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Home , Azlocillin, Cefmenoxime, Cefonicid, Ceforanide, Ceftizoxime, Cephalosporin

Henry Ford Hospital Medical Journal

Volume 32 Number 2 Article 3

6-1984

An Overview of the Newer

Ramon del Busto

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Recommended Citation del Busto, Ramon (1984) "An Overview of the Newer Antibiotics," Henry Ford Hospital Medical Journal : Vol. 32 : No. 2 , 90-98. Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol32/iss2/3

This Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Henry Ford Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons. Henry Ford Hospital Med J Vol. 32, No. 2, 1984

An Overview of the Newer Antibiotics

Ramon del Busto, MD*

The introduction of a large number of new antibiotics Newer has made selecting the one most appropriate for treat­ All the cephalosporins consist of a dihydrothiazine ring, ment a confusing task for the practicing physician. One which is a six-sided nucleus attached to a four-sided, problem is that the differences in , in beta-lactam ring (Fig. 1). They all have a sulfur atom at vitro activity, and clinical indications between some of position 1, except for moxalactam which has an oxygen these agents may be relatively minor; this is especially true of the new cephalosporins. Another problem is that the generic names of the cephalosporins are so similar that it is impractical, even for the infectious 0 H diseases specialist, to be familiar with all of them. This review attempts to summarize the most important char­ [R]—CONH R acteristics of these new antibiotics and emphasizes their indications in clinical practice. 1

A list of the new parenteral antibiotics appears in Table I. Among the so-called second-generation ceph­ 0 alosporins, and have been re­ cently introduced for clinical use in the United States. GOGH The third-generation cephalosporins that are available Fig. 1 commercially include , moxalactam, cefo­ Basic molecular structure of the cephalosporins. perazone, and . The fourth-generation include the , , atom and is therefore not considered a true ceph­ and as well as a piperazine-derivative, piper­ alosporin but an oxa-beta-lactam . In the acillin. Among the aminoglycosides, the newest agent search for cephalosporins with greater antibacterial ac­ available is netilmicin, a derivative of sisomicin. tivity and better pharmacological properties, innumer­ able substitutions and modifications have been made at virtually all positions on the molecule. The most important changes have been made at posi­ tions 3 and 7. In general, substitutions at position 3 of the dihydrothiazine ring usually affect pharmacokinetic TABLE 1 properties, and modifications to the acyl chain at posi­ Newer Parenteral Antibiotics tion 7 of the beta-lactam ring mostly affect the micro­ biological activity of the cephalosporin (1-3). In addition, the presence of a methylthiotetrazole ring at position 3 is associated with some side effects of these Cephalosporins agents. Second-Generation Cefuroxime (Zinacef) Cefonicid (Monocid) Currently, 12 parenteral and four oral cephalosporins Third-Generation Cefotaxime (Claforan) are available commercially. As if these were not Moxalactam (Moxam) enough, many more cephalosporins and cephalosporin (Cefobid) Ceftizoxime (Cefizox) Submitted for publication: April 5, 1984 Fourth-Generation Penicillins Mezlocillin (Mezlin) Accepted for publication: May 29, 1984 Azlocillin (Aziin) •Department of Internal Medicine, Division of Infectious Diseases, Henry Ford (Pipracil) Hospital Address reprint requests to Dr. del Busto, Internal Medicine, Henry Ford Aminoglycosides Netilmicin (Netromycin) Hospital, 2799 W Grand Blvd, Detroit, Ml 48202,

90 Newer Antibiotics

derivatives are currently being investigated and will aureus, and monocytogenes. However, the soon be available for clinical use (Table 11). first-generation cephalosporins, as represented by or cephalothin, are more active than the later ones, especially in comparison with moxalactam, a TABLE 11 third-generation cephalosporin with the weakest ac­ Classification of Parenteral Cephalosporins tivity against gram-positive organisms (4).

First-Generation Second-Generation Third-Generation Table IV compares the in vitro activity of the cephalo­ sporins against gram-negative organisms. The first- Cephalothin (Keflin) Cefotaxime generation cephalosporins are active only against these Cefazolin (Ancef, (Mandol) (Claforan) few gram-negative organisms: E. coli, Klebsiella, and Kefzol) * (Mefoxin) Moxalactam* mirahilis. Even some of these organisms are Cephapirin (Cefadyl) Cefuroxime (Zinacef) (Moxam) now resistant to the first-generation cephalosporins, as Cephradine (Velosef) Cefonicid (Monocid) Cefoperazone evidenced by their high MlCgoS. The first-generation ** (Cefobid) Ceftizoxime cephalosporins are not active against many other gram- (Cefizox) negative organisms, such as , , ** Morganella, Providencia, or , which are * frequently seen in hospital-acquired . Nor are ** they active against H. influenzae or . * Not a true cephalosporin ** The second-generation cephalosporins have a some­ •* Investigational what wider anti-gram-negative . Cefaman­ dole, cefuroxime, and cefonicid are active against In vitro activity Enterobacter and H. influenzae. Cefoxitin has some Third-generation cephalosporins have a wider spec­ limited activity against indole-positive proteus and Ser­ trum of activity against aerobic gram-negative bacilli ratia but is particularly active against Bacteroides compared to the older agents, but they are less active fragilis. against gram-positive organisms. Table 111 compares the The third-generation cephalosporins have an even in vitro activity of the cephalosporins against gram- wider anti-gram-negative spectrum. Except for Ac­ positive organisms. All the cephalosporins are acti've inetobacter, they are fairly active against most of the against most gram-positive , except for Strep­ gram-negative organisms, including some weak anti- tococcus faecalis, -resistant pseudomonas activity. Apart from minor differences.

TABLE III

Comparative In-vitro Activity of the Cephalosporins against Gram-positive Organisms* (MIC<,o)**

Cefotaxime Cefazolin Ceftizoxime Moxalactam Cefoperazone Group A 0.05 0.12 4 0.12 Streptococcus Group B 0,1 4 0.25

S. pneumoniae 0.1 0.12 2 0.25 Streptococcus (alpha, non­ 0.25 0.25 2 0.25 hemolytic, non-group D) (Cephalothin)

Streptococcus faecalis >128 >128 >128 >128 0.5 2 16 4 (Cephalothin)

Listeria monocytogenes >128 >128 >128 >128

* Neu, H. (4) •MIC90 - minimal concentration of antibiotic in micrograms/ml required to inhibit 90% of isolates

91 del Busto

cefotaxime and ceftizoxime have very similar in vitro Pharmacokinetics (Table V) activity. Cefoperazone is less active than the other third- generation cephalosporins against most gram-nega­ The new cephalosporins have a more prolonged half- tives, except for . Moxalactam life than the older agents, except for cefazolin, which is most active against Bacteroides fragilis, and its activity has a half-life of 1.4 hours. Cefuroxime, a second- against this organism is comparable to that of cefoxitin. generation cephalosporin, has in vitro activity similar to

TABLE IV Comparative In-vitro Activity of the Cephalosporins against Cram-negative Organisms* (MIC90)**

Cefotaxime Cefazolin Ceftizoxime Moxalactam Cefoperazone

Escherichia coli >128 0.25 0.25 16

Klebsiella pneumoniae >128 0.25 0.25 16

Proteus mirahilis 16 0,1 0,2 1

Enterobacter aerogenes >128 0,2 0,2 2

Serratia marcescens >128 4 4 16

Morganella morganii , stuartii >128 2 0.5 4

Pseudomonas aeruginosa — 64 32 32

Haemophilus influenzae 0.39 0.03 0.06 (Cefamandole)

Bacteroides fragilis 16 64 16 64 (Cefoxitin)

* Neu, H. (4)

**MIC9o = minimal concentration of antibiotic in micrograms/ml required to inhibit 90% of isolates

TABLE V Pharmacokinetics of the New Cephalosporins*

Protein Peak Serum** Half- Usual Route Binding Levels (mcg/ml) Life (HR) of Excretion Metabolized Cefuroxime 33-50% 50 1.3 Renal No Cefonicid*** >90% 221 4.5 Renal No Cefotaxime 38% 42 1,1 Renal Ves Moxalactam 50% 60 2.3 Renal No Cefoperazone 90% 12.S 1,9 Liver No Ceftizoxime 31% 37 1,4 Renal No Ceftazidime 17% 80 1,8 Renal No Ceftriaxone 83-96% 150 8 Renal, liver No

• Neu H, (4) ** 1 gm IV, except for cefuroxime (750mg IV) *** Data from Smith, Kline and French Laboratories

92 Newer Antibiotics

cefamandole, but it also has a more prolonged half-life enterobacteriaceae that are resistant to the older ceph­ (1.3 vs 0.5 hours) and a better cerebrospinal fluid pen­ alosporins, although the number of patients treated is etration. The half-life of cefonicid is 4.5 hours, which relatively small (6,7). Since therapy in these cases lasts allows once-a-day doses. Of the third-generation ceph­ four or more weeks, the new cephalosporins offer a alosporins, cefotaxime has the shortest half-life (ap­ clear advantage over the more toxic aminoglycosides. proximately one hour). Moxalactam, cefoperazone, However, these cephalosporins should not be used to and ceftizoxime have half-lives of 2.3,1.9, and 1.4 hours, treat Pseudomonas osteomyelitis, since many failures respectively, which allows them to be administered ev­ have been reported (4). ery 8 hours, or even every 12 hours for less serious infections. Ceftriaxone, one ofthe investigational ceph­ Lower respiratory infections. The third-generation ceph­ alosporins, has a very prolonged half-life (about 8 alosporins are not indicated in the treatment of hours), which permits every 12 or even every 24-hour pneumococcal or staphylococcal , as older antibiotics are less expensive and more effective. It is doses. not known if the newer cephalosporins are better than All newer cephalosporins are excreted primarily by the or trimethoprim sulfamethoxazole in treating kidneys, except for cefoperazone which is excreted pneumonia, but they may be mainly by the liver. Only cefotaxime is metabolized to a useful against ampicillin-resistant Haemophilus. In less active desacetyl derivative. Except for cefonicid, the community-acquired aspiration pneumonia, which is newer cephalosponns have the additional advantage of generally caused by anaerobic organisms, or penetrating fairly well into the cerebrospinal fluid; they clindamycin is the drug of choice. Third-generation have been successfully used to treat bacterial men­ cephalosporins have been successfully used as single ingitis caused by susceptible organisms. agents to treat nosocomial caused by gram-negative bacilli; however, they should not be used alone to treat Pseudomonas pneumonia (4). Clinical Indications . The new cephalosporins are clearly superior In general, the third-generation cephalosporins are to , and to intrathecal and parenteral rarely indicated, especially when older, less expensive aminoglycosides to treat certain types of gram-negative antibiotics can be used. They are indicated, however, to meningitis (8-10). Cefotaxime or moxalactam is the drug treat infections resulting from organisms resistant to of choice for meningitis caused by such gram-negative older cephalosporins, infections that may require pro­ bacilli as E. coli, Klebsiella, or Proteus. The new ceph­ longed therapy with aminoglycosides (ie, osteomyelitis alosporins may also be used instead of chloramphenicol due to Enterobacteriaceae), and certain types of gram- for patients who have meningitis caused by H. influen­ negative bacillary meningitis. zae resistant to ampicillin. Cefuroxime (11) and cef­ triaxone (12) have been shown to be as effective as Urinary tract infections. Third-generation cepha­ ampicillin and chloramphenicol to treat meningitis losporins are indicated only in those urinary tract infec­ caused by H. influenzae, N. meningitidis, and S. pneu­ tions that are caused by organisms resistant to older moniae. Ceftizoxime also appears to be an excellent cephalosporins, penicillins, or aminoglycosides. These antibiotic to treat bacterial meningitis that results from organisms are usually seen in complicated, hospital- susceptible organisms, but clinical experience is still lim­ acquired urinary tract infections. In these instances, the ited (13). Cefoperazone may penetrate less well into the cure rates are comparable to those of the older ceph­ cerebrospinal fluid than other new cephalosporins (14). alosporins or the aminoglycosides. However, in urinary tract infections caused by Pseudomonas aeruginosa the The newer cephalosporins are not indicated in the fol­ cure rate has been only 50-70% (4). lowing types of meningitis: 1) as single therapy for purulent meningitis in the neonate before the causative Soft tissue and skeletal infections. In skin and soft tissue organism has been identified; they are not active infections, the newer cephalosporins should be used against Listeria monocytogenes, which is a relatively only in those infections caused by enterobacteriaceae frequent pathogen in this age group; 2) in Pseud­ resistant to older agents (5). The older cephalosporins omonas meningitis, where an aminoglycoside (intra­ are preferred to treat Staphylococcus aureus and sus­ thecal or intraventricular) and an anti-pseudomonal ceptible gram-negative organisms. In bone and joint penicillin should be used; 3) in meningitis beyond the infections caused by Staphylococcus aureus, or neonatal period and before an organism is identified, a first-generation cephalosporin is preferred because moxalactam should be avoided since it is insufficiently both offer greater activity at lower cost. The newer active against S. pneumoniae; 4) in meningococcal and cephalosporins may also replace the aminoglycosides pneumococcal meningitis, where penicillin remains the to treat osteomyelitis or resulting from drug of choice.

93 del Busto

Bacteremia and endocarditis. The third-generation ceph­ Adverse reactions alosporins have been used with good results in patients In general, the newer cephalosporins are very safe who have bacteremia caused by organisms which are drugs. Their adverse effects are similar to those seen resistant to the older cephalosporins and am­ with the older cephalosporins, except for two reac­ inoglycosides. However, some failures have been re­ tions: serious bleeding and a -like reaction ported with Pseudomonas, Enterobacter, Serratia, and after alcohol ingestion. Bleeding has been associated (4). They can be used as initial therapy in mostly with moxalactam, which has an incidence rate of suspected bacteremia as long as the patient is not neu­ approximately 2.5%, usually a result of hypoprothrom­ tropenic and Pseudomonas is not a likely organism. In binemia and, less frequently, platelet dysfunction. The patients who are febrile and neutropenic, most authors manufacturers of moxalactam now recommend giving agree that the initial therapy should consist of two anti­ prophylactic vitamin K, 10 mg/week, to all patients using biotics, generally a combination of an aminoglycoside the drug, limiting the dose to 4 gm/day whenever pos­ with an anti-pseudomonas penicillin. Preliminary studies sible, and monitoring the bleeding time if higher doses suggest that ceftazidime, a new cephalosporin with a are given (23). broad spectrum of activity that includes Pseudomonas, may be a successful single agent for the initial therapy of A disulfiram-like reaction after ingestion of alcohol has febrile granulocytopenic patients (15). The new ceph­ been reported with moxalactam, cefoperazone, and alosporins, particularly moxalactam, have been used in cefamandole. This reaction, like hypoprothrombine­ mia, appears to be related to the presence of a combination with an aminoglycoside or with ticaracil- methylthiotetrazole group in position 3 of the di­ lin, but further studies are needed to determine if these hydrothiazine ring of the three cephalosporins. The combinations are superior to currently used programs. pathogenesis of the disulfiram reaction seems to be The new cephalosporins are not useful in the treatment inhibition of the enzyme acetaldehyde dehydrogenase of endocarditis, as older agents are more active against by the cephalosporin, resulting in the accumulation of the gram-positive organisms associated with this dis­ toxic acetaldehyde (24). ease; in addition, failures have been reported in cases of Serratia and Pseudomonas endocarditis (4). Cost One fact that limits the usefulness of the newer ceph­ Abdominal and gynecologic infections. Some studies alosporins is their high cost. Table VI identifies the cost have found cefotaxime, moxalactam, and ceftizoxime, of the cephalosporins to the Henry Ford Hospital phar­ when used as single therapies for intra-abdominal and macy. The daily cost for the maximum dose of cefazolin gynecologic infections, to be as effective as a com­ is only $19, as compared with $66-81 for second- bination of clindamycin and (16-19). How­ ever, their use is still controversial, and many infectious diseases specialists prefer to use the standard com­ TABLE VI bination therapy. Two problems with the usage of the Cost of Cephalosporins at third-generation cephalosporins to treat intra­ Henry Ford Hospital* abdominal infections have been the appearance of resistant organisms, usually Pseudomonas and Enter­ Cost Daily Adult Daily Cost for obacter, and superinfection with Enterococci. per Gm Dosage Maximum Dosage First Generation Sexually transmitted diseases. The newer cephalosporins Cephalothin $ 2.75 2-12 gm $ 33.00 are very active against the gonococcus, but they should Cefazolin** 3,26 1- 6 gm 19.56 be used only in the treatment of penicillinase- producing gonorrhoeae. Cefotaxime (single Second Generation dose of 1 gm) and ceftriaxone (single dose of 250 mg IM) Cefamandole*' 5.58 1.5-12 gm 66.96 3-12 gm 81,84 have been effective against penicillinase-producing Cefoxitin** 6.82 Cefuroxime 4.90/750 mg 2.25-12 gm 78,40 (4,20). These agents are not Cefonicid 13.30 0.5- 2 gm 26,60 effective against or Ureaplasma organisms associated with non-gonococcal urethritis. Third Generation Cefotaxime 9.18 2-12 gm 110,16 Surgical prophylaxis. The new cephalosporins are not Moxalactam 10.62 2-12 gm 127,44 indicated for surgical prophylaxis; they are no more Cefoperazone 9.50 2-12 gm 114,00 effective than older, less expensive agents such as cefa­ Ceftizoxime** 9.71 2-12 gm 116.52 zolin. Two recent studies have shown no difference between cefotaxime and cefazolin in the prevention of • Cost to the Pharmacy. Does not include cost of IV fluids. after genitourinary or gynecological surgery pharmacy admixture fees, or nursing time. (21,22). •* HFH Formulary Agent

94 Newer Antibiotics

generation cephalosporins and approximately $120 for TABLE Vlll the third-generation. These costs do not include the Pharmacology of Piperacillin, Mezlocillin and Azlocillin cost of intravenous fluids, pharmacy admixture fees, or nursing time, which are lower for those drugs that can be administered every 8 or 12 hours, instead of every 6 Peak Elimina­ Maximum hours. Serum tion Half- Daily Sodium Levels* Life Dosage Content (mcg/ml) (minutes) (gm) (mEq/gm) Newer Penicillins Piperacillin 305 60 24 (q4-6h) 1.98 In vitro activity and pharmacology Mezlocillin 314 55 24 (q4-6h) 1.85 The so-called fourth-generation penicillins include Azlocillin piperacillin, mezlocillin, and azlocillin (25). They have 239 55-70 24 (q4-6h) 2.17 the advantage of being more active in vitro than ticar­ 257 70 24 (q4-6h) 5.20 cillin and against many gram-negative or­ ganisms. They are frequently active against such ticarcillin-resistant bacteria as Klebsiella, Serratia and •Following 2 gm IV bolus injection, except ticarcillin (3 Gm IV) . Table Vll compares the in vitro activity of the newer penicillins with that of ticarcillin (26,27). ampicillin-susceptible Haemophilus influenzae and Piperacillin and azlocillin are four times more active gram-positive cocci, except for Staphylococcus aureus. than ticarcillin and mezlocillin against Pseudomonas aeruginosa. Piperacillin and mezlocillin have similar The pharmacology of the newer penicillins (Table Vlll) activity against most of the Enterobacteriaceae and are is fairly similar to that of ticarcillin, with the advantage of more active than ticarcillin, with azlocillin having inter­ a sodium content that is less than half that of ticarcillin. mediate activity. Unlike the cephalosporins, all the new penicillins are active against the Enterococci. They are Clinical indications also fairly active against Bacteroides fragilis, although These newer agents are indicated in the treatment of high concentrations may be required to inhibit some infections caused by ticarcillin-resistant organisms. strains. The new penicillins are also active against There is no evidence that they are superior to ticarcillin against infections due to ticarcillin-susceptible organ­ isms. Because the newer penicillins are not bactericidal TABLE Vll except at high concentrations, and because resistance is Comparison of the in-vitro Activity (MIC90)* of a definite potentiality during therapy, they should not Ticarcillin and the Newer Penicillins** be used alone but in combination with an amino­ glycoside (25). These drugs, like ticarcillin and the third- generation cephalosporins, are not the drugs of choice Ticar­ Pipera­ Mezlo­ Azk for any gram-positive coccal infection. cillin cillin cillin cilli

Pseudomonas aeruginosa 64 16 64 16 Adverse reactions

Enterobacteriaceae The side effects of the new penicillins are similar to those reported with older, broad-spectrum penicillins Klebsiella spp. >128 16 32 64 and include allergic reactions, phlebitis, , >128 4 8 32 >128 32 32 128 elevation of liver enzymes, and prolongation of bleed­ Proteus mirahilis 4 « 1 « 1 4 ing time. Studies of a few volunteers have shown that >128 64 64 mezlocillin and piperacillin have a less profound effect >128' Enterobacter aerogenes >128 64 32 on bleeding time than ticarcillin or carbenicillin (28-30); Acinetobacter spp. 16 32 64 (>4 however, the clinical importance of these results has >128 >128 >128 >128 not been established. The risk of fluid overload and hypokalemia may also be lower with these new peni­ (•A 8 4 4 cillins, because their sodium content is less than that of Bacteroides fragilis 64 64 32 ticarcillin. The clinical significance ofthis difference has not been determined either (31). * MIC90 = minimal concentration of antibiotic in micrograms/ml required to inhibit 90% of isolates. Cost •* Parry MF. (26, 27) Although the difference in cost between the newer and *** For Enterobacter spp. older penicillins is not as much as that seen between the

95 del Busto

older and newer cephalosporins, the newer penicillins the cerebrospinal fluid penetration is poor. The dosage are still more expensive than ticarcillin (Table IX). of netilmicin is 4-6.5 mg/kg/day, slightly higher than that of gentamicin and tobramycin. Desirable peak and trough serum levels are 6-10 and 0.5-2 mcg/ml, respec­ TABLE IX tively. As with all the aminoglycosides, the dose has to Cost of the New Penicillins be adjusted in patients with decreased renal function. at Henry Ford Hospital Clinical experience and toxicity

Cost gm/ Daily Netilmicin appears to be as effective as tobramycin. In a per gm day Cost recent collaborative study, netilmicin in combination with ticarcillin was as effective as tobramycin and ticar­ Ticarcillin (Ticar)** $2,27 18 $40.86 cillin in the treatment of 164 patients (32). Netilmicin has Mezlocillin (Mezlin) 3.15 18 56.70 been found to be less ototoxic and nephrotoxic in animals than gentamicin and tobramycin, and the col­ Azlocillin (AzIin) 3.94 18 70.92 laborative study (32) showed that there was significantly Piperacillin (Pipracil) 3.47 18 62.40 less ototoxicity in humans treated with netilmicin than with tobramycin. In this same study, was *Cost to Pharmacist also less common with netilmicin, but the difference was not statistically significant. We are currently par­ **HFH Formulary Agent ticipating in a collaborative study to verify these results.

Cost Netilmicin The cost of aminoglycosides is shown in Table X. At A new aminoglycoside, netilmicin, is now available for Henry Ford Hospital, generic gentamicin is about five to clinical use in the United States. Netilmicin is the 1-ethyl eight times less expensive than the other amino­ derivative of sisomicin, an aminoglycoside related to glycosides. gentamicin IA. The ethyl group at the 1-amino position appears to protect netilmicin against the most common TABLE X of the aminoglycoside inactivating enzymes, the 2" Cost of Aminoglycosides adenyl transferase (Fig. 2). As a result, some gram- at Henry Ford Hospital negative bacilli that are resistant to gentamicin and tobramycin may be susceptible to netilmicin. However, they are more likely to be susceptible to , Daily Cost which remains the aminoglycoside of choice when re­ Cost Usual for Maximum sistant organisms are common. To Daily Dosage for Pharmacist Dosage 70 Kg/Patient Pharmacokinetics Gentamicin* $ 0.87/80mg 3-5mg/kg $ 3.80 The pharmacokinetics of netilmicin are similar to that of (generic) gentamicin. The serum half-life in the adult with normal renal function is about 2.5 hours, with 80% eliminated Tobramycin* 5.42/80mg 3-5mg/kg 23.71 unchanged in the urine. As with other aminoglycosides. (Nebcin) Amikacin* 15.17/500mg 15mg/kg 31.85 (Amikin) Netilmicin 6.05/1 SOmg 4-6.5mg/kg 18.35 3' OH (Netromycin) NHa" ^ 0 ll *HFH Formulary Agent

CH3NH-A-. \ OH] ^ 1 0 investigational Antibiotics 0^ ^NHa In addition to the newer antibiotics available com­ CH3CH2NH -\^ ^ mercially, there are a large number of agents under 1 clinical investigation. Some of the investigational cephalosporins include: ceftriaxone, ceforanide, cefta­ Fig. 2 zidime, and cefsulodin (4). Ceftriaxone is the ceph­ Molecular structure of netilmicin. alosporin with the most prolonged half-life (8 hours)

96 Newer Antibiotics

permitting every 12- or even 24-hour doses. It has been gram-negative bacilli. A new concept of used successfully in meningitis caused by H. influen­ combination is with or ticar­ zae, S. pneumoniae, and N. meningitidis. Ceforanide is cillin. Although clavulanic acid is a beta-lactam a first-generation cephalosporin with a prolonged half- compound with poor intrinsic activity, it permits the life of three hours, but its spectrum of activity is antibacterial action of amoxicillin or ticarcillin by in­ narrower than that of ceftriaxone. Ceftazidime has the hibiting the beta-lactamase. best activity against Pseudomonas aeruginosa, and cef­ sulodin is active against pseudomonas and only mod­ There are of course many other investigational anti­ erately so against Staphylococcus aureus. microbials, but a complete review of them is beyond the scope of this paper. Some of the new drugs will be a In addition to the cephalosporins, other investigational welcome replacement to less active antibiotics and beta-lactam compounds include (primaxin), more toxic aminoglycosides. However, their ap­ the , and clavulanic acid. Thienamycin is a pearance on the market will make the selection of very promising antibiotic. It has the widest in vitro antibiotics even more difficult for the practicing physi­ spectrum of all the , as that of the third- cian and, unless used judiciously, may cause greater generation cephalosporins, and in addition, it is active expense. against Streptococcus faecalis, methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, and Addendum Acinetobacter. In contrast to the penicillins and ceph­ Since this manuscript was submitted for publication, alosporins, the monobactams (eg, azthreonam) have a ceforanide (Precef) and the combination of clavulanic structural formula consisting of only one ring, the acid and amoxicillin (Augmentin) have been introduced beta-lactam ring. They are active only against aerobic on the market in the United States.

References

1. O'Callaghan CH, Description and classification of new ceph­ 10. Cherubin CC. Corrado M, Nair SR, Gombert ME, Landesman S, alosporins and their relationship with the established com­ Humbert G, Treatment of gram-negative bacillary meningitis: pounds. J Antimicrob Chemother 1979;5:635-71. Role of the new cephalosporin antibiotics. Rev Infect Dis 1982; 4(Suppl):453-64, 2. Hoover JRE, Dunn GL. The p-lactam antibiotics. In: Wolff ME, ed. Burger's medicinal chemistry. New York: John Wiley & Sons, Inc., 11. Swedish Study Group, Cefuroxime versus ampicillin and chloram­ 1979:83-172. phenicol for the treatment of bacterial meningitis. Lancet 1982; 1:295-9, 3. Neu HC. Structure-activity relations of new p-lactam compounds and in-vitro activity against common bacteria. Rev Infect Dis 12. Congeni BL. Comparison of ceftriaxone and traditional therapy of 1983;5(Suppl):319-37. bacterial meningitis. Antimicrob Agents Chemother 1984;25:40-4,

4. Neu HC. The new beta-lactamase-stable cephalosporins. Ann 13. Overturf GD, Cable DC, Forthal DN, Shikuma C. Treatment of Intern Med 1982;97:408-19. bacterial meningitis with ceftizoxime. Antimicrob Agents Chemo­ 5. LeFrock JL, McCloskey RV, Paparone P. Cefotaxime therapy of ther 1984;25:258-62. skin and soft tissue infections in 102 patients. Drug Ther 1981; 14. Cable D, Overturf G, Edralin G, Concentrations of cefoperazone (Suppl):81-6, in cerebrospinal fluid during bacterial meningitis, Antimicrob Agents Chemother 1983;23:688-91, 6. Mader JT, LeFrock J, Hyams KC, Molavi A, Reinarz JA. Cefotaxime therapy for patients with osteomyelitis and septic arthritis. Rev 15. Commers JR, Gress JG, Robichaud KJ, Longo DL, Pizzo PA, Keflin, Infect Dis 1982;4(Suppl):472-80. gentamicin, carbenicillin versus ceftazidime as empiric therapy 7. Mader JT, Shannon CR, Cierny G, Reinarz JA, Treatment of acute for febrile granulocytopenic cancer patients (abstr). Proceedings and chronic osteomyelitis with ceftizoxime, J Antimicrob Chemo­ of the 22nd interscience conference on antimicrobial agents and chemotherapy. 1982:66. ther 1982;10(Suppl C):265-71,

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