The oxacillin derivatives cloxacillin, dicloxacillin, and flucloxacillin (like nafcillin) are narrow-spectrum penicillins with activity against methicillin-susceptible staphylococci and many streptococci, but no relevant antimicrobial activity against enterococci and Listeria. Oxacillin and its derivatives are important drugs in severe staphylococcal infection and are considered to be superior to vancomycin and also to cefazolin and to cefuroxime in patients with bacteremic S. aureus infection. The MIC of oxacillin in staphylococci is typically ~0.25–0.5 μg/mL [35]. Based on population pharmacokinetic data, a daily dose of 6 g given as 2 g by 4 h extended infusion every 8 h is likely to provide an fT > MIC of 50 % at an MIC of 0.75–1 μg/mL [71]. Short infusion regimes will require higher daily dosages to maintain high probabilities of response. These data have been the basis for recommendations of 2 g given every 6–8 h daily for serious staphylococcal infection. Higher dosages (Table 14.2) may be required in staphylococcal endocarditis and central nervous system infection.

The most critical adverse event apart from rash associated with oxacillin and its derivatives is cholestatic jaundice and hepatitis. Risk factors appear to be older age, preexisting hepatic impairment, long-term use (>14 days), and probably the daily dose. It is unknown whether continuous or extended infusion regimens can lower the risk of hepatotoxicity. Flucloxacillin is stable at room temperature for at least 24 h.

As an oral drug, amoxicillin-clavulanic acid is commonly used together with ciprofloxacin for therapy in low-risk febrile neutropenia patients [42]. Amoxicillin is well absorbed. Its oral bioavailability is approximately 70 %. A dose of 500 mg yields a mean peak plasma concentration of ~7–10 μg/mL [41, 94]. The usual oral dose of 500 mg (together with 125 mg of clavulanic acid) every 8 h provides a ~55 % or greater T > MIC for Haemophilus and streptococci incl. pneumococci [6]. Almost similar results (T > MIC [1 μg/mL], 44 %) are obtained with the 875/125 mg tablets given every 12 h [5]. Elimination of amoxicillin is predominantly by the renal route (52 %), and high concentrations are achieved in the urine sufficient to treat urinary tract infection (including those due to Gram-negative bacteria susceptible at the breakpoint of 8 μg/mL) [41, 94]. Parenteral therapy with higher doses is needed to treat systemic infections due to susceptible Gram-negative bacteria. In some countries, organisms with an MIC of 1–8 μg/mL are therefore categorized as intermediate susceptible. Resistance in E. coli is not uncommon and is primarily due to enzymatic inactivation by OXA-1- or inhibitor-resistant TEM (IRT) enzymes and chromosomal AmpC hyperproduction [97].

Clavulanic acid is extensively metabolized and eliminated in urine and feces. Adverse effects include rash, gastrointestinal disturbances, and – rarely – cholestatic hepatitis usually associated with clavulanic acid rather than with amoxicillin. Age, preexisting liver disease, therapy duration, and probably genetic factors play a role in the risk for drug-induced hepatitis [106].

Ceftriaxone has become a most popular parenteral broad-spectrum cephalosporin because of its long half-life and the ease of the corresponding once daily dosing. It is a third-generation cephalosporin with antimicrobial activity very similar to that of cefotaxime. The usual dose in adults for infections outside the brain is 2 g every 24 h. This dosing regimen yields ~100 % fT > MIC (≤1 μg/mL), thus providing excellent in vivo activity against streptococci, Haemophilus, and wild-type Enterobacteriaceae. It has no relevant activity against P. aeruginosa (MIC typically >8 μg/mL). The breakpoint for resistance has been set at >2 μg/mL (EUCAST). The drug is very well tolerated. Gastrointestinal disturbance may occur, and Clostridium difficile infections are more common than with most other broad-spectrum cephalosporins due to its substantial effects on the intestinal microflora.

Both compounds are broad-spectrum cephalosporins approved for the treatment of skin and soft tissue infection and pneumonia. The two drugs have enhanced activity against MRSA and in the future might become interesting treatment options in febrile neutropenia. There is increasing experience with them in salvage therapy for MRSA infection [18].

Aztreonam is a monobactam available for clinical use since the 1980s. The antimicrobial activity comprises exclusively Gram-negative bacteria. Wild-type E. coli and Klebsiella species are highly susceptible with MICs typically <0.1 μ/mL [35]. Aztreonam is moderately active against P. aeruginosa (MIC, ~4 μg/mL) and has no clinically relevant activity against Acinetobacter and Stenotrophomonas [35]. The MIC distribution for E. coli, P. aeruginosa, and A. baumannii is shown in Fig. 14.2. Aztreonam is not inactivated by Ambler class B betalactamases (metalloenzymes) and represents an important therapeutic option in infections due to P. aeruginosa with metallobetalactamase-associated carbapenem resistance. In some countries, the drug (as aztreonam-lysine with a dose of 75 mg administered every 8 h using an ultrasonic nebulizer) has been approved for inhalation [92].

Recommended doses for an adult patient with normal renal function are 1–2 g every 6–8 h. Monte Carlo simulations with a target of an fT > MIC of 50–60 % at a dose of 1 g (infused over 1 h) every 8 h indicate a clinical breakpoint of 1–4 μg/mL. Thus, infections due to susceptible E. coli do not require high-dose therapy. The drug can be given as continuous infusion (24 h). Continuous infusion of 6–8 g per day produces plasma concentrations of ~40–50 μg/mL [16]. Such a regimen should be sufficient to treat infection due to low-level resistant P. aeruginosa.

The addition of avibactam to aztreonam is currently being evaluated in clinical trials [24]. The advantage of such a drug combination would be the restored activity of aztreonam against ESBL-positive organisms and its intrinsic activity in organisms with metalloenzyme-associated carbapenem resistance.