Gram-positive activity

The 5-position of quinolones can be substituted by small groups such as halogens, hydroxyl, or amino (54—56). The amino group at this position can be advantageous, particularly when appHed to 6,8-difluoro-7-piperazinyl or 6,8-difluoro-7-pyrrohdinyl quinolones. In contrast to 6,8-difluoro quinolones, when this replacement is appHed to ofloxacin, the resulting derivative has reduced antibacterial activity (57). Replacement of the 5-amino group with methylamine or dimethylamine causes activity to drop substantially. Sparfloxacin [110871-86-8] (21), a representative of 5-amino-6,8-difluoro quinolones, affords modest improvements in gram-positive activity as well as increased in vivo potency when compared with both ciprofloxacin and ofloxacin (54). 

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

Linezolid s a novel oxazolidinone antibiotic with exclusively Gram-positive activity (including MRSA) which acts at the level of the 30S and 70S ribosomal subunits by a unique mechanism it inhibits protein synthesis by preventing formation of initiation complexes. Linezolid has excellent oral bioavailability and tissue penetration the most important adverse effect is marrow suppression which is usually reversible. Its major indications are soft tissue infections and nosocomial pneumonia, although these will probably expand in the future. 

Ceftazidime Intravenous, third-generation drug, poor gram-positive activity, good activity versus Pseudomonas... 

Levofloxacin, gatifloxacin, gemifloxacin, and moxifloxacin, so-called respiratory fluoroquinolones, with their enhanced gram-positive activity and activity against atypical pneumonia agents (eg, chlamydia, mycoplasma, and legionella), are effective and used increasingly for treatment of upper and lower respiratory tract infections. 

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... 

Domagala JM, et al. l-Ethyl-7-[3-[(ethyl-amino)methyl]-l-pyrrolidinyl]-6,8-difluoro-l,4-dihydro-4-oxo-3-quinoline-carboxylic acid. New quinolone antibacterial with potent gram-positive activity. J. Med. Chem., 1986, 29, 445-448. 

Others. Leoofloxacin (t) 7h) has greater activity against Streptococcus pneumoniae than ciprofloxacin and is used for respiratory and urinary tract infection. Moxifloxacin (t) 12 h) has strong anti-Gram-positive activity, and may prove useful for respiratory tract infections including those caused by atypical pathogens and penicillin-resistant Streptococcus pneumoniae. 

If the hydrophobic character is increased, there is little effect on the Gram-positive activity, but what activity there is against Gram-negative bacteria drops even more. 

Hydrophilic groups on the side-chain have either little effect on Gram-positive activity (e.g. penicillin T) or cause a reduction of activity (e.g. penicillin N) (Fig. 10.35). However, they lead to an increase in activity against Gram-negative bacteria. 

Best activity is obtained if the alpha-carbon is monosubstituted (i.e. RCH2CO-7 AC A). Further substitution leads to a drop in Gram-positive activity. 

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

Possibly less efficacy in profound neutropenia or prolonged neutropenia limited gram-positive activity no potential for additive/synergistic effects increased selection of resistant organisms increased colonization and superinfection rates Limited gram-positive activity potential for nephrotoxicity need for therapeutic monitoring of aminoglycoside concentrations... 

No demonstrated benefit of vancomycin empirical therapy vs. addition of vancomycin if needed later increased risk of selection for vancomycin-resistant enterococci risk of toxicities excessive cost need for therapeutic monitoring of vancomycin concentrations Marginal gram-positive activity fluoroquinolones not recommended as monotherapy resistance may develop rapidly... 

Prophylaxis of infections in HSCT patients is in many ways similar to that used in other neutropenic patients. Selective decontamination with oral antimicrobials is used commonly considerations are the same as those discussed previously. Although some studies have shown decreased rates of bacteremia and other bacterial infections after HSCT, overall mortality rates were not reduced. The routine use of prophylactic antibiotics in HSCT therefore is still controversial. Fluoroquinolones have become the most frequently used agents, often combined with another agent (e.g., macrolides or rifampin) for enhanced gram-positive activity. These regimens usually are begun... 

Azithromycin appears to have less gram-positive activity but greater gram-negative activity than erythromycin. 

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