Gram-negative activity

Whereas introducing a thiol moiety at C-7 markedly reduced the antibacterial activity relative to lincomycin (79), the 7(3)-7-deoxy-7-alkylthiolincomycins exhibited considerably enhanced antibacterial activity without apparent regard for the size of the alkyl group (80—82). A marked increase in gram-negative activity was shown when the 7(3)-substituent contained a 2- or 3-hydroxy or amino group, but this activity was insufficient to be effective in infected mice (83—85). 

Second generation Examples are ampicillin, amoxicillin etc. which have both Gram positive and Gram negative activities, but these antibiotics are susceptible to fylactamases. 

The first-generation and oldest quinolones exhibit limited gram-negative activity. Nalidixic acid and cinoxacin do not achieve systemic antibacterial levels and are thus restricted to therapy of bladder infections caused by urinary pathogens, such as E. coli and Klebsiella and Proteus spp. Although they are bactericidal agents, their use is restricted by resistance. 

Good Gram-negative activity poor Gram-positive activity... 

Ceftobiprole1, ceftaroline1 Intravenous, active against methicillin-resistant staphylococci, broad gram-negative activity... 

The term generation has been primarily used as a means of classifying these antibiotics on the basis of their in vitro antibacterial potency and spectrum of activity. With the introduction of each cephalosporin generation, there was a loss of gram-positive but an increase in gram-negative activity, a widening of the spectrum, an enhancement of the resistance to -lactamases, and a marked increase in cost (71, 72). 

The study of several analogues of CPC with varying side chains at the 7-position has demonstrated that the best activity is obtained if the ct-carbon is monosubstituted. Besides, lipophilic substituents on the aromatic ring increase the Gram-positive activity and decrease the Gram-negative activity. However, access to analogues of CPC by variation of the 7-acylamino side chain initially posed a problem. Until recently, it proved impossible to obtain... 

Florfenicol (IX) was patented by Schering-Plough as a broad spectrum antibiotic with Gram-positive and Gram-negative activity comparable to chloramphenicol (X). Chloramphenicol had become severely restricted in use, owing to its propensity to cause blood dyscrasia (aplastic anemia) in some patients. 

Ofloxacin (t/ 4h) has modestly greater Grampositive activity, but less Gram-negative activity than ciprofloxacin. It is indicated for urinary and respiratory tract infections and gonorrhoea. Nalidixic acid (t5 6 h) is now used principally for the prevention of urinary tract infection. It may cause haemolysis in glucose-6-phosphate dehydrogenase deficient subjects. 

Primarily gram-positive organisms such as streptococcal species, enterococcus, penicillin-susceptible pneumococci. Treponema pallidum. Compared with penicillin, aminopenicillins have greater gram-negative activity including H. influenzae (non-beta-lactamase producing). 

Enhancement of Gram-negative activity is found to be greatest if the hydrophilic group (e.g. NH2, OH, C02H) is attached to the carbon, alpha to the carbonyl group on the side-chain. 

Lipophilic substituents on the aromatic or heteroaromatic ring increase the Gran positive activity and decrease the Gram-negative activity. 

Modifications of the cephamycins are aimed at increasing Gram-positive activity whilst retaining Gram-negative activity, as in cefoxitin (Fig. 10.50). 

In Vivo Actives.—The Gram-negative activity of nalidixic acid I is seen from further work to be very structurally specific. Several 1,5-naphthyri-dlne analogs apparently had little, if any, activity in vitro or in vivo while one 1,6-anaJLog (3-carboxy-i4-oxo-1,5,7-trimethyl-1,6-naphthyridine)... 

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