. Scully BE, Ores C, Prince AS, Neu HC. Treatment of lower respiratory tract infections due to Pseudomonas aeruginosa in patients with cystic fibrosis. Rev Infect Dis 1985;7(Suppl 4):669-674.

11. Scully BE, Neu HC, Parry MF, Mandell W. Oral ciprofloxacin therapy of infections due to Pseudomonas aeruginosa. Lancet 1986;1:819-822.