The clinical implications of ß-lactamases

ANTIMICROBICS AND INFECTIOUS DISEASES NEWSLETTER The Clinical

Implications

Charles W. Stratton, MD Associate Professor of Pathology and Medicine Vanderbilt University School of Medicine Nashville, Tennessee

Introduction In the past fifty years sincethe introduction of ELlactamantimicrobial agents, the clinical implications of B-lactamaseshave beenexceedingly important and literally have dictated the successor failure of B-lactam therapy. The development of new B-lactam agentsstableto these enzymes as well asthe concomitant development of Blactamaseinhibitors might suggestthat theseenzymes today have fewer clinical implications. This, unfortunately, is not true. The current clinical implications remain much the samedue to the suprising flexibility of D-lactamases. This current statusis best appreciated by reviewing the complex interaction over time that hasoccured between Blactam agentsand R-lactamases.This interaction hasbeen that of a struggle and is characterized by wide fluctuations between successfulattempts by the medical and pharmaceuticalcommunities to prevent enzymatic hydrolysis of B-lactam agentsversus equally successful resistancemechanismsdevised by microorganismsto negatethesesuccesses.Therefore, it shouldnot be suprising to find that the clinical implications of B-lactamaseshasfluctuated in much the sameway. Of late, the unexpected diversity of theseenzymes for rapidly adapting to new substrate profiles via point mutations seemsto have once again given microbes the

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Editor-in-Chief Charles W. Stratton,

MD

Vanderbilt University School of Medicine Nashville. Tennessee editorial board appears on back cover Full

Volume 15, Number 10 October 1996

of R-Lactamases advantagein this conflict. This diversity hasproduced an amazing number of new enzymes that vary widely in function and molecular structure. Therefore, the clinical implications of B-lactamase today remain crucial and continue to determinethe successor failure of a-lactam therapy.

Previous

Clinical

Importance

The discovery of penicillin wasparticularly important for the therapy of staphylococcal infections asthis new antibiotic possessed bacteriocidal activity againstthis pathogen. However, soonafter the clinical useof penicillins began, somestrainsof Staphylococcus aureus were noted to be resistantto the bacteriocidal action of this new agent. An enzyme which could destroy penicillin had already beenrecovered from gram-negative bacilli, andrecovery of a similar enzyme from S. aureus soon followed. Theseenzymatic substances were initially labeled “penicillinases” until it was realized that this enzyme could also partially inactivate certain cephalosporins.This resultedin the term, “cephalosporinases,” andlater asa more inclusive term, “I3-1actamases.” The clinical implications of Blactamaseswere first noted in serious staphylococcal infections suchas endocarditis where therapy with penicillin invariably failed. Initial efforts by the pharmaceuticalcommunity understandably wereplacedon counteringthis newly encounteredl3-lactamase-mediated resistencein S. aureus. The ability to produce 6-aminopenicillanic acid (6 APA) by fermentation allowed chemists to substitutethe amino group of 6-APA

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with altered side chains, thus producing amongthe first semisyntheticpenicillins. The steric hinderancearound the amide bond produced by bulky sidechains such ascarbocyclic or heterocyclic rings with substituentsat the orthoposition of the 6-APA site gave these semisynthetic agentsincreasedstability againststaphylococal B-lactamase.A number of such antistaphylococcal penicillins with bulky sidechains were synthesized; including methicillin; nafcillin; and the isoxazolyl penicillins, oxacillin, cloxacillin, dicloxacillin, and flucloxacillin. The discovery of the cephalosporins wastimely in that theseagentspossessed intrinsic stability against staphylococcal R-lactamase.Moreover, one of the first cephalosporins,cephalosporinC, possessedan aminoadipic sidechain which could easily be chemically removed to give rise to 7-aminocephalosporonic acid (7-ACA) which is analogousto 6APA. From 7-ACA came semisynthetic cephalosporinssuch ascefazolin. Substitutions at the 7 position aswell as at the 3 position of the dihydrothiazine ring allow greater variation of semisynthetic cephalosporinsthat can be

In This Issue The Clinical Implications of lblactamases . . . . . . . . . . . . . . -67 Charles W Stratton

Vascular Graft Infection Due to Neisseria Subji’ava . . . . . . . .72 A case report

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achieved with the penicillins. Consequently, more cephalosporins have been developed. The substitutions at the 7 position are of particular importance in governing stability to B-lactamase. The clinical use of antistaphylococcal penicillins together with the use of “first generation” cephalosporins allowed clinicians to deal quite successfully with staphylococcal infections until the arrival of methicillin-resistant strains. As soon as the clinical problem of penicillin resistance with B-lactamasepositive staphylococci was resolved, it was replaced by that of serious gramnegative bacillary infections. Clinicians soon learned that aminoglycoside therapy alone was less than optimal for a number of severe gram-negative bacillary infections such as pneumonia, meningitis, and septicemia. The antistaphylococcal penicillins, of course, had no activity against coliforms. The early cephalosporins were useful in some of these gram-negative infections, but not all. As a result of the increasing prevalence of gram-negative bacillary infections, pharmaceutical chemists developed the extended-spectrum penicillins which were noted for increased activity against gram-negative bacilli. The first of these was ampicillin which was active against common members of the Enterobacteriaceae, but not against Pseudomonas aeruginosa. This was followed by the carboxy penicillins, carbenicillin and ticarcillin, which had reasonable activity against P aeruginosa, but less against members of the Enterobacteriaceae. Later, the ureido penicillins, azlocillin, mezlocillin and piperacillin, became available and provided a broader spectrum that included I? aeruginosa and members of the Enterobacteriaceae. Around the same time, researchers in medicinal pharmacology had developed newer (“second generation”) cephalosporins with increased activity against members of the Enterobacteriaceae and were work-

ing on extended spectrum (“third generation”) cephalosporins which had activity against P aeruginosa. In addition to these modifications to the cephalosporin molecule, researchers had isolated new B-lactam-related compounds with potent antimicrobial activity from microorganisms. These compounds and their semisynthetic derivatives promised two entirely new classes of B-lactam agents, the monobactams and the carbapenems.

The clinical

implications of J-lactamases continue to be exceedingly important and literally dictate the successor failure of &lactam therapy. Finally, the realization that penicillin activity could be potentiated by inhibition of the penicillinase by natural substances resulted in a search for similar agents that would be useful in clinical medicine. Eventually, this search led to the discovery of clavulanic acid, the first clinically useful l3-lactamase inhibitor. In addition, semisynthetic S-lactamase inhibitors such as sulbactam and tazobactam, were developed. Needless to say, the pharmacologists had returned the clinical advantage to the clinicians with a “wave” of new antibiotics. As earlier mentioned, a number of these extended-spectrum B-lactam agents were noted to have synergistic activity when combined with an aminoglycoside. Such synergistic activity proved to be especially useful in cancer

patients where infections caused by P aeruginosa had proven very difficult to treat with only an aminoglycocide. Although pseudomonal infections were to remain somewhat difficult to treat, the use of an antipseudomonal penicillin with an aminoglycocide was a marked improvement. Combination therapy using B-lactam agents with aminoglycosides also was found to be useful for the therapy of gram-negative rod bacteremia which had become a greater problem for hospitalized patients during the 1970’s and 1980’s. The second and third generation cephalosporins were a welcome addition during this time as these agents were very effective either alone or combined with an aminoglycoside against many serious gram-negatvie bacillary infections including bacteremias. An unexpected benefit of these newer cephalosporins was their efficacy in bacterial meningitis, including that caused by gram-negative bacilli. Although able to penetrate into the central nervous system no more than earlier cephalosporins, these newer agents proved successful for the therapy of bacterial meningitis due to their greater activity. The use of second (i.e., cefuroxime) and third generation cephalosporins for the therapy of bacterial meningitis was to become the critical factor for success after one of the most common bacterial causes of childhood meningitis, Haemophilis injluenzae, acquired plasmid-mediated l3-lactamase which confered resistance to penicillin. The clinical advantages conferred by the extended-spectrum penicillins and the newer cephalosporins was short- lived as during this wave of new antibiotics, there existed a less well appreciated undercurrent of emerging resist- ante. Much of this resistance was eventually found to be caused by O-lactamases in ways that had not even been imagined. The B-lactamases of gram-negative bacteria, although recognized early,

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were discovered to be more important clinically than had initially been thought. Moreover, these gram-negative enzymes proved better able to hydrolyze cephalosporins than had those of staphylococi. Needless to say, these gram-negative B-lactamases were easily able to hydrolyze both the extended-spectrum penicillins as well as newer “&lactamasestable” cephalosporins such as cefotaxime and cephtriaxone. Other problems related to 134actamases seemed to suddenly appear. Microorganisms which heretofore had not had S-lactamase-mediated resistance suddenly seemed to develop such resistance. One of these microbes, H. injluenzae, has already been mentioned. In addition, members of the Bacteroides fragilis group were found to harbor potent B-lactamases which hydrolized newer penicillins and cephalosporins and later also to harbor carbapenemases. Enterococci joined the ranks of microorgansims with B-lactamase-mediated resistance after receiving a plasmid confering this resistance from S. aureus. This in retrospect turned out to be less suprising after B-lactamase-mediated resistance was found to be transferrable between bacteria, including those of different species, on plasmids and transposons. Finally, the relationship between D-lactamase and antimicrobial diffusion through porin channels in the outer cell membrane of gram-negative bacteria became apparent. Of particular importance in this regard was the ability of porin proteins to alter their configuration in order to decrease the permeability of antimicrobial agents which, in turn, greatly enhanced the effectiveness of periplasmic B-lactamase. Finally, Pseudomonas aeruginosa was found to be capable, when fully derepressed, of pumping B-lactamase into its biofilm as well as into its peroplasmic space. It is likely that other gram-negative bacilli are able to pump Elactamase in their glycocalyx. One answer to these latest l34actamass related problems was to combine extended-spectrum penicillins with Blactamse inhibitors as well as to continue the developmemt of new generations of cephalosporins that had even greater stability to B-lactamase. Entirely new classes of antimicrobial agents with remarkable stability to all known B-

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lactamases were introduced into clinical practice. These agents included aztteonam, the first member of the new class of monobactam agents and imipenem, the first of a new class called carbapenems. This latter class, carbapenams, posessed unique stability to serinebased B-lactamases. These newer agents seemed to enjoy remarkable clinical success for a while. However, detepression of chromosomallymediated l3-lactamase production in certain members of the Enterobacteriaceae and in members of the Pseudomonas species was found to confer resistance even to these agents.

T o date, there

have been over thirty extended spectrum JMactamases which have originated from TEM-1 &luctamases. Current Clinical Importance The late 1970’s and early 1980’s mark what will undoubtely become the high point for pharmacologists and clinicians in the conflict between B-lactam agents and Clactamases. This highpoint included the introduction of a wide variety of f3-lactam agents and LLlactamase inhibitors into clinical practice. Among these B-lactam agents were representatives, aztreonam and imipenem, of two new classes of antimicrobial agents. In addition, potent extended spectrum penicillins were combined with B-lactamase inhibitors. Despite these advances, B-lactamase-mediated resistance today continues to be recognized as the major reason for clinical failure with l3-lactams. The microorganisms appear to have redoubled their efforts, much like pharmacologists and clinicians did in the previous decade, and to again take the lead in this struggle. The results of these microbial efforts are impressive. It is now recognized that various amino acid substitutions in the active site loop may, in general,

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confer B-lactamase mediated resistance to a diverse number of l3-lactam structures. These substitutions appear to function by providing greater access to the active site pocket of the enzyme by destabilizing the loop structure and making it “floppy.” Partial evidence that this is the case is provided by the observation that such substitution mutants are unstable. To date, there have been over thirty so-called extended spectrum l3-lactamases which have originated from TEM- 1 B-lactamases, and there seems to be no end in site. The importance of the chromosonally mediated S-lactamases (am& enzymes) has become clear. Derepression of ampC B-lactamase confers resistance against all newer Blactam agents except the carpapenams. In addition, these chromosonally-located ampC Glactamases have now been found on plasmids and hence are mobile. This promises increased resistance in those members of the Enterobacteriaceae such as Echerichia coli and Klebsiella species which normally do not possess these enzymes. Another factor in l34actamase mediated-resistance is the promiscuity of plasma-mediated l3-lactamases. Among the species of bacteria which have recently gained plasmid-mediated resistance to l3lactamase stable cephalosporins are Haemophilis infuenzae, Neisseria gonorrheae, Enterococcus species, Proteus mirabilis, Clostridium, and Clostridioforme. Intergeneric DNA transfer of extended-spectrum l3lactamases has been described for Bacteroides species and Pseudomonas aeruginosa. Many of the extendedspectrum l3-lactamases that are found today in clinical isolets are able to hydrolize all l3-lactam agents except carpapenams. Moreover, plasmidmediated B-lactamases which are not inactivated by currently available B-lactamase inhibitors are being seen with increasing frequency. The clinical importance of carbapenams for the therapy of infections caused by microrganisms posessing extended-spectrum l3-lactamases is considerable. The recent reports of carbapenases puts the continued usefulness of the new carbapenam class in question. These carbapenases, first described in B. fragilis, have now been found to be transferrable and have been described in

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F! aenrginosa. Class A serine-based Blactamases able to efficiently hydrolize carbapenams have now been reported from Enterabacter cloacae and Serratia ntarcecerts.

Summary The clinical importance of B-lactamases was recognized shortly after the clinical useof penicillins. This clinical importance hasnot diminished over the past fifty years, but insteadhas increased.It is clear that O-lactamaseswill continue to be one of the most important microbial resistance mechanismsagainst S-lactam agents.Clinicians need to appreciatethis resistancemechanism. Accordingly, a review of the most important aspectsof this form of resistancehave beenpresentedin three earlier issuesof the newsletter.

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resistance during therapy with the newer &lactams: role of inducible B-iactamases and implications for the future. Rev Infect Dis 5:639-648, 1983. Sanders CC, Sanders WE Jr: Microbial resistance to newergenerationB-lactam antibiotics:clinical andlaboratoryimplications.J Infect Dis 151:399-406, 1985. SandersCC, SandersWE Jr: Type I O-lactamases of gram-negativebacteria: interactionwith 8-lactamantibiotics. J Infect Dis 154:792-800,1986. Sanders WE Jr, SandersC C: Inducible l3-lactamases: clinical andepidemiologic implicationsfor theuseof newer cephalosporins. Rev Infect Dis 10:830838, 1988. SeebergAH, Tolxdorff-Neutzling RM, Wiedemann B: Chromosomal O-lactamases of Enterobacter cloacae are responsible for resistance to third-generationcephalosporins. AntimicrobAgents Chemother23:919-925,1983. Sirot D, ChanalC, HenquellC, LabiaR,

Sirot J, CluzelR: Clinicalisolatesof Esherichiu coli producingmultipleTEM mutantsresistantto l3-lactamase inhibitors.J AntimicrobChemother 33:1117-1126, 1994. SougakoffW, Goussard S, GerbaudG et al.: Plasmid-mediated resistance to thirdgeneration cephalosporins caused by point mutationsin TEM-type penicillinase genes.RevInfect Dis 10:879-884,1988. StrattonCW:Activity of &lactamases againstR-lactams. J Antimicrob Chemother22(Suppl.A):S23-S35,1988. StrattonCW,TauskF: Synergisticresistance mechanisms in Pseudomonas aeruginosa. J AntimicrobChemother .19:413-416,1987. SykesRB, MatthewM: The D-lactamases of gram-negative bacteriaandtheir rolein resistance to l3-lactam antibiotics.J AntimicrobChemother2:115-157,1976. TermanJW,Alford RH, Bryant RE: Hospital-acquired Klebsiella bacteremia. Am J Med Sci 264:91-96,1972.

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Case Report

Vascular Graft Infection Due to Neisseria Subflava G. StedmanHuard II, MD Lawrence Cone, MD Alan E. Williamson, MD David R. Woodard, MS Department of Surge? and Medicine Eisenhower Medical Center Ranch0 Mirage, California 92270

Narinder K. Midha, MS.M(ASCP)SM,

DLM

Assistant Director of the Clinical Microbiology Laboratory Vanderbilr University Medical Center Nashville, Tennessee 37323

Infection of vascular grafts is uncommon, ranging from 1 to 3%. However, once graft is infected, the combined morbidity is 30 to 70%. Staphylococci, non-hemolytic streptococci, gram-positive bacilli and Listeria monocytogenes have been isolated from vasculargrafts. Although non-pathogenic Neisseria species causeendocarditis, vascular graft infection has not previously beenreported. We describethe first caseof Neisseria subjlava infection which occurred nearly 6 years after bypasssurgery.

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Case Report A 72-year-old, white, male insulindependentdiabetic underwent bilateral femoropopliteal bypassin 1971 and, in 1987, he underwent revision of the bypasson the left with a PTEF graft. For a week in mid-December 1992he noted erythematousstreaking along the medial aspectof the left leg followed by fever and rigors. Aside from the absence of pulsesin the left lower extremity, as well aserythema and tendernessin the calf, physical examination was unremarkable. Laboratory data revealed a WBC of 15,000mm3and an automated chemistryprofile demonstratedonly an elevatedglucosewhile glycosuria was noted in the urinalysis. An EKG and chestX-ray were normal. Ultrasonography failed to show evidence of thrombophlebitis. A preliminary diagnosisof post saphenectomycellulitis wasentertained. Becauseof a history of immediatehypersensitivity to penicillin, the patient received empirically aztreonamand netilmicin with someimprovement

0 1996 Elsevier

Science

Inc.

in erythema and fever. Three blood cultures drawn on admission,grew N. subflava. After six days of therapy and a failure to respondcompletely, an indiurn- 111white cell scanwas ordered. This showedhigh-grade uptake of the tracer in the distal left leg (popliteal region) and proximal calf corresponding to the distribution of the femoral popliteal bypassgraft. The infected femoral popliteal bypassgraft was removed. No attempt was madeto revascularize the left limb sincethe infected graft had been occluded for sometime. A second organism,Staphylococcus aureus was isolatedfrom the surgical wound and treated with vancomycin for another week. The patient was dischargedwith ciprofloxacin 750 mg orally twice daily for an additional 4 weeks. His postoperative course was uneventful and he is currently asymptomatic 22 monthsfollowing the surgery. In vitro sensitivity studiesto the isolatedN. subflava are summarizedin Table 1.

Anrimicrobics

and Infectious

Diseases

Newsletter

15(10)

1996