Penicillins combinations

Children Safety and efficacy of carbenicillin, piperacillin, and the -lactamase inhibitor/penicillin combinations have not been established in infants and children younger than 12 years of age. Use caution in administering to newborns and evaluate organ system function frequently. 

In fasciitis or necrotizing infections caused by beta-hemolytic streptococci of group A, parenteral high-dose penicillin combined with clindamycin is the treatment of choice. For the treatment of abscesses, antibiotics which are able to kill large quantities of resting bacteria, such as clindamycin and the quinolones, are preferred. 

Hoigne R, Krebs A. Kombinierte anaphylaktische und embolisch-toxische Reaktion durch akzidentelle intravas-kulare Injektion von Procain-Penicillin. [Combined anaphylactic and embolic-toxic reaction caused by the accidental intravascular injection of procaine penicillin.] Schweiz Med Wochenschr 1964 94 610-14. 

Experiments with penicillin show that resistant strains of staphylococci, even those that produce no penicillinase, take up no penicillin from solution, but susceptible strains of various species combine with from 200 to 750 molecules per cell. This amount is held tightly, cannot be washed away, and does not exchange with non-radioactive penicillin (Rowley et al., 1950 Maass and Johnson, 1949). The first molecules of penicillin are bound by inert material but, when this is saturated, the penicillin combines covalently with a receptor playing a key role in the biosynthesis of cell wall. Mammalian cells do not take up penicillin, but the bacterial cell binds it in less than 2 minutes. The penicillinbinding component is on the exterior, in the cytoplasmic membrane where the cell wall is synthesized. This component occurs in a phospholipid-containing fraction of staphylococci (Cooper, 1956). 

A major trend in organic synthesis, however, is the move towards complex systems. It may happen that one needs to combine a steroid and a sugar molecule, a porphyrin and a carotenoid, a penicillin and a peptide. Also the specialists in a field have developed reactions and concepts that may, with or without modifications, be applied in other fields. If one needs to protect an amino group in a steroid, it is advisable not only to search the steroid literature but also to look into publications on peptide synthesis. In the synthesis of corrin chromophores with chiral centres, special knowledge of steroid, porphyrin, and alkaloid chemistry has been very helpful (R.B. Woodward, 1967 A. Eschenmoser, 1970). 

Historically, the development of penems is contemporary with that of the naturally occurring carbapenems and the direction of penem research has clearly been influenced by the stmctures of the closely related natural products. The origins of the two groups of compounds is, however, quite different. Unlike carbapenems, no penems have been found in nature. When first described (84,85) they were viewed as hybrid molecules combining stmctural features of penicillins and cephalosporins. 

Isolation. Isolation procedures rely primarily on solubiHty, adsorption, and ionic characteristics of the P-lactam antibiotic to separate it from the large number of other components present in the fermentation mixture. The penicillins ate monobasic catboxyHc acids which lend themselves to solvent extraction techniques (154). Pencillin V, because of its improved acid stabiHty over other penicillins, can be precipitated dkecdy from broth filtrates by addition of dilute sulfuric acid (154,156). The separation process for cephalosporin C is more complex because the amphoteric nature of cephalosporin C precludes dkect extraction into organic solvents. This antibiotic is isolated through the use of a combination of ion-exchange and precipitation procedures (157). The use of neutral, macroporous resins such as XAD-2 or XAD-4, allows for a more rapid elimination of impurities in the initial steps of the isolation (158). The isolation procedure for cephamycin C also involves a series of ion exchange treatments (103). 

One approach to combating antibiotic resistance caused by P-lactamase is to inhibit the enzyme (see Enzyme inhibition). Effective combinations of enzyme inhibitors with P-lactam antibiotics such as penicillins or cephalosporins, result in a synergistic response, lowering the minimal inhibitory concentration (MIC) by a factor of four or more for each component. However, inhibition of P-lactamases alone is not sufficient. Pharmacokinetics, stability, ability to penetrate bacteria, cost, and other factors are also important in determining whether an inhibitor is suitable for therapeutic use. Almost any class of P-lactam is capable of producing P-lactamase inhibitors. Several reviews have been pubUshed on P-lactamase inhibitors, detection, and properties (8—15). 

Substitution of penicillins by 6a-methoxy was found to be compatible with an a-acidic side chain in terms of antibacterial activity, but less beneficial when the side chain contained an a-acyl or a-ureido substituent. However, analogues of the ureido penicillin VX-VC-43 (Table 2) containing a 6a-methoxy substituent (10) were found to combine good stabiUty to P-lactamase and relatively high antibacterial activity (37). Following an extensive program to identify other 6a-substituents that would stabilize the acyl and ureido series of penicillins, the 6a-formamido series (11) represented by formidacillin (BRL 36650) (Table 2) was developed (38). 

Fermentation Processes. The efficient production of penicillin, yeasts, and single-ceUed protein by fermentation requires defoamers to control gas evolution during the reaction. Animal fats such as lard [61789-99-9] were formerly used as a combined defoamer and nutrient, but now more effective proprietary products are usually employed. Defoamer appHcation technology has also improved. For example, in modem yeast production faciHties, the defoamers are introduced by means of automatic electrode-activated devices. One concern in the use of defoamers in fermentation processes is the potential fouHng of membranes during downstream ultrafiltration (qv). SiHcone antifoams (43,44) seem less troubled by this problem than other materials. 

In those with gout, the serum uric acid level is usually elevated. Sulfinpyrazone increases the excretion of uric acid by the kidneys, which lowers serum uric acid levels and consequently retards the deposit of urate crystals in the joints. Probenecid (Benemid) works in the same manner and may be given alone or with colchicine as combination therapy when there are frequent, recurrent attacks of gout. Probenecid also has been used to prolong the plasma levels of the penicillins and cephalosporins. 

Indicahons for combined therapy are now considered to be much fewer than originahy thought. There is also the problem of a chemical or physical incompahbility between two dmgs. Examples where combinahons have an important role to play in anhbacterial chemotherapy were provided earlier (sections 2.3 and 2.9) in which a fi-lactamase inhibitor and an appropriate j3-lactamase-labile penicillin form a single... 

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