β-lactam antibiotics: The extended spectrum penicillins

β-lactam antibiotics: The extended spectrum penicillins

14 THE ANTIMICROBIC NEWSLETTER, -LACTAM ANTIBIOTICS: THE E X T E N D E D S P E C T R U M PENICILLINS D A N I E L F. S A H M , PaD • Clinical Mic...

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THE

ANTIMICROBIC

NEWSLETTER,

-LACTAM ANTIBIOTICS: THE E X T E N D E D S P E C T R U M PENICILLINS D A N I E L F. S A H M , PaD



Clinical Microbiology Laboratories, University o / C h i c a g o Chicago, Illinois

CLYDE THORNSBERRY,

Medical Center,

PaD

Center/or In/ectioas Diseases, Centers/or Disease Control, Atlanta, Georgia R O N A L D N. J O N E S , MD Kaiser-Permanente Medical Care Program, Clackoznas, Oregon Molecular manipulation of the 6aminopenicillanic acid structure resulted in the evolution of semisynthetic penicillins resistant to staphylococcal fl-lactamases and generated the development of broader spectrum penicillins that would be active against gram-negative bacilli. The first available representative of these extended spectrum penicillins was ampicillin. Subsequently, several other penicillins active against gram-negative bacilli were developed. Based on similarities in their molecular structure, the currently available extended spectrum penicillins are subdivided into several major groups (Table 1). Because these penicillins were designed for use against gram-negative bacilli, discussion of their antibacterial spectra will focus primarily on this particular group of organisms. The aminopenicillin group is comprised of ampicillin (and its prodrug analogues), amoxicillin, epicillin, and cyclacillin (Table 1). These penicillins share nearly identical spectra of activity and differ with respect to their oral pharmacologic properties. The aminopeniciUins are usually active against most strains of Escherichia coli, Proteus mirabilis, Salmonella spp., and ShigeUa spp., b u t are not active against other Enterobacteriaceae, Pseudomonas aeruginosa, or Acinetobacter spp. (Table 2). Additionally, they are active against fl-lactamase negative © 1985 B Y E L S E V I E R

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isolates of Haemophilus influenzae. Ampicillin or penicillin combined with an aminoglycoside is usually efficacious for serious systemic enterococcal infections. Although the aminopenicillins are active against fl-lactamase negative Neisseria spp., staphylococci, and various streptococci, they are less active than the original penicillins and penicillin remains the drug of choice for these particular organisms. The spectrum of activity of the carboxypenicillins (carbenicillin, ticarcillin) (Table 1), generally includes the spectrum of the aminopenicillins and is notably expanded to include P. aeruginosa, Acinetobacter spp., and most indole-positive Proteae (Table 2). The activities of carbenicillin and ticarcillin against Enterobacter spp. and Serratia spp. are more variable and neither drug

VOLUME

2, N U M B E R

2, F E B R U A R Y

1985

is active against Klebsiella spp. Temocillin, a 6a-methoxy derivative of ticarcillin, significantly differs from the true carboxypenicillins by being more active against Klebsiella spp. and Enterobacter spp., and by lacking significant activity against P. aeruginosa and Acinetobacter spp. The spectrum of activity of the acylureidopenicillins (mezlocillin, piperacillin, azlocillin) is most similar to that of the carboxypenicillins (Table 2). However, mezlocillin and piperacillin are more active than either carbenicillin or ticarcillin against the Enterobacteriaceae; especially Klebsiella spp. and Serratia spp. Similarly, the antipseudomonal activities of piperacillin and azlocillin are greater than the activities of either carbenicillin, ticarcillin, or mezlocillin. The aminopenicillanic acid, amdinocillin (formerly mecillinam), is apparently active against many of the Enterobacteriaceae but lacks activity against Serratia spp., P. aeruginosa, and Acinetobacter spp. (Table 2). However, because in vitro susceptibility results obtained with amdinocillin have been unreliable, the actual spectrum of activity of this drug is uncertain. Also listed in Table 1 as a major penicillin group are the co-drugs, antimicrobics that combine a penicillin with a fl-lactamase inhibitor (see The A M N , Vol. 1, No. 3, March 1984, p. 23). Among these are

T A B L E I. Extended Spectrum Penicillins AMINOPENICILLINS AmpiciUin Bacampicflliff Pivampicilliff Talampicilliff Hetadlliff Amo3dcillin

Epicillin

ACYLUREI DOPEN Medocillin Piperacillin Azlocillin

ICI LLI N S

Apaldllin AMINOPENICILLANIC ACID Amdinocillin(Meci]linarn)

Cycladllin CARBOXYPEN|CILLINS

Carbeaidllin 'Picarcillin

CO-DRUGS b Augmentin(Amoxicillin + Clavulanic Acid) "P[rnentin(Ticarci|lin+ Clavu]anic Acid)

SultamJcillin(Ampidllin + Sulbactam)

6a-METHOXYPEN|CILLIN Temocillin • Prodruga, compounds which, after ingestion, are released or converted to arnpicillin. b Penidllin plus a ~.[actamMe inhibitor combination.

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NEWSLETTER,

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15

Extended Spectrum Penicillin--Spectrum of Activities for Gram-Negative Bacilli" E. P. Salmonella- Klebswlla Indole + Enterobacter Serratta P. Acmetobacter cob mwabd~.~ S h ~ e l l a spp. Proteae spp. app. aerugtrmsa app.

AMINOPENICILLINS A m p i c i l l i n~ + Sulbactam~ Amoxicillin Clavulanate ~ Epicillin Cyclacillin CARBOXYPENICILLINS Carbenicillin Ticarcillin + Clavulanate~ 6a-METHOXYPENICILIA N Temocillin A C Y L U R E I D O P E N ICI LIA N S MtCJocillin Piperacillin Azlocillin AMINOPENICII.LANIC ACID Amdinocillin

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" E x t e n d e d s p e c t r u m penicillins will also d e m o n s t r a t e a c t i v i t y a g a i n s t s t r e p t o c o c c i a n d f l - l a c t a r n a s e n e g a t i v e s t a p h y l o c o c c i , NeL~etaa s p p . , and H. tnfluenzae. I n f o r m a t i o n c o m p i l e d from r e f e r e n c e s I 7. I'lncludt.~ bacarnpicillin, pivampicillin, t a l a m p i c i l l i n , a n d hetacillin. 'fl-lactama.se inhiliitor a d d e d to m a k e co-drug {see T a b l e 1) a c t i v e a g a i n s t ~ - I a c t a m a s e p r o d u c i n g o r g a n i s m s i n c l u d i n g s t a p h y l o cocci, NeL~serm s p p . a n d H . tn//uenzae. ( * ) - 75q[ of s t r a i n s s u s c e p t i b l e ; ( ± } - 25--75q, of s t r a i n s s u s c e p t i b l e ; ( " ) - 25~ of s t r a i n s stmceptible.

Augmentin (amoxacillin plus clavulanic acid), Timentin (ticarcillin plus clavulanic acid), and Sultamicillin (ampicillin plus sulbactam). By combining these penicillins with a fllactamase inhibitor (Table 2), the penicillin's spectrum of activity may be substantially expanded to include fl-lactamase- producing Bacteriodes spp., Staphylococcus spp., H. influenzae, N. gonorrhoeae, several species of Enterobacteriaceae, and more strains of P. aeruginosa and Acinetobacter spp. s- ~o As shown in Table 2, the various extended spectrum penicillins currently available for clinical use in the United States demonstrate considerable overlap in their spectra of activity. Because this overlap in antibacterial activity often complicates decisions concerning the drugs routinely chosen for in vitro susceptibility testing, we have outlined general guidelines that may facilitate the selection of these penicillins for testing (Table 3). However, we realize that the antibiotics actually selected by a particular institution may vary. Ampicillin is the "class" drug for testing aminopenicillins (Table 3). Ampicillin should be routinely tested against Enterobacteriaceae and may also be tested against H. influenzae. However, a rapid preliminary flr. 07:18-1751/8,)/$0.(D + 2.20

lactamase test is often preferred, although occasional fl-lactamasenegative strains may be resistant to ampicillin. For testing enterococci, ampicillin could replace penicillin G, but penicillin G is recommended for testing against other streptococci (except for use of the 1-/zg oxacillin disk to determine relative penicillin resistance of pneumococci). Penicillin G is also recommended for determining staphylococcal resistance to all penicillinase-labile penicillins. Although there is no "class" drug representative for either the carboxypenicillins or the acylureidopenicillins, the overlap of antibacterial activities among the carboxypenicillins and acylureidopenicillins eliminates the need to test all these drugs against a par-

T A B L E 3.

ticular bacterial isolate. A single drug from each group may be chosen for testing against the Enterobacteriaceae (Table 3). Similarly, for testing P. aeruginosa and Acinetobacter spp., one drug may be selected from among carbenicillin, ticarcillin, and mezlocillin. Additionally, because piperacillin and azlocillin have a slightly greater antipseudomonal activity, one of these two drugs should also be chosen for susceptibility testing. Again, because penicillin G is most reliable for determining the susceptibility of staphylococci and streptococci to the penicillin family of drugs, none of the carboxypenicillins or acylureidopenicillins need be tested against these isolates. Additionally, whenever possible, hospital formularies and laboratories should limit the availability and testing to only one drug from the carboxypenicillin a n d / o r acylureidopenicillin groups against gram-negative bacilli. The co-drugs such as Augmentin cannot be grouped with other penicillins because of their unique nature, and therefore need to be tested individually (Table 3). The uncertain clinical use of temocillin and amdinocillin currently prohibits us from making recommendations for the selection and use of these two drugs for in vitro testing. REFERENCES 1. Hoover JRE: fl-lactam antibiotics: structure-activity relationships. In Demain AL, Solomon NA (eds). An-

Recommended Ant)microbial Agents for In Vitro Susceptibility Testing

Penicillin gr o u p

Staphylococci

Streptococci

Enterococci

Enterobacteriaceae

O r i g i n a l penicillins" Penicillinmse- resist a n t penicillins" Aminopenicillins Carboxy- and a c y lu r e i d o p e n i c i l l i n s

Penicillin G

Penicillin G

Penicillin G

h

Oxacillin ---

(Oxacillin) ~ ---

-Ampicillina --

-Ampicillin Carbenicillin O R Ticarcillin

A ND Mezlocillin O R Piperacillin " C o - d r u g " penicillins"

Augmentin

--

--

Augmentin

Pseudomonas

--Carbenicillin OR Ticarcillin O R Mezlocillin

AND Piperacillin O R Azlocillin --

• ) ~ . e c o m m e n d a t i o n s d i s c u . s ~ l in The A M N , Vol. 2, No. I, J a n u a r y 1985. i,(__) , Routine testing of drugs from these penicillin g r o u p s against these o r g a n i s m s is n o t r e c o m m e n d e d , • Oxacillin (lug d i s k ) s h o u l d be used to d e t e c t p n e u m o c o c c i r e l a t i v e l y resistant to penicillin. 'lAmpicillin m a y be s e l e c t e d to replace ptmicillin G. .... C o - d r u g s " - Penicillin plus a fi-lactarnase i n h i h i t o r (see T a b l e 1L

~" 1985 BY E L S E V I E R S C I E N C E P U B L I S H I N G CO., INC.

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THE ANTIMICROBIC NEWSLETTER, VOLUME 2, NUMBER 2, FEBRUARY 1985

tibiotics containing the beta-lactarn structure II. Heidelberg, SpringerVerlag, pp. 119-245, 1983. 2. Lid JV, Actor P: Therapeutic application of fl-lactam antibiotics. In Demain AL, Solomon N A (eds).Antibioticscontaining the beta-lactarn structure If. Heidelberg, Springer. Verlag, pp. 399-429, 1983. 3. Jones R N : Antimicrobial susceptibility testing (AST): a review of changing trends, quality control guidelines, test accuracy, and recommendations for testing of 13-1actarn drugs. Diagn Microbiol Infect Dis 1:1-24, 1983. 4. Gaya H: Susceptibilitystudies with the new penicillins.In Periti P, Gra~qi GG (eds). Proceedings of the 12th International Congress of Chemotherapy, Florence, Italy. Washington, DC, American Society for Microbiology, 1981. 5. Fass RJ: Statistical comparison of t h e antibacterial activities of broadspectrum penicillins against gramnegative bacilli. Antimicrob Agents Chemother 24:156-162, 1983. 6. Barry AL, Jones RN, Ayers LW, Gavan TL, Gerlach EH, Sommers

7.

8.

9.

10.

HM: In vitro activity of apalcillin compared with those of piperacillin and carbenicillin against 6,797 bacterial isolates from four separate medical centers. Antimicrob Agents Chemother 25:669-671, 1984. Bolivar R, Weaver SS, Bodey GP: Comparative in vitro study of temociUin (BRL 17421), a new penicillin. Antimicrob Agents Chem o t h e r 21:641-645, 1982. Retsema JA, English AR, Girard AE: CP-45,899 in combination with penicillin or ampicillin against penicillin-resistant Staphylococcus, Haemophilus influenzae, and Bacteroides. Antimicrob Agents Chemother 17:615-622, 1980. M a t s u r a M, Nakazawa H, Hashimoto T, Mitsuhashi: Combined antibacterial activity of amoxicillin with clavulanic acid against ampicillin-resistant strains. Antimicrob Agents Chemother 17:908-911, 1980. H u n t e r PA, Coleman K, Fisher J, T a y l o r D: In vitro synergistic properties of clavulanic acid with ampicillin,arnoxyciUin, and ticarcillin.J Antimicrob Agents Chemother 6:445-457, 1980.

ERRATUM In t h e a r t i c l e b y P i d d o c k and Wise in t h e J a n u a r y 1985 issue of T h e A M N (Vol. 2, No. 1), t h e t h i r d s e n t e n c e of t h e second p a r a g r a p h on page t h r e e is incorrect. T h e b e g i n n i n g of t h a t p a r a g r a p h should read N a l i d i x i c acid a n d o t h e r 4-quinolones will, a t levels close to t h e m i n i m u m i n h i b i t o r y concentration ( M I C ) , i n h i b i t D N A synthesis, as will c o u m e r m y c i n A, novobiocin, etc. I t is k n o w n t h a t c o u m e r m y c i n A a n d s i m i l a r a n t i m i c r o b i c s ina c t i v a t e t h e 13 s u b u n i t s of gyr, 9 w h i c h is p a r a l l e l e d by relaxation of t h e D N A b e c a u s e only t h e a subunits are operating. The a subunits of D N A g y r i n t r o d u c e t h e single s t r a n d incisions, necessary for rel a x a t i o n of t h e supercoiled D N A to allow t r a n s c r i p t i o n , and resealing of t h e incision a f t e r w a r d s when n e g a t i v e supercoils have been introd u c e d b y t h e 13 subunits.

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