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Novel plasmid-mediated extended spectrum beta-lactamases
IIDNI V o l u m e 11, N u m b e r 5, M a y 1 9 9 2 Editor
Associate Editors
Charles W. Stratton, MD Departmentof Pathology VanderbiltUniversityMedicalCenter Nashville,Tennessee
Charles E. Cherubin, MD VeteransAdministrationMedicalCenter Wilkes-Barre,Pennsylvania
ArkansasChildren'sHospital LittleRock,A~kansas
R o g e r G. Finch, FRCP, IVlRCPath NottinghamCityHospital Nottingham, UnitedKingdom
John T. $innott IV, MD Universityof SouthFlorida Tampa,Florida
H. B r a d f o r d H a w l e y , IVlD Wright StateSchoolof Medicine Dayton,Ohio
Philippe Van der Auwera, MD, Phi) LastitutJulesBorder Brussels, Belgium
~liltq|l'
Novel Plasmid-Mediated Extended Spectrum Beta.Lactamases John P. Quinn Congenital Tuberculosis John T. Sirmot,IV Tunothy C. Gompf Sandra Gonzalez Gompf CASE REPORT Acute HIV Infection Presenting as Cytomegalovirus Mononucleosis in a Young Woman Charles W. Stratton
Elsevier 0278-2316/92/$0.00 + 3.00
Richard E J a c o b s , MD
Novel Plasmid-Mediated Extended Spectrum Beta-Lactamases J o h n P. Q u i n n , M D Internal MedicineResidencyProgram,InfectiousDiseases,Universityof Illinois,MichaelReese Hospital & MedicalCenter,Chicago,Illinois 33
37
39
Historically, beta-lactamases have represented the most common mechanism of resistance to beta-lactam compounds among clinically important pathogens. One of the earliest examples of this phenomenon was the rapid spread of plasmid-mediated betalactamases among Staphylococcus aureus strains in the 1950s, following the widespread introduction of penicillin in clinical practice. In the 1970s and 1980s, plasmid-mediated resistance to penicillin and first-generation cephalospofins spread rather quickly among Hemophilus influenzae and Escherichia coli isolates. The third-generation cephalosporins, monobactams, and carbapenems are all semisynthetic molecules that are engineered in part to confer resistance to hydrolysis by these plasmid-mediated beta-lactamases. In the early 1980s, the effort to confer resistance was quite success-
ful in that nearly all strains of Escherichia coli and Klebsiella pneumoniae were susceptible to thirdgeneration cephalosporins. The major stumbling block in terms of emergence of antibiotic resistance to these compounds occurred in inducible enterics (like Enterobacter and Serratia) and P seudomonas aeruginosa harbor. ing chromosomal (also known as type 1) enzymes. Resistance in these cases was due to selection of spontaneous mutants that hyperproduce those enzymes. Nevertheless, although this problem was substantial in those bacteria, the genes responsible for the enzymes are chromosomal and hence not able to spread between unrelated genera. The latest threat to our beta-lactam agents comes from novel plasmid-mediated beta-lactamases that are capable of destroying advanced spectrum compounds. The first such organisms 0278-2316 IDINDN 11(5) 33-40, 1992
34 Infectious Diseases Newsletter 11 (5) May 1992
Table 1. Extended-Spectxmn Beta-Lactamases in the TEM Faxnilya
Beta-Lactamase
Species
Country of Origin
Year of First Isolation (I) or Report (R)
MICb of: pl
Cefotaxime
Ceftazidime
Aztreonam
Pareatal types TEM-I
E. coli
Greece
TEM-2
P. aeruginosa
TEM-13
M. morganii
1963 (I)
5.4
0.125
0.25
England
1969 (I)
5.6
c
1990 (R)
5.6
--
--
K. pneumoniae
France
1984 (I)
6.3
32
64
16
E. coli
France
1986 (I)
5.9
32
32
16
K. pneumoniae
France
1987 (I)
5.55
4
128
8
TEM-6
E. coli
Germany
1987 (R)
5.9
1
128
64
TEM-7
Citrobacter freundii
France
1988 (R)
5.41
0.5
64
2
TEM-8
K. pneumoniae
c
1989 (R)
5.9
--
TEM-9 (RHH- 1)
K. pneumoniae
England
1989 (R)
5.5
TEM-10
K. pneumoniae
United States
1989 (R)
5.57
TEM-11 (Cazl0)
K. pneumoniae
Belgium
1989 (R)
5.7
0.06
TEM-12
E. coil
United States
1989 (R)
5.25
TEM-14
K. pneumoniae
c
1990 (R)
6.3
--
0.125
0.125
0.5
0.25 --
Proven unique TEM-3 (Ctx- 1) TEM-4 TEM-5 (Caz-l)
--
--
2
128
128
1
64
32
0.06
4 4 --
0.25 0.25 --
TEM-15
K. pneumoniae
c
1990 (R)
6.0
--
--
--
TEM-16
K. pneumoniae
c
1990 (R)
6.3
--
--
--
TEM-17
K. pneumoniae
c
1990 (R)
5.9
--
--
--
TEM-18
K. pneumoniae
c
1990 (R)
6.3
--
--
--
TEM-19
E. coli
c
1990 (R)
5.4
--
--
--
aAdapted from Philipon et at., A A C 33:1131-1136, 1989, and Jaeoby & Medeiros, A A C 35:1697-1704, 1991. bM~Cs are generally given for E. coil transeonjugants producing the given beta-lactamase. Some were determined in a uai.form genetic backgnaund, but most were determined by a variety of techniques that may make thea'n only closely comparable. When no values are given, data are not available. ¢Strains producing these enzymes originated in France, Belgium, England, Chile, and Germany, but the exact country of origin for each has not yet been reported.
were d i s c o v e r e d in the F e d e r a l R e p u b lic o f G e r m a n y in K l e b s i e l l a strains in 1983 and h a v e since spread rapidly across continental E u r o p e and n o w worldwide. This has n o w b e c o m e a substantial clinical p r o b l e m , w h i c h will b e the f o c u s o f this b r i e f review.
Characteristics of Extended Spectrum B e t a - L a c t a m a s e s M o r e than 30 u n i q u e p l a s m i d - m e d i -
ated e n z y m e s h a v e b e e n distinguished based on b i o c h e m i c a l and genetic characterization. A m o n g ampicillin-resistant strains o f E. coli, the T E M - 1 and T E M - 2 e n z y m e s are the m o s t c o m m o n . A m o n g Klebsiella species, m e m b e r s o f the S H V family p r e d o m i nate. T E M - 1 , T E M - 2 , and SHV-1 are e n z y m e s that h y d r o l y z e ampicillin preferentially but usually c o n f e r resistance to cephalothin as well. T h e y are unable to h y d r o l y z e e x t e n d e d spec-
trum c o m p o u n d s , such as the thirdgeneration c e p h a l o s p o r i n s and m o n o bactams. M o s t o f the n o v e l e n z y m e s described since 1983 that h y d r o l y z e third-generation c e p h a l o s p o r i n s and other a d v a n c e d s p e c t r u m c o m p o u n d s are point mutants that h a v e arisen from the g e n e s for the older w i d e spread T E M (Table 1) and S H V (Table 2) families o f e n z y m e s . T h e s e observations h a v e several o b v i o u s
NOT~: No re~oesibilily is assumed by the Publisher for any injur~ and/or damage to person~ or prope~y ~ a matt~ of products liability, negligeace or olhea-wise, or from any use or operation of say method.s, products, insla'uctions or ideas contained in the material herein. No suggested test or procedure should be carded out unless, in the reader's judgment, its risk is justified. Because of rapid advances in the medical ~ciances, we recomm,md that the inck~endant verification of diagnosea end drug dosages should be made. Discussions, views, and recommendations ~ to medical procedure~, choice of drug~ and drug do~ages are the responsibility of the authors. Infectio~ Diseases Newsle~er (ISSN 0278-2316) is i~sued monthly in one indexed volume pet year by Els~ier Science Publishing Co., Inc., 655 Avenue of the Americas, New York. New York 10010. Printed in USA at Hanover, PA 17331. Subscription price per year: institutions, $158.00; individuals, $92.00. For postage outside the U.S., add $40.00 (Canada and Mexico require no ad ditional postage). Second-class postage paid at New York, NY, and at additional mailing offices. Postnaaster: Send address changes to Infectious Diseases Newsletter, Elsevier Science Publishing Co., Inc., 655 Avenue of the Americas, New York, New York 10010.
© 1992 Elsevier Science Publishing Co., Inc. 0278-2316/92/$0.00 + 3.00
35 Infectious Diseases Newsletter 11(5) May 1992
Table 2. Extended-Spectrum Beta-Laetamases Not Related to TEMa Country Yearof First Beta-Lactamase
Species
of Origin
Isolation (I) or Report (R)
Switzerland
1974 (R)
7.6
Greece
1983 (I)
7.6
pI
Inhibition
MIC of: Cefotaxime
Ceftazidime
by
Aztreonam Cefoxitin
Imipenem Clavulanate
SHVderivatives SHV-1 SHV-2
E. c o i l K. ozaenae
SHV-3
K. pneumoniae
France
1986 (I)
7.0
SHV-4 (CazS)
K. pneumoniae
France
1987 (1)
7.75
SHV-5 (Caz4) Responsible for eephamycin resistance MIR-I
0.125 64
1
32
16
0.5
+
32
0.5
16
~5
+
64
32
32
16
~25
+
128
128
256
16
0.25
+
256
8
0.25
+
128
>256
K. pneumoniae
Chile
1987 (I)
8.2
64
128
K. pneumoniae
USA
1989 (R)
8.0
64
128
1
E. coli aAdapted from Philipon et al., AAC 33:1131-1136, 1989, and Jacoby & Medeiros, AAC 35:1697-1704, 1991.
clinical implications. First, the genetic pool from which such .mutants arise is extraordinarily large. For instance, about 40% ofE. coli strains in the United States are ampicillin-resistant due to TEM- 1 or TEM-2 production. Often, a mutation resdting in a single base pair change is sufficient to convert an ampicillin-hydrolyzing enzyme into one capable of destroying third-generation compounds. The resistance phenotypes of some of the novel extended spectrum enzymes of interest are displayed in Tables 1 and 2. It should be noted that some of these enzymes have unique appetites for destroying one compound over another. In general, they confer resistance to oxyimino beta-lactams like cefotaxime, ceftazidime, and aztreonam, while cephamycins and carbapenems are not affected. However, there are clear differences in their resistance proclivities. For instance, TEM-5 and some other related enzymes have a greater ability to destroy ceftazidime and aztreonam. Nevertheless, it is fair to say that in general most of these enzymes confer greater resistance to ceftazidime and aztreonam than cefotaxime.
Epidemiology Since their initial discovery in the Federal Republic of Germany, these enzymes have been reported throughout the European continent and many countries around the world. Of local interest, several novel enzymes have been described in the United States. The fast such enzyme to be fully described in North America, TEM- 10, is a potent ceftazidimase fast discovered in Klebsiella isolates from Chicago. Since then, other American investigators have described similar enzymes. The interested reader is referred to the works of Drs. Rice, Papanicolaou, and Weber. It should be noted that there is nothing terribly unique about these enzymes in different geographic locations and many enzymes have been described simultaneously in different countries. It should also be noted that many of the plasmids harboring these enzymes co-transfer other resistance genes. Hence, one may see tdmethoprim-sulfamethoxazole, aminoglycoside, and beta-lactam resistance transferred on the same plasmid. Once organisms harboring these re© 1992
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sistance enzymes have entered a hospi. tal, it is difficult to eradicate them. At the present time, approximately 16% of Klebsiella pneumoniae isolates from intensive care unit patients in Chicago are resistant to eeftazidime and aztreonam due to the introduction of these resistance genes (author's unpublished observations). There is, of course, great variation in the local preference of these resistance determinants, so that some hospitals have very high rates of resistance and others have very low rates, reflecting local epidemiologic factors. Nevertheless, these enzymes are clearly spreading quickly across the USA and worldwide and are likely to remain with us for the foreseeable future.
Molecular Studies Studies of the molecular basis for resistance due to the novel extended spectrum enzymes have added considerably to our understanding of structure-activity relations in beta-laetams. The preferential destruction of ceftazidime and aztreonam by many of these enzymes, for instance, suggests that there is something unique about
36 Infectious Diseases Newsletter 11(5) May1992 the structure of these compounds lhat makes them uniquely susceptible. This is, indeed, the case. In nature, the beta-lactamase molecule forms a cave that has a novel topology made up of two closely associated domains. The active site is located at the interface between these domains, with the key catalytic residue being a serine at position 70. This is the active site of the enzyme, which allows it to bind to the beta-lactam ring and destroy the beta-lactam compound. Molecular studies of the new enzymes have revealed that the serine residue at position 70 is retained in each case. Amino acid substitutions have recurred at remote locations. We are beginning to understand how mutations at these remote locations can confer resistance to specific drugs. For example, the potential interaction of serine at position 236 in the enzyme TEM-3 is known to interact with the methyl-oxime side chain of cefotaxime, allowing the serine residue to bind to and destroy the betalactam ring.
Future Prospects Each year brings a bewildering array of new beta-lactamases with unique properties. A few such enzymes merit special attention. Dr. Papanicolaou and colleagues recently described a novel plasmid-mediated enzyme known as MIR-1 that confers resislance to all beta-lactams other than imipenem among Kiebsiella pneumoniae isolates. This antibiogram is quite reminiscent of that which is typically conferred by chromosomal enzymes. In fact, genetic studies of this enzyme reveal that it was derived from the Enterobacter cloacae AmpC gene, the structural chromosomal gene for type 1 beta-lactamase in that organism. Therefore, this is a chromosomal gene that spreads on a plasmid among Klebsiella isolates, presumably on a transposon. Dr. Watanabe and colleagues have also described an alarming enzyme in
Japan in a Pseudomonas aeruginosa isolate. This enzyme conferred resistance to carbapenems like imipenem and meropenem as well as antipseudomonal penicillins and cephalosporins and has an exceptionally broad substrate. It is resistant to inhibition by clavulanic acid, unlike most of the novel extended spectrum enzymes, and it belongs to the same family of chromosomally determined imipenem hydrolyzing enzymes found in Xanthomonas maltophilia and Bacteroides fragilis. There are several practical concerns for the microbiologist and clinician that result from the spread of these enzymes. The first is that our clinical microbiology laboratories must begin to look for these organisms specifically by testing ceftazidime against enteric Gram-negative rods. Since many of these enzymes will confer resistance to ceftazidime but not other cephalosporins, class susceptibility testing may not detect organisms harboring these enzymes. Another clinical concern results from the increasing popularity of monotherapy with an advanced spectrum cephalosporin for various and sundry life-threatening infections. This is best exemplified by empiric ceftazidime monotherapy for febrile neutropenic cancer patients, a widespread practice in this country. We have recently described a large epidemic of ceftazidime-resistant Klebsiella and E. coli infections among children with cancer at a university hospital in California. This epidemic proved to be due to TEM-9, a plasmicmediated ceftazidime-hydrolyzing enzyme first described in a hospital in England in 1987. While the source of the epidemic was never identified by epidemiologic studies, the epidemic was terminated by abolishing empiric monotherapy and switching to a conventional triple-drug regimen of azlocillin, nafcillin, and amikacin for neutropenic fever. Clinicians and microbiologists must remain in the front line of awareness for new resistance determinants and © 1992 Elsevier Science Publishing Co., Inc. ~'T~_'~
l ~1(~'~ /~,~ ~X~ .~- "~ ~(~
must be able to respond appropriately.
Bibliography Gutmann L, Kitzis MD, Billot-Klein D, et al: Plasmid-mediated beta-lactamase (TEM-7) involved in resistance to ceftazidime and azlreonam. Rev Infect Dis 10:860-866, 1988. Herzberg O, Moult J: Bacterial resistance to beta-lactam antibiotics: crystal structure of beta-lactamase from Staphylococcus aureus PC1 at 2.5 A resolution. Science 236:694-701, 1987. Jacoby G, Medeiros A: More extendedspeclrum beta-lactamases. Antimicrob Agents Chemother 35:1697-1704, 1991. Kiutzis MD, Billot-Klein D, Goldstein FW, et al: Dissemination of the novel plasmid-mediated beta-lactamase Ctx-1 which confers resistance to broad-spectrum cephalosporins and its inhibition by beta-lactamase inhibitors. Antimicrob Agents Chemother 32:9-14, 1988. Knothe H, Shah E Kremery V, et at: Transferable resistance to cefotaxime, cefoxitin, cefamandole and cefuroxime in clinical isolates of Klebsiella pneumoniae and Serratia marcescens. Infection 11:315-317, 1983. Medeiros AA: Plasmid-determined betalactamases. In Bryan LE (ed.) Microbial Resistance to Drugs. Vol. 91 of Handbook of Experimental Pharmacology. Berlin, Springer-Verlag, pp 101-127, 1989. Papanicolaou GA, Medeiros AA, Jacoby GA: Novel plasmid-mediated beta-lactamase (MIR-1) conferring resistance to oxyimino- and alpha-methoxy beta-lactams in clinical isolates of Klebsiella pneumoniae. Antimicrob Agents Chemother 34:2200-2209, 1990. Philipon A, Labia R, Jacoby G: Extendedspectrum beta-lactamases. Antimicrob Agents Chemother 33:1131-1136, 1989. Quinll JP, Miyashiro D, Sahm D, Flamm R, Bush K. Novel plasmid-mediated beta-lactamase (TEM-10) hydrolyzing ceftazidime and aztreonam in clinical isolates of Klebsiella pneumoniae. Antimicrob Agent Chemother 33:14511456, 1989. Quinn JP, Naumovsky L, Arvin A: Epidemic of ceftazidime-resistant gramnegative bacillary infections among pediatric cancer patients. 1991 Annual Meeting, American Society for Microbiology; abstract number A-30. Rice LB, Wiley SH, Papanicolaou GA, et al: Outbreak of ceftazidirae resistance caused by extended spectrum beta-lacta~nases at a Massachusetts chronic care
37 Infectious Diseases Newsletter 11(5) May 1992 facility. Antimicrob Agents Chemother 34:2193-2199, 1990. Sanders CC: The chromosomal beta-lactamases. In Bryan LE (ed) Microbial Resistance to Drugs. Vol. 91 of Handbook of Experimental Pharmacology. Berlin, Springer-Verlag, pp 129-149, 1989. Sougakoff W, Goussard S, Gerbaud G, Courvain P: Plasmid-mediated resistance to third generation cephalosporins caused by point mutations in TEM-type penicillinase genes. Rev Infect Dis 10:879-884, 1988. SougakoffW, Petit A, Gosussard S, et al:
Characterization of the plasmid genes blaT-4 and blaT-5 which encode the broad-spectrum beta-klactamases TEM4 and TEM-5 in Enterobacteriaceae.
Gene 339-348 1989. Spencer RC, Wheat PF, Winstanley TG, et al.: Novel beta-lactarnase in a clinical isolate of Klebsiella pneumoniae conferring unusual resistance to beta-lactara antibiotics. J Antimicrob Chemother 20:919-921, 1987. Watanabe M, lyobe S, lnoue M, Mitsuhashi S: Transferable imipenem resistance in Pseudomonas aeruginosa.
Antimicrob Agents Chemother 35:147151, 1991. Weber D, Sanders C, Bakken J, Quinn JP: A novel chromosomal "lEJd-derivafive (TEM-12) and altered outer membrane proteins together mediate selective ceftazidime resistance in E. coli. J Infect Dis 162:460-465, 1990 Address correspondence and reprint request to John P. Quinn, MD, Associate Professor of Medicine, University of Illinois, Michael Reese Hospital and Medical Center, Lake Shore Drive at 31st Street, Chicago, IL 60616.
Congenital Tuberculosis John T. Sinnott, IV, MD, FACP1, Timothy C. Gompf, BS,2 and Sandra Gonzalez Gompf, MD2 lDivision of Infectious and Tropical Diseases, 2Departmentof Internal Medicine, University of South Florida, College of Medicine, Tampa, Florida
With the recent resurgence of Mycobacterium tuberculosis (MTB) as a dangerous pathogen, the wise physician should recall an unusual complication: congenital tuberculosis. This uncommon but devastating complication of pregnancy will, in all likelihood, also become more frequent. Congenital MTB was originally described before the start of the "isoniazid era" of tuberculosis therapy. In 1985, 36 cases of congenital tuberculosis were reported in the literature since the 1950s, and some have been added to the literature since. However, considering the difficulty encountered in distinguishing congenital from postnatal disease, the true prevalence of congenital tuberculosis in the USA is probably not known.
C o n g e n i t a l I n f e c t i o n W i t h MTB
Congenital tuberculosis occurs more frequently in pregnancies complicated by primary maternal infection. Pri-
mary TB has a greater propensity for lymphohematogenous dissemination than does reactivation pulmonary TB. MTB can be congenitally transmitted either through the umbilical vein or by the amniotic fluid. Hematogenous spread of the pathogen through the umbilical vein results from maternal hematogenous spread to the placenta, miliary tuberculosis involving the placent,a, or from the local extension of tuberculosis endometdtis. Amniotic fluid becomes a vehicle when placental or genitourinary lesions rupture into the amniotic fluid leading to infection through aspiration or swallowing of the infected fluid in utero or at delivery. If the umbilical vein carries the pathogen to the fetus, the infection initially develops in the liver because of the anatomy of the fetal circulation as well as the high oxygen level of the liver. Many other sites may become secondarily involved, including the lungs, meninges, skin, gastrointestinal tract, lymphatics, and bone marrow. ©1992 Elsevier Science Publishing Co., Inc. 0278-2316/92/$0.00 + 3.00
When the amniotic fluid is the vehicle for spread, the primary infection may occur in the lungs or the gastrointestinal tract. Typically, infants with congenital tuberculosis present around 1 month of age with nonspecific symptoms or with a persistent pneumonia. Respiratory distress, fever, and hepatomegaly with or without splenomegaly are the most commonly noted findings, accompanied also by poor feeding, lethargy and/or irritability, and lymphadenopathy. Less common f'mdings include abdominal distention, failure to thrive, otorrhea, polymorphic skin lesions, jaundice, and seizures.
Diagnosis
The diagnosis of congenital MTB should be entertained in any infant with the aforementioned symptoms when associated with a maternal history of tuberculosis during pregnancy. Interestingly, congenital tuberculosis
Associate Editors
Charles W. Stratton, MD Departmentof Pathology VanderbiltUniversityMedicalCenter Nashville,Tennessee
Charles E. Cherubin, MD VeteransAdministrationMedicalCenter Wilkes-Barre,Pennsylvania
ArkansasChildren'sHospital LittleRock,A~kansas
R o g e r G. Finch, FRCP, IVlRCPath NottinghamCityHospital Nottingham, UnitedKingdom
John T. $innott IV, MD Universityof SouthFlorida Tampa,Florida
H. B r a d f o r d H a w l e y , IVlD Wright StateSchoolof Medicine Dayton,Ohio
Philippe Van der Auwera, MD, Phi) LastitutJulesBorder Brussels, Belgium
~liltq|l'
Novel Plasmid-Mediated Extended Spectrum Beta.Lactamases John P. Quinn Congenital Tuberculosis John T. Sirmot,IV Tunothy C. Gompf Sandra Gonzalez Gompf CASE REPORT Acute HIV Infection Presenting as Cytomegalovirus Mononucleosis in a Young Woman Charles W. Stratton
Elsevier 0278-2316/92/$0.00 + 3.00
Richard E J a c o b s , MD
Novel Plasmid-Mediated Extended Spectrum Beta-Lactamases J o h n P. Q u i n n , M D Internal MedicineResidencyProgram,InfectiousDiseases,Universityof Illinois,MichaelReese Hospital & MedicalCenter,Chicago,Illinois 33
37
39
Historically, beta-lactamases have represented the most common mechanism of resistance to beta-lactam compounds among clinically important pathogens. One of the earliest examples of this phenomenon was the rapid spread of plasmid-mediated betalactamases among Staphylococcus aureus strains in the 1950s, following the widespread introduction of penicillin in clinical practice. In the 1970s and 1980s, plasmid-mediated resistance to penicillin and first-generation cephalospofins spread rather quickly among Hemophilus influenzae and Escherichia coli isolates. The third-generation cephalosporins, monobactams, and carbapenems are all semisynthetic molecules that are engineered in part to confer resistance to hydrolysis by these plasmid-mediated beta-lactamases. In the early 1980s, the effort to confer resistance was quite success-
ful in that nearly all strains of Escherichia coli and Klebsiella pneumoniae were susceptible to thirdgeneration cephalosporins. The major stumbling block in terms of emergence of antibiotic resistance to these compounds occurred in inducible enterics (like Enterobacter and Serratia) and P seudomonas aeruginosa harbor. ing chromosomal (also known as type 1) enzymes. Resistance in these cases was due to selection of spontaneous mutants that hyperproduce those enzymes. Nevertheless, although this problem was substantial in those bacteria, the genes responsible for the enzymes are chromosomal and hence not able to spread between unrelated genera. The latest threat to our beta-lactam agents comes from novel plasmid-mediated beta-lactamases that are capable of destroying advanced spectrum compounds. The first such organisms 0278-2316 IDINDN 11(5) 33-40, 1992
34 Infectious Diseases Newsletter 11 (5) May 1992
Table 1. Extended-Spectxmn Beta-Lactamases in the TEM Faxnilya
Beta-Lactamase
Species
Country of Origin
Year of First Isolation (I) or Report (R)
MICb of: pl
Cefotaxime
Ceftazidime
Aztreonam
Pareatal types TEM-I
E. coli
Greece
TEM-2
P. aeruginosa
TEM-13
M. morganii
1963 (I)
5.4
0.125
0.25
England
1969 (I)
5.6
c
1990 (R)
5.6
--
--
K. pneumoniae
France
1984 (I)
6.3
32
64
16
E. coli
France
1986 (I)
5.9
32
32
16
K. pneumoniae
France
1987 (I)
5.55
4
128
8
TEM-6
E. coli
Germany
1987 (R)
5.9
1
128
64
TEM-7
Citrobacter freundii
France
1988 (R)
5.41
0.5
64
2
TEM-8
K. pneumoniae
c
1989 (R)
5.9
--
TEM-9 (RHH- 1)
K. pneumoniae
England
1989 (R)
5.5
TEM-10
K. pneumoniae
United States
1989 (R)
5.57
TEM-11 (Cazl0)
K. pneumoniae
Belgium
1989 (R)
5.7
0.06
TEM-12
E. coil
United States
1989 (R)
5.25
TEM-14
K. pneumoniae
c
1990 (R)
6.3
--
0.125
0.125
0.5
0.25 --
Proven unique TEM-3 (Ctx- 1) TEM-4 TEM-5 (Caz-l)
--
--
2
128
128
1
64
32
0.06
4 4 --
0.25 0.25 --
TEM-15
K. pneumoniae
c
1990 (R)
6.0
--
--
--
TEM-16
K. pneumoniae
c
1990 (R)
6.3
--
--
--
TEM-17
K. pneumoniae
c
1990 (R)
5.9
--
--
--
TEM-18
K. pneumoniae
c
1990 (R)
6.3
--
--
--
TEM-19
E. coli
c
1990 (R)
5.4
--
--
--
aAdapted from Philipon et at., A A C 33:1131-1136, 1989, and Jaeoby & Medeiros, A A C 35:1697-1704, 1991. bM~Cs are generally given for E. coil transeonjugants producing the given beta-lactamase. Some were determined in a uai.form genetic backgnaund, but most were determined by a variety of techniques that may make thea'n only closely comparable. When no values are given, data are not available. ¢Strains producing these enzymes originated in France, Belgium, England, Chile, and Germany, but the exact country of origin for each has not yet been reported.
were d i s c o v e r e d in the F e d e r a l R e p u b lic o f G e r m a n y in K l e b s i e l l a strains in 1983 and h a v e since spread rapidly across continental E u r o p e and n o w worldwide. This has n o w b e c o m e a substantial clinical p r o b l e m , w h i c h will b e the f o c u s o f this b r i e f review.
Characteristics of Extended Spectrum B e t a - L a c t a m a s e s M o r e than 30 u n i q u e p l a s m i d - m e d i -
ated e n z y m e s h a v e b e e n distinguished based on b i o c h e m i c a l and genetic characterization. A m o n g ampicillin-resistant strains o f E. coli, the T E M - 1 and T E M - 2 e n z y m e s are the m o s t c o m m o n . A m o n g Klebsiella species, m e m b e r s o f the S H V family p r e d o m i nate. T E M - 1 , T E M - 2 , and SHV-1 are e n z y m e s that h y d r o l y z e ampicillin preferentially but usually c o n f e r resistance to cephalothin as well. T h e y are unable to h y d r o l y z e e x t e n d e d spec-
trum c o m p o u n d s , such as the thirdgeneration c e p h a l o s p o r i n s and m o n o bactams. M o s t o f the n o v e l e n z y m e s described since 1983 that h y d r o l y z e third-generation c e p h a l o s p o r i n s and other a d v a n c e d s p e c t r u m c o m p o u n d s are point mutants that h a v e arisen from the g e n e s for the older w i d e spread T E M (Table 1) and S H V (Table 2) families o f e n z y m e s . T h e s e observations h a v e several o b v i o u s
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35 Infectious Diseases Newsletter 11(5) May 1992
Table 2. Extended-Spectrum Beta-Laetamases Not Related to TEMa Country Yearof First Beta-Lactamase
Species
of Origin
Isolation (I) or Report (R)
Switzerland
1974 (R)
7.6
Greece
1983 (I)
7.6
pI
Inhibition
MIC of: Cefotaxime
Ceftazidime
by
Aztreonam Cefoxitin
Imipenem Clavulanate
SHVderivatives SHV-1 SHV-2
E. c o i l K. ozaenae
SHV-3
K. pneumoniae
France
1986 (I)
7.0
SHV-4 (CazS)
K. pneumoniae
France
1987 (1)
7.75
SHV-5 (Caz4) Responsible for eephamycin resistance MIR-I
0.125 64
1
32
16
0.5
+
32
0.5
16
~5
+
64
32
32
16
~25
+
128
128
256
16
0.25
+
256
8
0.25
+
128
>256
K. pneumoniae
Chile
1987 (I)
8.2
64
128
K. pneumoniae
USA
1989 (R)
8.0
64
128
1
E. coli aAdapted from Philipon et al., AAC 33:1131-1136, 1989, and Jacoby & Medeiros, AAC 35:1697-1704, 1991.
clinical implications. First, the genetic pool from which such .mutants arise is extraordinarily large. For instance, about 40% ofE. coli strains in the United States are ampicillin-resistant due to TEM- 1 or TEM-2 production. Often, a mutation resdting in a single base pair change is sufficient to convert an ampicillin-hydrolyzing enzyme into one capable of destroying third-generation compounds. The resistance phenotypes of some of the novel extended spectrum enzymes of interest are displayed in Tables 1 and 2. It should be noted that some of these enzymes have unique appetites for destroying one compound over another. In general, they confer resistance to oxyimino beta-lactams like cefotaxime, ceftazidime, and aztreonam, while cephamycins and carbapenems are not affected. However, there are clear differences in their resistance proclivities. For instance, TEM-5 and some other related enzymes have a greater ability to destroy ceftazidime and aztreonam. Nevertheless, it is fair to say that in general most of these enzymes confer greater resistance to ceftazidime and aztreonam than cefotaxime.
Epidemiology Since their initial discovery in the Federal Republic of Germany, these enzymes have been reported throughout the European continent and many countries around the world. Of local interest, several novel enzymes have been described in the United States. The fast such enzyme to be fully described in North America, TEM- 10, is a potent ceftazidimase fast discovered in Klebsiella isolates from Chicago. Since then, other American investigators have described similar enzymes. The interested reader is referred to the works of Drs. Rice, Papanicolaou, and Weber. It should be noted that there is nothing terribly unique about these enzymes in different geographic locations and many enzymes have been described simultaneously in different countries. It should also be noted that many of the plasmids harboring these enzymes co-transfer other resistance genes. Hence, one may see tdmethoprim-sulfamethoxazole, aminoglycoside, and beta-lactam resistance transferred on the same plasmid. Once organisms harboring these re© 1992
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sistance enzymes have entered a hospi. tal, it is difficult to eradicate them. At the present time, approximately 16% of Klebsiella pneumoniae isolates from intensive care unit patients in Chicago are resistant to eeftazidime and aztreonam due to the introduction of these resistance genes (author's unpublished observations). There is, of course, great variation in the local preference of these resistance determinants, so that some hospitals have very high rates of resistance and others have very low rates, reflecting local epidemiologic factors. Nevertheless, these enzymes are clearly spreading quickly across the USA and worldwide and are likely to remain with us for the foreseeable future.
Molecular Studies Studies of the molecular basis for resistance due to the novel extended spectrum enzymes have added considerably to our understanding of structure-activity relations in beta-laetams. The preferential destruction of ceftazidime and aztreonam by many of these enzymes, for instance, suggests that there is something unique about
36 Infectious Diseases Newsletter 11(5) May1992 the structure of these compounds lhat makes them uniquely susceptible. This is, indeed, the case. In nature, the beta-lactamase molecule forms a cave that has a novel topology made up of two closely associated domains. The active site is located at the interface between these domains, with the key catalytic residue being a serine at position 70. This is the active site of the enzyme, which allows it to bind to the beta-lactam ring and destroy the beta-lactam compound. Molecular studies of the new enzymes have revealed that the serine residue at position 70 is retained in each case. Amino acid substitutions have recurred at remote locations. We are beginning to understand how mutations at these remote locations can confer resistance to specific drugs. For example, the potential interaction of serine at position 236 in the enzyme TEM-3 is known to interact with the methyl-oxime side chain of cefotaxime, allowing the serine residue to bind to and destroy the betalactam ring.
Future Prospects Each year brings a bewildering array of new beta-lactamases with unique properties. A few such enzymes merit special attention. Dr. Papanicolaou and colleagues recently described a novel plasmid-mediated enzyme known as MIR-1 that confers resislance to all beta-lactams other than imipenem among Kiebsiella pneumoniae isolates. This antibiogram is quite reminiscent of that which is typically conferred by chromosomal enzymes. In fact, genetic studies of this enzyme reveal that it was derived from the Enterobacter cloacae AmpC gene, the structural chromosomal gene for type 1 beta-lactamase in that organism. Therefore, this is a chromosomal gene that spreads on a plasmid among Klebsiella isolates, presumably on a transposon. Dr. Watanabe and colleagues have also described an alarming enzyme in
Japan in a Pseudomonas aeruginosa isolate. This enzyme conferred resistance to carbapenems like imipenem and meropenem as well as antipseudomonal penicillins and cephalosporins and has an exceptionally broad substrate. It is resistant to inhibition by clavulanic acid, unlike most of the novel extended spectrum enzymes, and it belongs to the same family of chromosomally determined imipenem hydrolyzing enzymes found in Xanthomonas maltophilia and Bacteroides fragilis. There are several practical concerns for the microbiologist and clinician that result from the spread of these enzymes. The first is that our clinical microbiology laboratories must begin to look for these organisms specifically by testing ceftazidime against enteric Gram-negative rods. Since many of these enzymes will confer resistance to ceftazidime but not other cephalosporins, class susceptibility testing may not detect organisms harboring these enzymes. Another clinical concern results from the increasing popularity of monotherapy with an advanced spectrum cephalosporin for various and sundry life-threatening infections. This is best exemplified by empiric ceftazidime monotherapy for febrile neutropenic cancer patients, a widespread practice in this country. We have recently described a large epidemic of ceftazidime-resistant Klebsiella and E. coli infections among children with cancer at a university hospital in California. This epidemic proved to be due to TEM-9, a plasmicmediated ceftazidime-hydrolyzing enzyme first described in a hospital in England in 1987. While the source of the epidemic was never identified by epidemiologic studies, the epidemic was terminated by abolishing empiric monotherapy and switching to a conventional triple-drug regimen of azlocillin, nafcillin, and amikacin for neutropenic fever. Clinicians and microbiologists must remain in the front line of awareness for new resistance determinants and © 1992 Elsevier Science Publishing Co., Inc. ~'T~_'~
l ~1(~'~ /~,~ ~X~ .~- "~ ~(~
must be able to respond appropriately.
Bibliography Gutmann L, Kitzis MD, Billot-Klein D, et al: Plasmid-mediated beta-lactamase (TEM-7) involved in resistance to ceftazidime and azlreonam. Rev Infect Dis 10:860-866, 1988. Herzberg O, Moult J: Bacterial resistance to beta-lactam antibiotics: crystal structure of beta-lactamase from Staphylococcus aureus PC1 at 2.5 A resolution. Science 236:694-701, 1987. Jacoby G, Medeiros A: More extendedspeclrum beta-lactamases. Antimicrob Agents Chemother 35:1697-1704, 1991. Kiutzis MD, Billot-Klein D, Goldstein FW, et al: Dissemination of the novel plasmid-mediated beta-lactamase Ctx-1 which confers resistance to broad-spectrum cephalosporins and its inhibition by beta-lactamase inhibitors. Antimicrob Agents Chemother 32:9-14, 1988. Knothe H, Shah E Kremery V, et at: Transferable resistance to cefotaxime, cefoxitin, cefamandole and cefuroxime in clinical isolates of Klebsiella pneumoniae and Serratia marcescens. Infection 11:315-317, 1983. Medeiros AA: Plasmid-determined betalactamases. In Bryan LE (ed.) Microbial Resistance to Drugs. Vol. 91 of Handbook of Experimental Pharmacology. Berlin, Springer-Verlag, pp 101-127, 1989. Papanicolaou GA, Medeiros AA, Jacoby GA: Novel plasmid-mediated beta-lactamase (MIR-1) conferring resistance to oxyimino- and alpha-methoxy beta-lactams in clinical isolates of Klebsiella pneumoniae. Antimicrob Agents Chemother 34:2200-2209, 1990. Philipon A, Labia R, Jacoby G: Extendedspectrum beta-lactamases. Antimicrob Agents Chemother 33:1131-1136, 1989. Quinll JP, Miyashiro D, Sahm D, Flamm R, Bush K. Novel plasmid-mediated beta-lactamase (TEM-10) hydrolyzing ceftazidime and aztreonam in clinical isolates of Klebsiella pneumoniae. Antimicrob Agent Chemother 33:14511456, 1989. Quinn JP, Naumovsky L, Arvin A: Epidemic of ceftazidime-resistant gramnegative bacillary infections among pediatric cancer patients. 1991 Annual Meeting, American Society for Microbiology; abstract number A-30. Rice LB, Wiley SH, Papanicolaou GA, et al: Outbreak of ceftazidirae resistance caused by extended spectrum beta-lacta~nases at a Massachusetts chronic care
37 Infectious Diseases Newsletter 11(5) May 1992 facility. Antimicrob Agents Chemother 34:2193-2199, 1990. Sanders CC: The chromosomal beta-lactamases. In Bryan LE (ed) Microbial Resistance to Drugs. Vol. 91 of Handbook of Experimental Pharmacology. Berlin, Springer-Verlag, pp 129-149, 1989. Sougakoff W, Goussard S, Gerbaud G, Courvain P: Plasmid-mediated resistance to third generation cephalosporins caused by point mutations in TEM-type penicillinase genes. Rev Infect Dis 10:879-884, 1988. SougakoffW, Petit A, Gosussard S, et al:
Characterization of the plasmid genes blaT-4 and blaT-5 which encode the broad-spectrum beta-klactamases TEM4 and TEM-5 in Enterobacteriaceae.
Gene 339-348 1989. Spencer RC, Wheat PF, Winstanley TG, et al.: Novel beta-lactarnase in a clinical isolate of Klebsiella pneumoniae conferring unusual resistance to beta-lactara antibiotics. J Antimicrob Chemother 20:919-921, 1987. Watanabe M, lyobe S, lnoue M, Mitsuhashi S: Transferable imipenem resistance in Pseudomonas aeruginosa.
Antimicrob Agents Chemother 35:147151, 1991. Weber D, Sanders C, Bakken J, Quinn JP: A novel chromosomal "lEJd-derivafive (TEM-12) and altered outer membrane proteins together mediate selective ceftazidime resistance in E. coli. J Infect Dis 162:460-465, 1990 Address correspondence and reprint request to John P. Quinn, MD, Associate Professor of Medicine, University of Illinois, Michael Reese Hospital and Medical Center, Lake Shore Drive at 31st Street, Chicago, IL 60616.
Congenital Tuberculosis John T. Sinnott, IV, MD, FACP1, Timothy C. Gompf, BS,2 and Sandra Gonzalez Gompf, MD2 lDivision of Infectious and Tropical Diseases, 2Departmentof Internal Medicine, University of South Florida, College of Medicine, Tampa, Florida
With the recent resurgence of Mycobacterium tuberculosis (MTB) as a dangerous pathogen, the wise physician should recall an unusual complication: congenital tuberculosis. This uncommon but devastating complication of pregnancy will, in all likelihood, also become more frequent. Congenital MTB was originally described before the start of the "isoniazid era" of tuberculosis therapy. In 1985, 36 cases of congenital tuberculosis were reported in the literature since the 1950s, and some have been added to the literature since. However, considering the difficulty encountered in distinguishing congenital from postnatal disease, the true prevalence of congenital tuberculosis in the USA is probably not known.
C o n g e n i t a l I n f e c t i o n W i t h MTB
Congenital tuberculosis occurs more frequently in pregnancies complicated by primary maternal infection. Pri-
mary TB has a greater propensity for lymphohematogenous dissemination than does reactivation pulmonary TB. MTB can be congenitally transmitted either through the umbilical vein or by the amniotic fluid. Hematogenous spread of the pathogen through the umbilical vein results from maternal hematogenous spread to the placenta, miliary tuberculosis involving the placent,a, or from the local extension of tuberculosis endometdtis. Amniotic fluid becomes a vehicle when placental or genitourinary lesions rupture into the amniotic fluid leading to infection through aspiration or swallowing of the infected fluid in utero or at delivery. If the umbilical vein carries the pathogen to the fetus, the infection initially develops in the liver because of the anatomy of the fetal circulation as well as the high oxygen level of the liver. Many other sites may become secondarily involved, including the lungs, meninges, skin, gastrointestinal tract, lymphatics, and bone marrow. ©1992 Elsevier Science Publishing Co., Inc. 0278-2316/92/$0.00 + 3.00
When the amniotic fluid is the vehicle for spread, the primary infection may occur in the lungs or the gastrointestinal tract. Typically, infants with congenital tuberculosis present around 1 month of age with nonspecific symptoms or with a persistent pneumonia. Respiratory distress, fever, and hepatomegaly with or without splenomegaly are the most commonly noted findings, accompanied also by poor feeding, lethargy and/or irritability, and lymphadenopathy. Less common f'mdings include abdominal distention, failure to thrive, otorrhea, polymorphic skin lesions, jaundice, and seizures.
Diagnosis
The diagnosis of congenital MTB should be entertained in any infant with the aforementioned symptoms when associated with a maternal history of tuberculosis during pregnancy. Interestingly, congenital tuberculosis