What is the impact of broad-spectrum antibiotics in the prevention and control of health care-associated infections?

Broad-spectrum antibiotics are invaluable in the control of modern healthcare-associated infections (HAIs); however, limiting their overuse represents an equally important means of preventing HAIs that are increasingly caused by multidrug-resistant organisms (MDROs). Accordingly, The Joint Commission has continued to list the prevention of MDRO-related HAIs among their National Patient Safety Goals based upon the Society for Healthcare Epidemiology of America (SHEA)/Infectious Diseases Society of America (IDSA) “Compendium of strategies to prevent healthcare-associated infections in acute care hospitals.”

Targeted organisms include but are not limited to methicillin-resistant Staphylococcus aureus (MRSA), Clostridium difficile, vancomycin-resistant enterococci (VRE), and multidrug-resistant Gram-negative bacilli (MDR-GNB). Associations between specific antibiotics or antibiotic classes and MDROs have been repeatedly observed.

Antimicrobial stewardship programs can assist in reducing the emergence of MDROs by optimizing antimicrobial use and enhancing clinical outcomes. There are no available vaccines that target HAIs caused by MDROs, although this is an active area of investigation.

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Which broad-spectrum antibiotics play a key role in the prevention and control of health care-associated infections?

No broad-spectrum antibacterial stands out among others in its capacity to prevent or control HAIs. Rather, the use and misuse of these agents have been associated with morbidity and mortality resulting from infection with MDROs and Clostridium difficile infection (CDI). In combination with enhanced infection control practices, formal antibiotic restriction policies may play a role in controlling outbreaks attributed to these organisms.

The availability and efficacy of therapeutic options for MDROs, however, varies widely depending on the causative pathogen. While the antibiotic pipeline has largely focused on resistant Gram-positive organisms in recent years, new options for multidrug-resistant (MDR) Gram-negative bacilli remain scarce. Increasing reports of infection due to organisms resistant to all available agents highlight the important partnership between hospital epidemiology and antimicrobial stewardship programs in responding to the current resistance crisis.

Which antibiotics are commonly used, and what are key distinguishing features of each?

Antibiotics associated with MDROs

Decreased use of the following antibiotics or antibiotic classes may be associated with a decreased incidence of specific MDROs (usually in combination with enhanced infection control practices):

  • Fluoroquinolones: MRSA, fluoroquinolone-resistant Gram-negative bacilli

  • Vancomycin: vancomycin-resistant enterococci (VRE)

  • 3rd-generation cephalosporins: extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, cephalosporin-resistant Enterobacter

  • Carbapenems: carbapenem-resistant Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacteriaceae

  • Linezolid: linezolid-nonsusceptible enterococci and staphylococci

  • Virtually all antibacterials have been associated with CDI. SHEA/IDSA guidelines recommend minimizing the frequency, duration, and number of prescribed antimicrobials in order to prevent disease. Implementation of an antimicrobial stewardship program to assist with these efforts is also recommended.

Antibiotics used in the treatment of MDROs: focus on newer agents.

Anti-gram-positive agents

  • Vancomycin is predominantly used for serious infection due to resistant Gram-positive infections, including MRSA. HAIs associated with VRE and S. aureus with increasing vancomycin MICs have prompted the need for alternative therapies. Therapeutic drug monitoring is often required.

  • Linezolid, the first oxazolidinone, offers bacteriostatic activity against both MRSA and VRE with both oral and parenteral options. Prolonged use may be limited by toxicity.

  • Daptomycin is a bactericidal cyclic lipopeptide with activity against resistant Gram-positive organisms, including MRSA and VRE. Although available only for IV administration, it is preferred for long-term use given its favorable toxicity profile in comparison to linezolid. Daptomycin should not be used for treatment of pneumonia due to its inactivation by pulmonary surfactant.

  • Telavancin is a new lipoglycopeptide with activity against resistant Gram-positive organisms while ceftaroline is the first FDA-approved b-lactam with activity against MRSA. Both may provide new options for S. aureus with reduced susceptibility to vancomycin.

Anti-gram-negative agents

  • Carbapenem antibiotics remain the last line of defense against many MDR-Gram negative bacilli. Doripenem is the newest carbapenem and may offer a potency advantage for select isolates of Pseudomonas aeruginosa. It is not useful for the treatment of carbapenemase-producing organisms.

  • HAIs with carbapenem-resistant organisms have prompted a resurgence of colistin use. However, efficacy is variable and an optimal dosing strategy remains elusive. Nephrotoxicity and neurotoxicity may be less frequent than once feared.

  • Tigecycline provides activity against carbapenem-resistant Acinetobacter baumannii and many Enterobacteriaceae but is not useful for P. aeruginosa. Its use in the setting of bacteremia is controversial. Nausea and vomiting occur in 30% and 20% of patients, respectively.

  • Treatment failure with colistin and tigecycline monotherapy is not uncommon. Combination therapy and optimization of pharmacokinetic-pharmacodynamic (PK/PD) parameters are important considerations.

Available agents and their features, efficacy and safety.

Although HAIs need not be caused by resistant organisms, it is beyond the scope of this discussion to list all available antimicrobials that may be used in therapy. Thus, this section will focus on the potential role of newer agents in the management of MDRO-related infection. Specifically, the “ESKAPE” pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.), describe organisms known to cause the majority of U.S. hospital infections and are so-named given that their propensity to develop resistance allows their “escape” from the effects of available antibacterials. Consequently, infection with these organisms results in less favorable clinical outcomes compared to their more susceptible counterparts.

Anti-gram-positive agents

Vancomycin continues to be frequently used for invasive disease due to resistant Gram-positive infections, including MRSA. However, the emergence of VRE and treatment failure associated with increasing staphylococcal MICs has prompted the need for alternative therapies.

As the first oxazolidinone antibiotic, linezolid is indicated for VRE infection including cases with concurrent bacteremia, in addition to nosocomial pneumonia and complicated skin and skin structure infections (cSSSI) due to MRSA. It inhibits bacterial protein synthesis by preventing the formation of a functional 70S initiation complex and is bacteriostatic against staphylococci and enterococci.

Given its high bioavailability and lack of need for therapeutic drug monitoring, it has been widely used as an alternative to vancomycin in many settings. Linezolid is typically well tolerated but serious adverse effects such as myelosuppression (especially thrombocytopenia), lactic acidosis, and peripheral/optic neuropathy (that may be irreversible) do occur, particularly during prolonged use. As a weak monoamine oxidase inhibitor, caution should be exercised if considering concurrent use of serotonergic or adrenergic agents.

Daptomycin is a cyclic lipopeptide with bactericidal activity against a broad range of Gram-positive bacteria, including MRSA and VRE. Calcium-dependent insertion of its lipophilic tail into the bacterial cytoplasmic membrane causes rapid depolarization, potassium efflux, and inhibition of DNA, RNA, and protein synthesis. FDA-approved indications include treatment of cSSSI and S. aureus bloodstream infections, including those with right-sided endocarditis.

The latter indication followed a randomized, open-label study of daptomycin 6 mg/kg daily compared to initial low-dose gentamicin plus either an antistaphylococcal penicillin or vancomycin in patients with S. aureus bacteremia with or without endocarditis. Overall success was similar at 44% and 42%, respectively. Left-sided endocarditis and the absence of necessary surgical intervention were common reasons for treatment failure. Clinically significant creatine phosphokinase elevations occurred in 6.7% of daptomycin recipients. Rhabdomyolysis, peripheral neuropathy, and eosinophilic pneumonia have also been reported. In contrast to linezolid, daptomycin binds to pulmonary surfactant and should not be used for the treatment of pneumonia.

Quinupristin/dalfopristin is a streptogramin combination product that was FDA-approved in 1999 for the treatment of cSSSI and serious or life-threatening infection with vancomycin-resistant E. faecium (VREF). Approval for the latter was originally accelerated due to the drug’s ability to clear bacteremia in the absence of alternative therapies. Since alternatives have become available, quinupristin/dalfopristin use has been limited by concern for adverse effects such as infusion-related reactions, myalgias, arthralgias, and hepatotoxicity. As an inhibitor of CYP 3A4, the potential for drug-drug interactions is significant. Its indication for the treatment of VREF was removed in 2010 after submitted data failed to verify clinical benefit.

Telavancin is a semi-synthetic lipoglycopeptide that was FDA-approved in 2009 for the treatment of adults with cSSSI caused by susceptible strains of: (methicillin-susceptible and –resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group, or Enterococcus faecalis (vancomycin-susceptible isolates only). Its mechanism of action encompasses features of both vancomycin and daptomycin in that it inhibits cell wall synthesis and disrupts membrane barrier function.

Among patients with a normal baseline serum creatinine, increases of 1.5 times baseline occurred more frequently in telavancin- versus vancomycin-treated patients. Common adverse effects include taste disturbance, nausea, vomiting, headache, and foamy urine. A black box warning recommends that women of childbearing potential should have a serum pregnancy test prior to use given observations of adverse developmental outcomes in animal studies. Despite its limited activity against VRE, telavancin may serve as an option for infection with vancomycin-intermediate S. aureus (VISA) and heteroresistant VISA (hVISA). Guidelines for the treatment of MRSA list telavancin as an option for the management of persistent bacteremia in the presence of reduced susceptibility to vancomycin and daptomycin.

Ceftaroline is a new cephalosporin that was FDA-approved in 2010 for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI). With enhanced affinity for PBP 2a, it is the first b-lactam approved for the treatment of MRSA and is of particular interest given its activity against hVISA, VISA, and VRSA (including daptomycin-nonsusceptible strains). Similar to most cephalosporins, ceftaroline exhibits poor activity against enterococci and some nosocomial Gram-negative bacilli, including P. aeruginosa. Ceftaroline was generally well tolerated in phase 3 studies with adverse effect rates similar to ceftriaxone (CABP) and vancomycin/aztreonam (ABSSSI) comparators. Of note, patients with known or suspected MRSA were excluded from both phase 3 CABP trials and further study is needed to establish its role in the therapy of pneumonia and other serious MRSA infections.

Anti-gram-negative agents

The carbapenem class of antibiotics has traditionally represented the last line of defence against nosocomial Gram-negative bacilli. Doripenem, the newest carbapenem, was FDA-approved in 2007 for the treatment of complicated intra-abdominal infections and complicated urinary tract infections including pyelonephritis. Headache, nausea, diarrhea, rash, and phlebitis were the most common adverse effects, occurring in at least 5% of patients. Cases of rare but serious adverse effects such as anaphylaxis, neutropenia, leukopenia, Stevens-Johnson syndrome, and toxic epidermal necrolysis are described in postmarketing reports. The potential for seizure-induction appears minimal.

Two randomized, open-label trials for the treatment of nosocomial pneumonia have also been completed; however, an NDA for this indication was not approved by the FDA and further study is underway. Similar to imipenem and meropenem, the anti-Gram-negative activity of doripenem includes P. aeruginosa, A. baumannii, and ESBL/AmpC producing-Enterobacteriaceae. In the case of P. aeruginosa, doripenem may offer a potency advantage for a limited number of isolates, while selecting for resistant mutants with greater difficulty in vitro; however, how this translates to clinical practice remains unclear. Regardless, doripenem adds little to the antibacterial armamentarium as efforts to curtail the global spread of carbapenem-resistant bacteria continue.

Discovered in 1947 and available since 1959, colistin (also known as polymixin E) is far from new but retains activity against many MDR Gram-negative bacilli, including those described by the “ESKAPE” pathogens. Once obsolete due to the availability of effective and less toxic alternatives, its use has resurged in recent years as Gram-negative bacteria resistant to most if not all other options have become endemic in many institutions. Colistin is administered parenterally as colistimethate, an inactive prodrug, and interacts electrostatically with the Gram-negative outer membrane to competitively displace divalent cations from the negatively charged phosphate groups of membrane lipids. It may also act as an anti-endotoxin by neutralizing bacterial lipopolysaccharide. Efficacy data for polymixins are primarily derived from case reports and case series rather than controlled clinical trials and are summarized elsewhere. Although clinical improvement was documented in 15-100% of cases, mortality was significant and ranged from 18-76%.

Due to the era in which colistin was approved and subsequent decades of disinterest, more detailed pharmacokinetic and pharmacodynamic information is only now beginning to gain clarity. An optimal dosing strategy that maximizes efficacy while minimizing toxicity and the emergence of resistance has yet to be defined. Its toxicity profile, however, appears more favorable than was once feared. Neurotoxicity remains rare while nephrotoxicity, which may be more likely with concurrent nephrotoxic drugs and a higher total cumulative dose, is generally reversible.

Tigecycline, a minocycline derivative, was FDA-approved in 2005 for the treatment of cSSSI and intra-abdominal infection. An indication for CABP was since added. Nausea and vomiting occurred more frequently in tigecycline- versus comparator-treated patients in phase 3 studies. Pancreatitis and hepatotoxicity have been reported rarely. Tigecycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit and exhibits bacteriostatic activity against a broad range of pathogenic aerobic and anaerobic bacteria, including MRSA, VRE, MDR-A. baumannii and carbapenem-resistant Enterobacteriaceae.

Similar to colistin, tigecycline efficacy in the treatment of MDR-Gram-negative infection has not been well-established in controlled clinical trials. Both treatment success and failure, primarily in association with bacteremia, pulmonary, and intra-abdominal infection have been reported. In 2010, the FDA issued a drug safety communication warning that pooled analysis of phase 3 and 4 clinical trials revealed increased all-cause mortality associated with tigecycline use. This was primarily observed among patients with ventilator-associated pneumonia (VAP), where more deaths occurred in tigecycline- versus imipenem-treated patients.

Given the inconsistent clinical efficacy of colistin and tigecycline, the emergence of resistance to both agents, and a paucity of alternative therapies, combination therapy with adjunctive aminoglycosides, β-lactams, and/or rifampin may provide benefit. Interestingly, in vitro synergy between colistin and vancomycin for clinical isolates of MDR-A. baumannii was recently described. Careful consideration of PK/PD principles is also warranted and may serve to optimize outcomes.

Available agents, with important PK/PD data, dosing information for prevention versus treatment, drug-drug interactions, and adverse reactions.

See Table I for a list of the available agents, as well as key features for each.

Table I.
Agent Dose Adjust dose in renal insufficiency PK/PD parameter of interest Drug-drug interactions Adverse effects
ceftaroline 600mg IV Q12H Yes T>MIC none significant diarrhea, nausea, rash
colistin Optimal dose unclear: some suggest 5 mg/kg day IV in divided doses Yes AUC/MIC agents with additive toxicity nephrotoxicity, neurotoxicity
daptomycin 4-6 mg/kg IV Q24H Yes AUC/MICCp/MIC HMG-CoA reductase inhibitors: potential additive toxicity rhabdomyolysis, eosinophilic pneumonia
doripenem 500mg IV Q8H Yes T>MIC Decreased serum valproate concentrations headache, nausea, diarrhea, rash, phlebitis
linezolid 600mg IV/PO Q12H No AUC/MIC adrenergic and serotonergic agents; rifampin may decrease linezolid Cmax and AUC myelosuppression, peripheral/optic neuropathy, lactic acidosis
telavancin 10 mg/kg IV Q24H Yes AUC/MIC use caution with concurrent drugs known to prolong QTc metallic taste, nausea/vomiting, headache, foamy urine, nephrotoxicity, infusion-related reactions, possible QTc prolongation in high risk patients
tigecycline 100mg IV LD, 50mg IV Q12H Adjust in severe hepatic disease AUC/MIC monitor anticoagulant effect with concurrent warfarin; unlikely to require dose adjustment nausea/vomiting, pancreatitis

LD = loading dose; AUC = area under the curve; Cp = peak concentration; Cmax = maximum concentration; MIC = minimum inhibitory concentration; T = time

Drugs in development.

See Table II for a description of drugs currently in development.

Table II.
Agent Description/potential target Developer
NDA submitted
fidaxomicin (OPT-80) Monocyclic inhibitor of bacterial RNA polymerase studied for treatment of C. difficile. Cure rates similar to oral vancomycin with lower recurrences rates in patients not infected with a hypervirulent strain. Optimer Pharmaceuticals
Phase III
ceftobiprole Cephalosporin with anti-MRSA activity Basilea
dalbavancin Lipoglycopeptide with MRSA activity and long half life permitting once weekly dosing Durata Therapeutics
oritavancin Glycopeptide with activity against VRE and VISA/hVISA The Medicines Company
PTK 0796 Aminomethylcycline, an orally bioavailable minocycline derivative with activity against tetracycline-resistant organisms. Not as potent as tigecycline against Gram-negative bacilli. Paratek/Novartis
torezolid Oxazolidinone derivative with activity against cfr-mediated linezolid-resistant S. aureus Trius Therapeutics
Phase II
ACAM-CDIFFTM C. difficile vaccine containing inactivated toxins A and B Sanofi-Pasteur
BC-3781 Pleuromutilin/ribosomal protein synthesis inhibitor with activity against Gram positive pathogens including MRSA and S. pneumoniae. Nabriva
CXA-101/201 Antipseudomonal cephalosporin with activity against class A and C b-lactamases. CXA-201 is a CXA-101/tazobactam combination product. Cubist
delafloxacin (RX 3341) Fluoroquinolone with enhanced antibacterial activity, including fluoroquinolone-resistant MRSA Rib-X
linopristin/flopristin (NXL-103) Oral streptogramin Novexel/AstraZeneca
MK-3415A Monoclonal antibody to C. difficile toxins A and B Merck
NXL-104 b-lactamase inhibitor studied in combination with ceftazidime (phase II) and ceftaroline (phase I). Active against class A, C, and some class D b-lactamase-producing Enterobacteriaceae and class A and C b-lactamase-producing P. aeruginosa Novexel/Forest
radezolid Oxazolidinone derivative with activity against linezolid-resistant bacteria Rib-X
solithromycin (CEM-101) Fluoroketolide with enhanced activity against macrolide-resistant organisms and potential for reduced toxicity versus telithromcyin Cempra
V710 Vaccine against S. aureus Merck
Phase I
ACHN-409 Aminoglycoside with activity against aminoglycoside-resistant Gram-negative bacteria Achaogen
BAL30072 Siderophore sulfactam (monobactam) with activity against MDR-Gram negative bacilli (P. aeruginosa, A. baumannii, B. cepacia, S. maltophilia) including strains susceptible only to colistin. Basilea
TP434 Anti-Gram-negative tetracycline. IV and oral formulations are in phase I and preclinical study, respectively. Tetraphase Pharmaceuticals

Other novel agents in preclinical study include compounds such as: efflux pump inhibitors, outer membrane synthesis inhibitors, metallo-beta-lactamase inhibitors, lipopolysaccharide synthesis inhibitors, and unique inhibitors of the 50S ribosomal subunit.

Summary of current controversies.

SHEA members have identified the treatment and prevention of infection with multidrug-resistant Gram-negative rods, MRSA, and C. difficile among the five most important clinical problems facing the discipline of healthcare epidemiology. The need for a “much more robust understanding of how patterns of antimicrobial use in healthcare institutions influence the development of MDROs, as well as the optimal approach to antimicrobial stewardship” were also acknowledged as critical knowledge gaps.

  • The management of infection with MDR-Gram-negative bacilli is perhaps the most daunting challenge. With the widespread emergence of carbapenem-resistant organisms, clinicians have turned to agents such as colistin and tigecycline with increasing frequency. Largely abandoned decades ago due to the availability of effective and less toxic alternatives, questions related to the efficacy and safety of colistin remain given a poor understanding of optimal dosing, confusion with existing dosage recommendations, and ongoing reports of resistance. Tigecycline resistance has also become problematic and its use in the setting of bacteremia is particularly controversial given that maximum serum concentrations may not exceed the organism MIC. Whether or not increased doses would serve to improve efficacy without compromising safety is unknown. Inherent microbiologic limitations also exist given that tigecycline has no useful activity against P. aeruginosa and neither agent is effective against other genera such as Proteus spp.; Klebsiella pneumoniae carbapenemase (KPC)-producing isolates of P. aeruginosa and P. mirabilis have already emerged.

  • In an outcomes assessment of patients infected with carbapenem-resistant Klebsiella pneumoniae, it is sobering to note that treatment with at least one active antibiotic was not associated with patient survival. Rather, adjunctive measures such as debridement, drainage, or catheter removal represented the only therapeutic intervention associated with a mortality benefit. This highlights not only the importance of source control when possible, but also the dire need for new antibiotics with reliable clinical efficacy against MDR-Gram-negative pathogens. Authors describing the first US outbreak of colistin-resistant Klebsiella pneumoniae serve as the latest reminder of the need for “infection control and antimicrobial stewardship interventions geared towards preventing the dissemination of these essentially untreatable pathogens and their associated resistance determinants.”

  • Effective agents for the treatment of VRE infection have been welcome additions to the antimicrobial armamentarium in the last decade and have been useful in outbreaks. However, linezolid-resistant enterococci have emerged in both the presence and absence of increased linezolid consumption. A linezolid-resistant S. aureus outbreak related to clonal spread and excess linezolid consumption was controlled with enhanced infection control measures and a reduction in linezolid use from 202 to 25 defined daily doses. While daptomycin nonsusceptible enterococci and staphylococci have not been reported in the outbreak setting, daptomycin resistance and treatment failure have occurred, including during therapy with currently approved doses (6 mg/kg). Many experts recommend higher doses (8-12 mg/kg) for invasive disease due these organisms. Combination therapy has achieved clinical cure in many cases and remains an area of active investigation.

  • The optimal management of patients experiencing treatment failure with vancomycin and daptomycin nonsusceptible strains of S. aureus is unknown. Given that prolonged therapy is often required, linezolid use may be limited by toxicity. Further study is needed to define the role of telavancin or ceftaroline in this setting.

Are there specific guidelines for the use of broad-spectrum agents?

Guidelines issued by the ISDA and the SHEA provide recommendations for the management of C. difficile in adults and for developing an institutional program to enhance antimicrobial stewardship. IDSA guidelines for the treatment of MRSA infections in adults and children became available more recently. Apart from guidelines for therapeutic drug monitoring of vancomycin, no agent-specific guidelines exist, nor are there formal recommendations for the management of infections due to VRE and multidrug-resistant Gram-negative bacilli.

A consensus statement from the European carbapenem-non-susceptible Enterobacteriaceae (CNSE) Working Group identified antibiotic policy as one of ten areas for improvement in the response to these organisms. Noting the contribution of antibiotic overuse and misuse to the selection of CNSE from commensal flora, antibiotic diversification and de-escalation, particularly with respect to carbapenems, fluoroquinolones, and third-generation cephalosporins were recommended.


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